Gene Literature Dashboard

Body mass index (BMI) is a complex disease risk factor known to be influenced by genes acting via both metabolic pathways and appetite regulation. In this study, we aimed to gain insight into the phenotypic consequences of BMI-associated genetic variants, which may be mediated by their expression in different tissues. First, we harnessed meta-analyzed gene expression datasets derived from subcutaneous adipose (n = 1257) and brain (n = 1194) tissue to identify 86 and 140 loci, respectively, which provided evidence of genetic colocalization with BMI. These two sets of tissue-partitioned loci had differential effects with respect to waist-to-hip ratio, suggesting that the way they influence fat distribution might vary despite their having very similar average magnitudes of effect on BMI itself (adipose = 0.0148 and brain = 0.0149 standard deviation change in BMI per effect allele). For instance, BMI-associated variants colocalized with TBX15 expression in adipose tissue (posterior probability [PPA] = 0.97), but not when we used TBX15 expression data derived from brain tissue (PPA = 0.04) This gene putatively influences BMI via its role in skeletal development. Conversely, there were loci where BMI-associated variants provided evidence of colocalization with gene expression in brain tissue (e.g., NEGR1, PPA = 0.93), but not when we used data derived from adipose tissue, suggesting that these genes might be more likely to influence BMI via energy balance. Leveraging these tissue-partitioned variant sets through a multivariable Mendelian randomization framework provided strong evidence that the brain-tissue-derived variants are predominantly responsible for driving the genetically predicted effects of BMI on cardiovascular-disease endpoints (e.g., coronary artery disease: odds ratio = 1.05, 95% confidence interval = 1.04-1.07, p = 4.67 × 10^-14). In contrast, our analyses suggested that the adipose tissue variants might predominantly be responsible for the underlying relationship between BMI and measures of cardiac function, such as left ventricular stroke volume (beta = 0.21, 95% confidence interval = 0.09-0.32, p = 6.43 × 10^-4).

Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-γ) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-γ leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological-based therapies for MS.

<h4>Objectives</h4>Patients presenting to hospital with suspected coronavirus disease 2019 (COVID-19), based on clinical symptoms, are routinely placed in a cohort together until polymerase chain reaction (PCR) test results are available. This procedure leads to delays in transfers to definitive areas and high nosocomial transmission rates. FebriDx is a finger-prick point-of-care test (PoCT) that detects an antiviral host response and has a high negative predictive value for COVID-19. We sought to determine the clinical impact of using FebriDx for COVID-19 triage in the emergency department (ED).<h4>Design</h4>We undertook a retrospective observational study evaluating the real-world clinical impact of FebriDx as part of an ED COVID-19 triage algorithm.<h4>Setting</h4>Emergency department of a university teaching hospital.<h4>Patients</h4>Patients presenting with symptoms suggestive of COVID-19, placed in a cohort in a 'high-risk' area, were tested using FebriDx. Patients without a detectable antiviral host response were then moved to a lower-risk area.<h4>Results</h4>Between September 22, 2020, and January 7, 2021, 1,321 patients were tested using FebriDx, and 1,104 (84%) did not have a detectable antiviral host response. Among 1,104 patients, 865 (78%) were moved to a lower-risk area within the ED. The median times spent in a high-risk area were 52 minutes (interquartile range [IQR], 34-92) for FebriDx-negative patients and 203 minutes (IQR, 142-255) for FebriDx-positive patients (difference of -134 minutes; 95% CI, -144 to -122; <i>P</i> < .0001). The negative predictive value of FebriDx for the identification of COVID-19 was 96% (661 of 690; 95% CI, 94%-97%).<h4>Conclusions</h4>FebriDx improved the triage of patients with suspected COVID-19 and reduced the time that severe acute respiratory coronavirus virus 2 (SARS-CoV-2) PCR-negative patients spent in a high-risk area alongside SARS-CoV-2-positive patients.

Dopaminergic neurons modulate neural circuits and behaviors via dopamine (DA) release from expansive, long range axonal projections. The elaborate cytoarchitecture of these neurons is embedded within complex brain tissue, making it difficult to access the neuronal proteome using conventional methods. Here, we demonstrate APEX2 proximity labeling within genetically targeted neurons in the mouse brain, enabling subcellular proteomics with cell-type specificity. By combining APEX2 biotinylation with mass spectrometry, we mapped the somatodendritic and axonal proteomes of midbrain dopaminergic neurons. Our dataset reveals the proteomic architecture underlying proteostasis, axonal metabolism, and neurotransmission in these neurons. We find that most proteins encoded by DA neuron-enriched genes are localized within striatal dopaminergic axons, including ion channels with previously undescribed axonal localization. These proteomic datasets provide a resource for neuronal cell biology, and this approach can be readily adapted for study of other neural cell types.

The South African Mutton Merino (SAMM), a dual-purpose (meat and wool) sheep breed, is characterized by its excellent performance on growth, carcass traits and meat quality compared to other fine-wool Merino breeds. Nowadays, the SAMM breed has been widely used to cross with commercial and indigenous fine-wool or coarse-wool breeds to improve the growth and meat performance in many countries. To date, however, little is known about the genetic basis for its prominent characteristics. In this study, whole-genome sequences of 10 SAMM were sequenced and the selection signatures were analyzed together with those of 39 Australian Merino and Chinese Merino (wool-type Merino) by F_ST , iHS, and XP-EHH methods. In total, 313 genes in 277 regions were identified by at least 2 methods with the signal of selection and 21 of them were identified by all three methods. We highlighted a list of interesting genes, including GHR, LCORL, SMO, NCAPG, DCC, IBSP, PPARGC1A, PACRGL, PRDM5, XYLB, AHCYL2, TEFM, AFG1L, and FAM184B, which have been shown to be involved in growth, carcass traits, and meat quality by previous studies. Herein, GHR, encoding a transmembrane receptor for growth hormone, is the most notable one. We report the first study on selection signatures analysis of SAMM at whole-genome sequence level. These results provide new insights into the genetic mechanisms underlying the growth and carcass traits in SAMM.

<h4>Background</h4>The aim was to compare the genetic information of varicose vein patients with that of a healthy population attempting to identify certain significant genetic associations.<h4>Method</h4>Patients' clinical characteristics and demographics were collected, and their genetic samples were examined. The results were compared to the genetic information of one thousand sex-matched healthy controls from Taiwan Biobank database. The Clinical-Etiology-Anatomy-Pathophysiology classification was applied for further subgroup analysis.<h4>Results</h4>After comparison of genetic information of ninety-six patients to that of healthy controls, two significant single nucleotide polymorphisms (SNPs) were identified. One was in DPYSL2 gene, and the other was in VSTM2L gene. A further comparison between C2-3 patient subgroup and C4-6 subgroup identified another four significant SNPs, which were located in ZNF664-FAM101A, PHF2, ACOT11, and TOM1L1 genes.<h4>Conclusion</h4>Our preliminary result identified six significant SNPs located in six different genes. All of them and their genetic products may warrant further investigations.

<h4>Introduction</h4>The mucociliary transport function of the airway epithelium is largely dependent on ciliary beating. The control signal of ciliary beating is thought to be intracellular Ca2+. We herein investigated the expression of T-type voltage-gated calcium channel (VGCC), a generator of intracellular Ca2+ oscillation, in the human nasal mucosa.<h4>Methods</h4>The inferior turbinate was collected from patients with chronic hypertrophic rhinitis. The expression of T-type VGCC α1 subunits was examined by immunohistochemistry, transmission immunoelectron microscopy, Western blot, and real-time reverse transcription-polymerase chain reaction (RT-PCR). Participation of T-type VGCC in the ciliary beat regulation was examined by pharmacological inhibition tests using specific blockers of T-type VGCC in ex vivo measurements of the ciliary beat frequency (CBF) and ATP release and in intracellular Ca2+ imaging of isolated ciliated cells.<h4>Results</h4>Immunohistochemical staining showed the expressions of T-type VGCC α1 subunits, Cav3.1 and Cav3.3, on the surface of the epithelial cells. At the ultrastructural level, immunoreactivity for Cav3.1 was localized on the surface of the cilia, and that for Cav3.3 was localized in the cilia and at the base of the cilia. The existence of Cav3.1 and Cav3.3 was confirmed at the protein level by Western blot and at the transcriptional level by real-time RT-PCR. Specific blockers of T-type VGCC, mibefradil and NNC 55-0396, significantly inhibited CBF. These blockers also inhibited a CBF increase induced by 8-bromo-cAMP/8-bromo-cGMP and significantly lowered the intracellular Ca2+ level of isolated ciliated cells in a time-dependent manner. On the other hand, the ATP release from the nasal mucosa was not changed by mibefradil or NNC 55-0396.<h4>Conclusion</h4>These results indicate that T-type VGCC α1 subunits, Cav3.1 and Cav3.3, exist at the cilia of the nasal epithelial cells and participate in the regulation of ciliary beating and that these channels act downstream of cAMP/cGMP.

<h4>Background</h4>Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility.<h4>Aim</h4>To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent.<h4>Methods</h4>Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups.<h4>Results</h4>No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR  = 1.20; 95% CI 1.13-1.27; p  = 5.6 × 10^-10) and never smokers (e.g., maker rs1133683 Axin2; OR  = 1.27; 95% CI 1.19-1.35; p  = 1.0 × 10^-12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants.<h4>Conclusions</h4>The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.

Repeat-associated non-AUG (RAN) translation of mRNAs/transcripts responsible for polyglutamine (polyQ) diseases may generate peptides containing different mono amino acid tracts such as polyserine (polyS) and polyleucine (polyL). The propagation of aggregated polyQ from one cell to another is also an intriguing feature of polyQ proteins. However, whether the RAN translation-related polyS and polyL have the ability to propagate remains unclear, and if they do, whether the exogenous polyS and polyL exert toxicity on the recipient cells is also not known yet. In the present study, we found that aggregated polyS and polyL peptides spontaneously enter neuron-like cells and astrocytes in vitro. Aggregated polyS led to the degeneration of the differentiated neuron-like cultured cells. Likewise, the two types of aggregates taken up by astrocytes induced aberrant differentiation and cell death in vitro. Furthermore, injection of each of the two types of aggregates into the ventricles of adult mice resulted in their behavioral changes. The polyS-injected mice showed extensive vacuolar degeneration in the brain. Thus, the RAN translation-related proteins containing polyS and polyL have the potential to propagate and the proteins generated by all polyQ diseases might exert universal toxicity in the recipient cells.

The study of sex-specific genetic associations with opioid response may improve the understanding of inter-individual variability in pain treatments. We investigated sex-specific associations between genetic variation and opioid response. We identified participants in the RIGHT Study prescribed codeine, tramadol, hydrocodone, and oxycodone between 01/01/2005 and 12/31/2017. Prescriptions were collapsed into codeine/tramadol and hydrocodone/oxycodone. Outcomes included poor pain control and adverse reactions within six weeks after prescription date. We performed gene-level and single-variant association analyses stratified by sex. We included 7169 non-Hispanic white participants and a total of 1940 common and low-frequency variants (MAF > 0.01). Common variants in MACROD2 (rs76026520), CYP1B1 (rs1056837, rs1056836), and CYP2D6 (rs35742686) were associated with outcomes. At the gene level, FAAH, SCN1A, and TYMS had associations for men and women, and NAT2, CYP3A4, CYP1A2, and SLC22A2 had associations for men only. Our findings highlight the importance of considering sex in association studies on opioid response.

Stroke is a common and serious nervous system disease caused by the rupture or blockage of the cardiovascular system. It causes millions of deaths and disabilities every year, which is a huge burden on humanity. It may be induced by thrombosis, hypertension, hyperlipidemia, hyperglycemia, smoking, advanced age and so on. According to different causes, stroke can be generally divided into hemorrhagic stroke and ischemic stroke, whose pathogenesis and treatment are quite different. Ferroptosis is a new type of cell death first defined in 2012, which is characterized by non-apoptotic, iron-dependent, and over-accumulated lipid peroxides. Excess lipid reactive oxygen species produced during ferroptosis eventually leads to oxidative cell death. Ferroptosis has been shown to occur and play an important role in tumors, neurological diseases, kidney injury, and ischemia-reperfusion injury. Ferroptosis is also closely related to the pathogenesis of stroke. Moreover, scientists have successfully intervened in the process of stroke in animal models by regulating ferroptosis, indicating that ferroptosis is a new potential target for the treatment of stroke. This paper systematically summarizes the involvement and role of ferroptosis in the pathogenesis of stroke and predicts the potential of ferroptosis in the treatment of stroke. Ferroptosis in stroke. Stroke induces iron overload and lipid metabolism disorders. Elevated iron catalyzes lipid peroxidation and eventually triggers ferroptosis. Conversely, the GSH/GPX4 pathway, as well as CoQ10, Fer-1, and Lip-1, inhibits lipid peroxidation and, thus, alleviates ferroptosis. GSH glutathione; GPX4 glutathione peroxidase 4; CoQ10 coenzyme Q10; Lip-1 liproxstatin-1; Fer-1 ferostatin-1.

This work reports on the influence of 5 MeV electron beam radiations on the morphological features and chemical structure of magnesium-doped hydroxyapatite/chitosan composite coatings generated by the magnetron sputtering technique. The exposure to ionizing radiation in a linear electron accelerator dedicated to medical use has been performed in a controllable manner by delivering up to 50 Gy radiation dose in fractions of 2 Gy radiation dose per 40 s. After the irradiation with electron beams, the surface of layers became nano-size structured. The partial detachment of irradiated layers from the substrates has been revealed only after visualizing their cross sections by scanning electron microscopy. The energy dispersive X-ray spectral analysis of layer cross-sections indicated that the distribution of chemical elements in the samples depends on the radiation dose. The X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy and X-ray diffraction analysis have shown that the physicochemical processes induced by the ionizing radiation in the magnesium doped hydroxyapatite/chitosan composite coatings do not alter the apatite structure, and Mg remains bonded with the phosphate groups.

<h4>Background</h4>For decades, regenerative medicine and dentistry have been improved with new therapies and innovative clinical protocols. The aim of the present investigation was to evaluate through a critical review the recent innovations in the field of bone regeneration with a focus on the healing potentials and clinical protocols of bone substitutes combined with engineered constructs, growth factors and photobiomodulation applications.<h4>Methods</h4>A Boolean systematic search was conducted by PubMed/Medline, PubMed/Central, Web of Science and Google scholar databases according to the PRISMA guidelines.<h4>Results</h4>After the initial screening, a total of 304 papers were considered eligible for the qualitative synthesis. The articles included were categorized according to the main topics: alloplastic bone substitutes, autologous teeth derived substitutes, xenografts, platelet-derived concentrates, laser therapy, microbiota and bone metabolism and mesenchymal cells construct.<h4>Conclusions</h4>The effectiveness of the present investigation showed that the use of biocompatible and bio-resorbable bone substitutes are related to the high-predictability of the bone regeneration protocols, while the oral microbiota and systemic health of the patient produce a clinical advantage for the long-term success of the regeneration procedures and implant-supported restorations. The use of growth factors is able to reduce the co-morbidity of the regenerative procedure ameliorating the post-operative healing phase. The LLLT is an adjuvant protocol to improve the soft and hard tissues response for bone regeneration treatment protocols.

Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for <i>BRCA1/2</i> germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (<i>NTRK</i>) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.

Generation of relevant and robust models for neurological disorders is of main importance for both target identification and drug discovery. The non-cell autonomous effects of glial cells on neurons have been described in a broad range of neurodegenerative and neurodevelopmental disorders, pointing to neuroglial interactions as novel alternative targets for therapeutics development. Interestingly, the recent breakthrough discovery of human induced pluripotent stem cells (hiPSCs) has opened a new road for studying neurological and neurodevelopmental disorders "in a dish". Here, we provide an overview of the generation and modeling of both neuronal and glial cells from human iPSCs and a brief synthesis of recent work investigating neuroglial interactions using hiPSCs in a pathophysiological context.

A novel conjugate of docetaxel and biotin (designated as IDD-1010) was designed and chemically synthesized via an ester linkage at position 2' carbon in docetaxel. The synthesized pure IDD-1010 exhibits a potent anti-cancer activity in in vitro and in vivo studies. At 10 nM, IDD-1010 has induced increased apoptosis and mitotic arrest of PC3-Luc prostate cancer cells, causing aneuploidy and cell death at higher concentrations. Toxicology studies indicate that the maximal tolerated dose (MTD) of IDD-1010 is 150 mg/kg in mice; equivalent to about 12.2 mg/kg of body weight, or to about an 850 mg dose for a patient weighing 70 kg. The MTD-treated mice exhibited weight gain similar to that of the control group, with no gross pathological signs at 14 days post-dosing. At a lower dose, IDD-1010 treatment did not lead to any significant weight loss in mice, although decreased the tumor volume stemming from injecting cancer cells into the dorsal loop of mouse prostate, and it was found to be more potent than Paclitaxel (reference drug). Similarly, IDD-1010 treatment significantly reduced tumor weight and thereby increased the percentage of mice survival as compared to reference drug-treated and control groups. To summarize, the described experiments using IDD-1010, as compared to the reference drug, strongly suggest a potential treatment utility with a wider therapeutic window for prostate cancer. Henceforth, clinical research on such a novel drug candidate would be greatly worthwhile.

Understanding the molecular basis of sex differences in neural response to acute hypoxic insult has profound implications for the effective prevention and treatment of ischemic stroke. Global hypoxic-ischemic induced neural damage has been studied recently under well-controlled, non-invasive, reproducible conditions using a zebrafish model. Our earlier report on sex difference in global acute hypoxia-induced neural damage and recovery in zebrafish prompted us to conduct a comprehensive study on the mechanisms underlying the recovery. An omics approach for studying quantitative changes in brain proteome upon hypoxia insult following recovery was undertaken using iTRAQ-based LC-MS/MS approach. The results shed light on the altered expression of many regulatory proteins in the zebrafish brain upon acute hypoxia following recovery. The sex difference in differentially expressed proteins along with the proteins expressed in a uniform direction in both the sexes was studied. Core expression analysis by Ingenuity Pathway Analysis (IPA) showed a distinct sex difference in the disease function heatmap. Most of the upstream regulators obtained through IPA were validated at the transcriptional level. Translational upregulation of H3K9me3 in males led us to elucidate the mechanism of recovery by confirming transcriptional targets through ChIP-qPCR. The upregulation of H3K9me3 level in males at 4 h post-hypoxia appears to affect the early neurogenic markers nestin, klf4, and sox2, which might explain the late recovery in males, compared to females. Acute hypoxia-induced sex-specific comparison of brain proteome led us to reveal many differentially expressed proteins, which can be further studied for the development of novel targets for better therapeutic strategy.

ASB17, a member of the ankyrin repeat and SOCS box-containing protein (ASB) family, has been supposed to act as an E3 ubiquitin ligase. Actually, little is known about its biological function. In this study, we found that ASB17 knocking-out impaired the expression of the pro-inflammatory cytokines CCL2 and IL-6 in bone marrow-derived dendritic cells (BMDCs) stimulated by lipopolysaccharide (LPS), indicating an inflammation-promoting role of this gene. We reveal that ASB17 promotes LPS-induced nuclear factor kappa B (NF-κB) signal activation through interacting with TNF receptor-associated factor 6 (TRAF6) which is a crucial adaptor protein downstream of toll-like receptors (TLR). ASB17 <i>via</i> its aa177-250 segment interacts with the Zn finger domain of TRAF6. The interaction of ASB17 stabilizes TRAF6 protein through inhibiting K48-linked TRAF6 polyubiquitination. Therefore, we suggest that ASB17 facilitates LPS-induced NF-κB activation by maintaining TRAF6 protein stability. The inflammation enhancer role of ASB17 is recognized here, which provides new understanding of the activation process of inflammation and immune response.

The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.

Exposures to stress at all stages of development can lead to long-term behavioural effects, in part through changes in the epigenome. This review describes rodent research suggesting that stress in prenatal, postnatal, adolescent and adult stages leads to long-term changes in epigenetic regulation in the brain which have causal impacts on rodent behaviour. We focus on stress-induced epigenetic changes that have been linked to behavioural deficits including poor learning and memory, and increased anxiety-like and depressive-like behaviours. Interestingly, aspects of these stress-induced behavioural changes can be transmitted to offspring across several generations, a phenomenon that has been proposed to result via epigenetic mechanisms in the germline. Here, we also discuss evidence for the differential impact of stress on the epigenome in males and females, conscious of the fact that the majority of published studies have only investigated males. This has led to a limited picture of the epigenetic impact of stress, highlighting the need for future studies to investigate females as well as males.

Herb-induced liver injury (HILI) can be caused by supplements containing herbs, natural products, and products used in traditional medicine. Herbal products' most common adverse reaction is hepatotoxicity. Almost every plant part can be used to make herbal products, and these products can come in many different forms, such as teas, powders, oils, creams, capsules, and injectables. HILI incidence and prevalence are hard to estimate and vary from study to study because of insufficient large-scale prospective studies. The diagnosis of HILI is a challenging process that requires not only insight but also a high degree of suspicion by the clinician. HILI presents with unspecific symptoms and is a diagnosis of exclusion. For diagnosis, it is necessary to make a causality assessment; the Council for International Organizations of Medical Sciences assessment is the preferred method worldwide. The most effective treatment is the suspension of the use of the suspected herbal product and close monitoring of liver function. The objective of this review is to highlight the necessary steps for the clinician to follow to reach a correct diagnosis of herb-induced liver injury. Further studies of HILI are needed to better understand its complexity and prevent increased morbidity and mortality.

The heart is an essential organ in the human body. It contains various types of cells, such as cardiomyocytes, mesothelial cells, endothelial cells, and fibroblasts. The interactions between these cells determine the vital functions of the heart. Therefore, identifying the different cell types and revealing the expression rules in these cell types are crucial. In this study, multiple machine learning methods were used to analyze the heart single-cell profiles with 11 different heart cell types. The single-cell profiles were first analyzed via light gradient boosting machine method to evaluate the importance of gene features on the profiling dataset, and a ranking feature list was produced. This feature list was then brought into the incremental feature selection method to identify the best features and build the optimal classifiers. The results suggested that the best decision tree (DT) and random forest classification models achieved the highest weighted F1 scores of 0.957 and 0.981, respectively. The selected features, such as NPPA, LAMA2, DLC1, and the classification rules extracted from the optimal DT classifier played a crucial role in cardiac structure and function in recent research and enrichment analysis. In particular, some lncRNAs (LINC02019, NEAT1) were found to be quite important for the recognition of different cardiac cell types. In summary, these findings provide a solid academic foundation for the development of molecular diagnostics and biomarker discovery for cardiac diseases.

<h4>Objective</h4>The aim of this study was to examine effects of radiation therapy (RT) for head and neck cancer (HNC) on periodontal disease and relationships to caries.<h4>Study design</h4>A multicenter prospective observational cohort study (OraRad) was conducted in patients undergoing RT for HNC. Assessments were conducted by calibrated examiners at the pre-RT (baseline) visit (n = 533), the 12-month visit (n = 414), and the 24-month visit (n = 365).<h4>Results</h4>The average whole mouth mean (standard error (SE)) distance from the cementoenamel junction to the gingival margin (CEJ-GM) decreased significantly from 0.43 (0.04) mm at baseline to 0.24 (0.04) mm at 12 months and 0.11 (0.04) mm at 24 months (P ≤ .001). Whole mouth mean (SE) percentage of sites with CEJ-GM distance of <0 mm increased significantly from 23.3% (1.0%) at baseline to 28.5% (1.0%) at 12 months and 30.5% (1.1%) at 24 months (P ≤ .02). Higher mean radiation dose to the mandible was associated with a greater increase in the percentage of mandibular sites with CEJ-GM distance of <0 mm (P = .003). Both mean CEJ-GM distance and the percentage of sites with a CEJ-GM distance <0 mm were strongly associated with whole mouth mean proportion of decayed, missing, and filled surfaces, as well as proportion of decayed or filled facial/buccal surfaces specifically, (P < .001), with greater gingival recession associated with increased caries.<h4>Conclusions</h4>RT for HNC leads to mandibular gingival recession in a dose-dependent manner. This gingival recession may contribute to increased risk for cervical caries seen in these patients.

<h4>Background</h4>Changes of the coagulation system are promoted by serious infectious or noninfectious diseases, surgical procedures, and exogenous substances, including drugs. This study aimed to assess the effect of methylprednisolone pulses on selected parameters of the coagulation system.<h4>Methods</h4>The study group consisted of patients suffering from multiple sclerosis, thyroid orbitopathy, or sudden sensorineural hearing loss. 48 patients and 20 healthy volunteers were examined. The hemostatic parameters: activity of coagulation factors (VIII, IX, and XI), antithrombin activity, protein C and S activity, and concentration of soluble tissue factor were analyzed at baseline and after 3 g and 5 g of methylprednisolone administration.<h4>Results</h4>A statistically significant increase was noted in the activity of all the studied plasma coagulation factors, plasma coagulation inhibitors (except protein S activity), and the concentration of soluble tissue factor after methylprednisolone administration.<h4>Conclusion</h4>The glucocorticoids administered in the intravenous pulses of methylprednisolone shift the balance toward thromboembolic complications.

<h4>Background/aims</h4>Non-alcoholic fatty liver disease (NAFLD) is widespread chronic disease of the live in humans with the prevalence of 30% of the United States population.^1,2 The goal of the study is to validate the performance of quantitative ultrasound algorithms in the assessment of hepatic steatosis in patients with suspected NAFLD.<h4>Methods</h4>This prospective study enrolled a total of 31 patients with clinical suspicion of NAFLD to receive liver fat measurements by quantitative ultrasound and reference MRI measurements (proton density fat-fraction, PDFF). The following ultrasound (US) parameters based on both raw ultrasound RF (Radio Frequency) data and 2D B-mode images of the liver were analyzed with subsequent correlation with MRI-PDFF: hepatorenal index, acoustic attenuation coefficient, Nakagami coefficient parameter, shear wave viscosity, shear wave dispersion and shear wave elasticity. Ultrasound parameters were also correlated with the presence of hypertension and diabetes.<h4>Results</h4>The mean (± SD) age and body mass index of the patients were 49.03 (± 12.49) and 30.12 (± 6.15), respectively. Of the aforementioned ultrasound parameters, the hepatorenal index and acoustic attenuation coefficient showed a strong correlation with MRI-PDFF derivations of hepatic steatosis, with <i>r</i>-values of 0.829 and 0.765, respectively. None of the remaining US parameters showed strong correlations with PDFF. Significant differences in Nakagami parameters and acoustic attenuation coefficients were found in those patients with and without hypertension.<h4>Conclusions</h4>Hepatorenal index and acoustic attenuation coefficient correlate well with MRI-PDFF-derived measurements of hepatic steatosis. Quantitative ultrasound is a promising tool for the diagnosis and assessment of patients with NAFLD.

Oxytocin is a peptide hormone that mainly functions to control the contractility of smooth muscles and sex-related steroidogenesis in male reproductive tracts. However, specific information concerning this hormone in controlling the reproductive organs of cats is limited. This study aimed to investigate the expression of oxytocin receptors (OTRs) and their signal mediator via prostacyclin synthase (PTGIS) in reproductive structures following oxytocin assisted electroejaculation. In Experiment 1, the testis, cauda epididymis and vas deferens from five cats were examined by immunohistochemistry and quantitative polymerase chain reaction in order to study the responses of OTR and PTGIS mRNA to oxytocin injection. Experiment 2 examined the effect of oxytocin administration prior to electroejaculation on ejaculate characteristics and sperm quality in terms of motility, viability and fertilizing ability. Immunohistochemistry revealed the expression of OTRs in Leydig's, peritubular myoid cells and some spermatogenic cells. The expression was found in the epithelium and smooth muscle of the epididymis and vas deferens. After oxytocin administration, the OTR mRNA was upregulated in the epididymis (p > .05) and vas deferens (p = .01). The expression level of PTGIS mRNA increased in the response to oxytocin treatment only for the vas deferens (p > .05). Oxytocin treatment before electroejaculation resulted in an approximately twofold increase in sperm concentration and total sperm output/ejaculate, while this intervention did not significantly affect ejaculate volume, sperm quality or fertilizing ability. This study concluded that the oxytocin cascade is locally present in the reproductive structures and plays a role in promoting sperm delivery during electroejaculation in cats.

Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aimed to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. We profiled DNA methylation in nuclei of non-neuronal cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n = 8) in comparison to white matter of control individuals (n = 14), using Infinium MethylationEPIC BeadChip. We identified 1,226 significant (genome-wide adjusted <i>P</i>-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alterations of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.

A growing body of experimental evidence suggests that <i>sirtuins</i> (<i>SIRTs</i>) are associated with tumorigenesis in differentiated thyroid cancer (DTC). Nevertheless, the involvement of <i>SIRTs</i> in the pathogenesis of DTC and their clinical value remain ill-defined and should be thoroughly examined. We explored the transcription of SIRTs and survival data of patients with DTC by the systematic utilization of bioinformatics to analyze data of publicly accessible databases including Oncomine, cBioPortal, Kaplan-Meier Plotter, Gene Expression Profiling Interactive Analysis (GEPIA), Protein Atlas, LinkedOmics, and GSCALite. The examination of gene expression profiles showed that <i>SIRT2</i>, <i>SIRT3</i>, <i>SIRT4</i>, <i>SIRT5</i>, and <i>SIRT6</i> were downregulated in DTC tissues compared with the normal thyroid tissues. The decreased expression levels of <i>SIRT2</i>, <i>SIRT4</i>, and <i>SIRT5</i> were correlated with advanced tumor stages. The survival results showed that the increased <i>SIRT4</i> mRNA expression level was associated with improved overall survival (OS) in the DTC patients. In addition, patients with DTC with high <i>SIRT2</i>, <i>SIRT3</i>, <i>SIRT4</i>, and <i>SIRT5</i> mRNA levels had higher disease-free survival (DFS). These results showed that <i>SIRT2</i>, <i>SIRT3</i>, <i>SIRT4</i>, <i>SIRT5</i>, and <i>SIRT6</i> are potential targets for precise treatment of DTC patients and that <i>SIRT2</i>, <i>SIRT3</i>, <i>SIRT4</i>, and <i>SIRT5</i> are novel potential biomarkers for the prognosis of DTC.

Protein glycosylation governs key physiological and pathological processes in human cells. Aberrant glycosylation is thus closely associated with disease progression. Mass spectrometry (MS)-based glycoproteomics has emerged as an indispensable tool for investigating glycosylation changes in biological samples with high sensitivity. Following rapid improvements in methodologies for reliable intact glycopeptide identification, site-specific quantification of glycopeptide macro- and micro-heterogeneity at the proteome scale has become an urgent need for exploring glycosylation regulations. Here, we summarize recent advances in N- and O-linked glycoproteomic quantification strategies and discuss their limitations. We further describe a strategy to propagate MS data for multilayered glycopeptide quantification, enabling a more comprehensive examination of global and site-specific glycosylation changes. Altogether, we show how quantitative glycoproteomics methods explore glycosylation regulation in human diseases and promote the discovery of biomarkers and therapeutic targets.

Virus-infected cells trigger a robust innate immune response and facilitate virus replication. Here, we review the role of autophagy in virus infection, focusing on both pro-viral and anti-viral host responses using a select group of viruses. Autophagy is a cellular degradation pathway operated at the basal level to maintain homeostasis and is induced by external stimuli for specific functions. The degradative function of autophagy is considered a cellular anti-viral immune response. However, autophagy is a double-edged sword in viral infection; viruses often benefit from it, and the infected cells can also use it to inhibit viral replication. In addition to viral regulation, autophagy pathway proteins also function in autophagy-independent manners to regulate immune responses. Since viruses have co-evolved with hosts, they have developed ways to evade the anti-viral autophagic responses of the cells. Some of these mechanisms are also covered in our review. Lastly, we conclude with the thought that autophagy can be targeted for therapeutic interventions against viral diseases.

This study compared the impact of a higher nutrient density (HND) or lower nutrient density (LND) diet fed during early lay to either heavier weight (HW) or lighter weight (LW) ISA Brown hens. At 18 wk of age (WOA) pullets (n = 240) were evenly assigned to either HW (n = 120) or LW (n = 120). Sixty birds from each weight group were then randomized to either the HND or LND diet treatments which were fed from 18 to 24 WOA inclusive. At 25 WOA the LND diet replaced the HND diet. All hens remained on LND diet to 50 WOA. Hen performance was measured from 18 to 50 WOA. Femur and liver health were evaluated at 50 WOA. Egg quality was assessed from 46 to 50 WOA. The 18 WOA HW hens had higher BW, cumulative egg production, cumulative feed intake (CFI), and cumulative egg mass (CEM) to both 24 and 50 WOA (P < 0.01). At 24 WOA the HND diet also generated higher BW (P < 0.001), CEM (P < 0.001) and lower cumulative feed conversion ratio (CFCR) (P < 0.01), the latter being sustained to 50 WOA (P < 0.01). At 50 WOA CFCR of LW birds was lower than HW birds (P < 0.01). Egg weight (EW), yolk diameter, and percent yolk weight were higher (P < 0.05) in the HW birds with the highest albumen to yolk ratio in LW birds (P < 0.05). Egg shape index was higher in LND diet fed birds (P < 0.01) while LW hens had higher shell phosphorus (P < 0.05). Body weight and diet nutrient density interacted on femoral diameter and cortical thickness being higher (P < 0.01) in LW birds fed HND than LW birds fed LND diets. Fatty liver hemorrhagic scores (P < 0.05) and liver lipid peroxidase (P < 0.001) at 50 WOA were higher in HW and LND diet treatments. Concurrently HW birds had the highest CFI and EW while CFCR and liver health were superior in LW and the HND diet treatment.

<b>BACKGROUND</b>: To evaluate the effects of <i>Helicobacter pylori (HP)</i> eradication on liver function tests (LFT) and fat content (LFC) in non-diabetic non-alcoholic steatohepatitis (NASH). <b>METHODS</b>: This randomized clinical trial included dyspeptic HP infected non-diabetic NASH participants. The intervention arm received HP eradication treatment, while the control arm did not get any HP treatment. In the meantime, the standard management of NASH was performed in both trial arms. Mean alterations in LFT were the primary outcome and the secondary outcomes included the mean changes in LFC and serum metabolic profile. The trial follow-up period was 5 years. <b>RESULTS</b>: 40 participants (female: 20), with a mean age of 41.58 (±12.31) years, were enrolled in the study. The HP eradication arm included 20 participants (female: 11) with a mean age of 40.25 (±10.59) years, and the control arm consisted of 20 individuals (female: 9) with a mean age of 42.90 (±13.97) years. The tests of within-subjects effects showed a significant decrease in mean serum alanine aminotransferase (ALT; <i>P</i>=0.007), triglyceride (TG; <i>P</i>=0.04), cholesterol (<i>P</i>=0.004), and fasting blood sugar (FBS; <i>P</i><0.001), and an increase in high-density lipoprotein (HDL; <i>P</i>=0.04) in both research groups during the study period. The tests of between-subjects effects demonstrated a more significant decrement of FBS in HP eradicated patients than the controls (<i>P</i>=0.02). The reduction in waist circumference, aspartate aminotransferase (AST), ALT, alkaline phosphatase, triglyceride, cholesterol, low-density lipoprotein, insulin, and LFC were more prominent in the intervention group than the controls; however, these differences were not statistically significant. <b>CONCLUSION</b>: Adding HP eradication treatment to standard NASH treatment showed more therapeutic effect thanthe standard NASH treatment protocol alone regarding the decrement of FBS in participants with dyspeptic non-diabetic NASH. Considering the non-statistically significant improvement in other metabolic indices and LFT in this trial, further studies are recommended.

BACKGROUND Lipid metabolism has been proved to be related to the prognosis of breast cancer patients in previous studies, and the tumor immune microenvironment (TIME) plays an important role in tumorigenesis and development, but the dynamic regulation of these is still a challenge. MATERIAL AND METHODS This study used lipid metabolism-related pathways to score the gene expression of 980 breast cancer patients in the TCGA database. We used 4 pathways in HALLMARK related to lipid metabolism to score the genes in the database. The differentially expressed genes (DEGs) were further analyzed through survival analysis and Cox regression analysis, and MS4A1, which is associated with better prognosis, was finally determined to be a predictor. In-depth analysis found that MS4A1 was negatively correlated with patient age, clinical stage, tumor size, and distant metastasis. In the MS4A1 high-expression group, most genes were enriched in immune-related pathways, and CIBERSORT analysis found that MS4A1 expression was positively correlated with the abundance of 10 kinds of immune cells, such as CD8+T cells, which are related to the active immune status. RESULTS Our results suggest that MS4A1 expression can indicate the situation of lipid metabolism in breast cancer patients and reflect the status of the immune microenvironment. CONCLUSIONS MS4A1 has the potential to be an independent indicator of prognosis. Since the expression of MS4A1 is also related to the immune checkpoint mutation burden, detecting its expression level can also provide guidance for choosing treatment options.

Oncogene-induced replication stress characterizes many aggressive cancers. Several treatments are being developed that target replication stress, however, identification of tumors with high levels of replication stress remains challenging. We describe a gene expression signature of oncogene-induced replication stress. A panel of triple-negative breast cancer (TNBC) and non-transformed cell lines were engineered to overexpress CDC25A, CCNE1 or MYC, which resulted in slower replication kinetics. RNA sequencing analysis revealed a set of 52 commonly upregulated genes. In parallel, mRNA expression analysis of patient-derived tumor samples (TCGA, n = 10,592) also revealed differential gene expression in tumors with amplification of oncogenes that trigger replication stress (CDC25A, CCNE1, MYC, CCND1, MYB, MOS, KRAS, ERBB2, and E2F1). Upon integration, we identified a six-gene signature of oncogene-induced replication stress (NAT10, DDX27, ZNF48, C8ORF33, MOCS3, and MPP6). Immunohistochemical analysis of NAT10 in breast cancer samples (n = 330) showed strong correlation with expression of phospho-RPA (R = 0.451, p = 1.82 × 10^-20) and γH2AX (R = 0.304, p = 2.95 × 10^-9). Finally, we applied our oncogene-induced replication stress signature to patient samples from TCGA (n = 8,862) and GEO (n = 13,912) to define the levels of replication stress across 27 tumor subtypes, identifying diffuse large B cell lymphoma, ovarian cancer, TNBC and colorectal carcinoma as cancer subtypes with high levels of oncogene-induced replication stress.

<h4>Aims</h4>Many transcatheter aortic valve implantation (TAVI) candidates have underlying heart failure with preserved ejection fraction (HFpEF) in addition to symptomatic aortic stenosis. Diagnosis of HFpEF is challenging. The Heart Failure Association of the European Society of Cardiology proposed the HFA-PEFF score as part of a novel diagnostic algorithm. This study assessed the prognostic value of the HFA-PEFF score in patients with preserved ejection fraction after TAVI.<h4>Methods and results</h4>This single-centre study included 570 consecutive TAVI patients with a preserved left ventricular ejection fraction of ≥50%. Patients with an HFA-PEFF score of ≥5 [n = 239 (41.9%)] were compared with those with <5 points [n = 331 (58.1%)]. The primary outcome was a composite of all-cause mortality or first heart failure rehospitalization within 1 year after TAVI. Secondary endpoints were the individual components of the primary outcome. Patients with an HFA-PEFF score ≥ 5 had higher rates of comorbidities commonly associated with HFpEF, a higher rate of new pacemaker implantation after TAVI, were at increased risk of the primary composite endpoint (25.5% vs. 10.0%, P < 0.001), and rehospitalization for heart failure (11.7% vs. 3.9%, P < 0.001). Multivariable analysis confirmed an HFA-PEFF score ≥ 5 as an independent risk factor for the composite endpoint [hazard ratio 2.70, 95% confidence interval (CI) 1.70-4.28, P < 0.001] and for all-cause mortality (hazard ratio 2.58, 95% CI 1.46-4.53, P = 0.001).<h4>Conclusion</h4>The HFA-PEFF score is associated with all-cause mortality and heart failure rehospitalization in patients with preserved ejection fraction after TAVI. This practical tool can easily be incorporated into risk stratification algorithms for TAVI patients.

<h4>Purpose of the review</h4>Mesenchymal stromal cells (MSCs) are considered an attractive option for cell-based therapy because of their immune-privileged phenotype and paracrine activity. Substantial preclinical evidence indicates that MSC exosomes recapitulate MSC cellular function in cardiac regeneration and repair. Therefore, in this review, we briefly discuss the latest research progress of MSC exosomes in cardiac repair and regeneration.<h4>Recent findings</h4>The recent revolutionary advance in controlling the contents of the exosomes by manipulating parental cells through bioengineering methods to alter specific signaling pathways in ischemic myocardium has proven to be beneficial in the treatment of heart failure. MSC Exosomes appear to be leading candidates to treat myocardial infarction and subsequent heart failure by carrying rich cargo from their parental cells. However, more clinical and pre-clinical studies on MSC exosomes will be required to confirm the beneficial effect to treat cardiovascular diseases.

<h4>Background</h4>Helicobacter pylori (H. pylori) colonizes the human gastric mucosa with a high worldwide prevalence. Currently, H. pylori is eradicated by the use of antibiotics. However, elevated antibiotic resistance suggests new therapeutic strategies need to be envisioned: one approach being prophylactic vaccination. Pre-clinical and clinical data show that a urease-based vaccine is efficient in decreasing H. pylori infection through the mobilization of T helper (Th) cells, especially Th17 cells. Th17 cells produce interleukins such as IL-22 and IL-17, among others, and are key players in vaccine efficacy. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing Th17 cells have been identified.<h4>Aim</h4>This study explores the possibility that GM-CSF plays a role in the reduction of H. pylori infection following vaccination.<h4>Results</h4>We demonstrate that GM-CSF⁺ IL-17⁺ Th17 cells accumulate in the stomach mucosa of H. pylori infected mice during the vaccine-induced reduction of H. pylori infection. Secondly, we provide evidence that vaccinated GM-CSF deficient mice only modestly reduce H. pylori infection. Conversely, we observe that an increase in GM-CSF availability reduces H. pylori burden in chronically infected mice. Thirdly, we show that GM-CSF, by acting on gastric epithelial cells, promotes the production of βdefensin3, which exhibits H. pylori bactericidal activities.<h4>Conclusion</h4>Taken together, we demonstrate a key role of GM-CSF, most probably originating from Th17 cells, in the vaccine-induced reduction of H. pylori infection.

Fecundity in livestock is an economically important complex quantitative trait that is influenced by both genetics and the environment. However, the underlying genetic mechanism of reproductive performance in goats has not been well investigated. To investigate the genomic basis of fecundity in goats, genomic sequencing data of the Jining grey goat (a high prolificacy breed in China) were collected, as well as data for other commonly available goat breeds, and a mass of genomic variants were generated after variation calling. We screened the Jining grey goat (20 individuals) using a selective sweep with the Asian wild goat population (5 individuals), and potential candidate genes were proposed, such as STIM1, ESR1, LRRC14B and SLC9A3. Among, STIM1 is a most promising one associated with high reproductive capacity. When compared to Chinese domestic goats with low fecundity (17 individuals), the genes including MLLT10, SPIRE2, TCF25, ZNF276 and FANCA were screened, and the SPIRE2 gene was thought to be associated with fecundity traits. Meanwhile, the functional enrichment of these candidate genes revealed that they were involved in biological processes of mammary gland morphogenesis, uterus development, gastrulation, mesoderm morphogenesis and formation, and blood vessel development, which might undergo natural or artificial selection during reproductive trait formation in goats. Thus, our findings could enrich the genetic basis of reproductive trait selection during goat domestication, which may serve to improve goat breeding practices.

Regarding the epidemiological studies, neurological dysfunctions caused by cerebral ischemia or neurodegenerative diseases (NDDs) have been considered a pointed matter. Mount-up shreds of evidence support that both autophagy and reactive oxygen species (ROS) are involved in the commencement and progression of neurological diseases. Remarkably, oxidative stress prompted by an increase of ROS threatens cerebral integrity and improves the severity of other pathogenic agents such as mitochondrial damage in neuronal disturbances. Autophagy is anticipated as a cellular defending mode to combat cytotoxic substances and damage. The recent document proposes that the interrelation of autophagy and ROS creates a crucial function in controlling neuronal homeostasis. This review aims to overview the cross-talk among autophagy and oxidative stress and its molecular mechanisms in various neurological diseases to prepare new perceptions into a new treatment for neurological disorders. Furthermore, natural/synthetic agents entailed in modulation/regulation of this ambitious cross-talk are described.

A Japanese man in his 30s died suddenly. Postmortem computed tomography and autopsy revealed a pulmonary embolism from an organizing thrombus in the inferior vena cava as the cause of death. Genomic analysis of congenital thrombophilia-related genes (i.e., SERPINC1, PROC, PROS1, F2, F5, PLG, and MTHFR) revealed a heterozygous variant of PROS1 (p.A139V), which has been reported in patients with congenital protein S deficiency. After a genetic conference that included forensic pathologists, molecular scientists, genetic researchers, genetic clinicians, and clinical physicians, the results of the genetic analysis were explained to the family. Biochemical analyses of protein S (PS) activity and total PS antigen levels were performed with samples from the deceased's family and genetic analysis was not performed until clinical symptoms appear. Herein we demonstrate the importance of genetic background in cases of a sudden death due to pulmonary embolism.

Monoamine oxidases (MAOs) are attractive targets in drug design. The inhibition of one of the isoforms (A or B) is responsible for modulating the levels of different neurotransmitters in the central nervous system, as well as the production of reactive oxygen species. Molecules that act selectively on one of the MAO isoforms have been studied deeply, and coumarin has been described as a promising scaffold. In the current manuscript we describe a comparative study between 3-phenylcoumarin (<i>endo</i> coumarin-resveratrol-inspired hybrid) and <i>trans</i>-6-styrylcoumarin (<i>exo</i> coumarin-resveratrol-inspired hybrid). Crystallographic structures of both compounds were obtained and analyzed. 3D-QSAR models, in particular CoMFA and CoMSIA, docking simulations and molecular dynamics simulations have been performed to support and better understand the interaction of these molecules with both MAO isoforms. Both molecules proved to inhibit MAO-B, with <i>trans</i>-6-styrylcoumarin being 107 times more active than 3-phenylcoumarin, and 267 times more active than <i>trans</i>-resveratrol.

The avian influenza virus (AIV) mainly affects birds and not only causes animals' deaths, but also poses a great risk of zoonotically infecting humans. While ducks and wild waterfowl are seen as a natural reservoir for AIVs and can withstand most virus strains, chicken mostly succumb to infection with high pathogenic avian influenza (HPAI). To date, the mechanisms underlying the susceptibility of chicken and the effective immune response of duck have not been completely unraveled. In this study, we investigate the transcriptional gene regulation underlying disease progression in chicken and duck after AIV infection. For this purpose, we use a publicly available RNA-sequencing dataset from chicken and ducks infected with low-pathogenic avian influenza (LPAI) H5N2 and HPAI H5N1 (lung and ileum tissues, 1 and 3 days post-infection). Unlike previous studies, we performed a promoter analysis based on orthologous genes to detect important transcription factors (TFs) and their cooperation, based on which we apply a systems biology approach to identify common and species-specific master regulators. We found master regulators such as EGR1, FOS, and SP1, specifically for chicken and ETS1 and SMAD3/4, specifically for duck, which could be responsible for the duck's effective and the chicken's ineffective immune response.

Barley (<i>Hordeum vulgare</i> L.) is a salt-tolerant crop with considerable economic value in salinity-affected arid and semiarid areas. In the laboratory experiment, the halothermal time (HaloTT) model was used to examine barley seed germination (SG) at six constant cardinal temperatures (Ts) of 15, 20, 25, 30, 35, and 40 °C under five different water potentials (ψs) of 0, -0.5, -1.5, -1.0, and -2.0 MPa. Results showed that at optimum moisture (0 MPa), the highest germination percentage (GP) was recorded at 20 °C and the lowest at 40 °C. Moreover, GP increased with the accelerated aging period (AAP) and significantly (<i>p</i> ≤ 0.05) decreased with high <i>T.</i> In addition, with a decrease of ψ from 0 to -0.5, -1, 1.5, and -2.0 MPa, GP decreased by 93.33, 76.67, 46.67, and 33.33%, respectively, in comparison with 0 MPa. The maximum halftime constant (θHalo) and coefficient of determination (R2) values were recorded at 20 °C and 30 °C, respectively. The optimum temperature (T_o) for barley is 20 °C, base Ψ of 50th percentile (Ψb (50)) is -0.23 Mpa, and standard deviation of Ψb (σΨb) is 0.21 MPa. The cardinal <i>T</i>s for germination is 15 °C (T_b), 20 °C (T_o), and 40 °C (T_c). The GP, germination rate index (GRI), germination index (GI), coefficient of the velocity of germination (CVG), germination energy (GE), seed vigor index I and II (SVI-I & II), Timson germination index (GI), and root shoot ratio (RSR) were recorded maximum at 0 MPa at 20 °C and minimum at -2.0 MPa at 40 °C. Mean germination time (MGT) and time to 50% germination (T 50%) were maximum at -2 MPa at 40 °C, and minimum at 20 °C, respectively. In conclusion, the HaloTT model accurately predicted the germination time course of barley in response to T, Ψ, or NaCl. Therefore, barley can be regarded as a salt-tolerant plant and suitable for cultivation in arid and semi-arid regions due to its high resistance to salinity.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmissions are occurring rapidly; it is raising the alarm around the globe. Though vaccines are currently available, the evolution and mutations in the SARS-CoV-2 threaten available vaccines' significance. The drugs are still undergoing clinical trials, and certain medications are approved for "emergency use" or as an "off-label" drug during the pandemic. These drugs have been effective yet accommodating side effects, which also can be lethal. Complementary and alternative medicine is highly demanded since it embraces a holistic approach. Since ancient times, natural products have been used as drugs to treat various diseases in the medical field and are still widely practiced. Medicinal plants contain many active compounds that serve as the key to an effective drug design. The Kabasura kudineer and Nilavembu kudineer are the two most widely approved formulations to treat COVID-19. However, the mechanism of these formulations is not well known. The proposed study used a network pharmacology approach to understand the immune-boosting mechanism by the Kabasura kudineer, Nilavembu kudineer, and JACOM in treating COVID-19. The plants and phytochemical chemical compounds in the Kabasura kudineer, Nilavembu kudineer, and JACOM were obtained from the literature. The Swiss target prediction algorithm was used to predict the targets for these phytochemical compounds. The common genes for the COVID-19 infection and the drug targets were identified. The gene-gene interaction network was constructed to understand the interactions between these common genes and enrichment analyses to determine the biological process, molecular functions, cellular functions, pathways involved, etc. Finally, virtual screening and molecular docking studies were performed to identify the most potential targets and significant phytochemical compounds to treat the COVID-19. The present study identified potential targets as ACE, Cathepsin L, Cathepsin B, Cathepsin K, DPP4, EGFR, HDAC2, IL6, RIPK1, and VEGFA. Similarly, betulinic acid, 5″-(2⁗-Hydroxybenzyl) uvarinol, antofine, (S)-1'-methyloctyl caffeate, (Z)-3-phenyl-2-propenal, 7-oxo-10α-cucurbitadienol, and PLX-4720 collectively to be potential treatment agents for COVID-19.

<h4>Background</h4> Age-related hearing loss is a common, heterogeneous disease with a strong genetic component. More than 100 loci have been reported to be involved in human hearing impairment to date, but most of the genes underlying human adult-onset hearing loss remain unknown. Most genetic studies have focussed on very rare variants (such as family studies and patient cohort screens) or very common variants (genome-wide association studies). However, the contribution of variants present in the human population at intermediate frequencies is hard to quantify using these methods, and as a result, the landscape of variation associated with adult-onset hearing loss remains largely unknown. <h4>Results</h4> Here we present a study based on exome sequencing and self-reported hearing difficulty in the UK Biobank, a large-scale biomedical database. We have carried out variant load analyses using different minor allele frequency and impact filters, and compared the resulting gene lists to a manually-curated list of nearly 700 genes known to be involved in hearing in humans and/or mice. An allele frequency cutoff of 0.1, combined with a high predicted variant impact, was found to be the most effective filter settings for our analysis. We also found that separating the participants by sex produced markedly different gene lists. The gene lists obtained were investigated using gene ontology annotation, functional prioritisation and expression analysis, and this identified good candidates for further study. <h4>Conclusions</h4> Our results suggest that relatively common as well as rare variants with a high predicted impact contribute to age-related hearing impairment, and that the genetic contributions to adult hearing difficulty may differ between the sexes. Our manually-curated list of deafness genes is a useful resource for candidate gene prioritisation in hearing loss.

The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain.

Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent. Characteristic clinical findings in patients were mild to moderate ID, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. We used RNA sequencing of patients and age- and sex-matched healthy controls to assess the effect of the variant. RNA sequencing revealed that the SMG9 c.551T > C variant did not affect the splicing or expression level of SMG9 gene products, and allele-specific expression analysis did not provide evidence that the nonsense mRNA-induced NMD was affected. Differential gene expression analysis identified prevalent upregulation of genes in patients, including the genes SMOX, OSBP2, GPX3, and ZNF155. These findings suggest that normal SMG9 function may be involved in transcriptional regulation without affecting nonsense mRNA-induced NMD. In conclusion, we demonstrate that the SMG9 c.551T > C missense variant causes a neurodevelopmental disorder and impacts gene expression. NMD components have roles beyond aberrant mRNA degradation that are crucial for neurocognitive development.

Osteoarthritis (OA), one of the most common joint diseases, is characterized by fibrosis, rhagadia, ulcers and attrition of articular cartilage due to a number of factors. The etiology of OA remains unclear, but its occurrence has been associated with age, obesity, inflammation, trauma and genetic factors. Inflammatory cytokines are crucial for the occurrence and progression of OA. The intra‑articular proinflammatory and anti‑inflammatory cytokines jointly maintain a dynamic balance, in accordance with the physiological metabolism of articular cartilage. However, dynamic imbalance between proinflammatory and anti‑inflammatory cytokines can cause abnormal metabolism in knee articular cartilage, which leads to deformation, loss and abnormal regeneration, and ultimately destroys the normal structure of the knee joint. The ability of articular cartilage to self‑repair once damaged is limited, due to its inability to obtain nutrients from blood vessels, nerves and lymphatic vessels, as well as limitations in the extracellular matrix. There are several disadvantages inherent to conventional repair methods, while cartilage tissue engineering (CTE), which combines proinflammatory and anti‑-inflammatory cytokines, offers a new therapeutic approach for OA. The aim of the present review was to examine the proinflammatory factors implicated in OA, including IL‑1β, TNF‑α, IL‑6, IL‑15, IL‑17 and IL‑18, as well as the key anti‑inflammatory factors reducing OA‑related articular damage, including IL‑4, insulin‑like growth factor and TGF‑β. The predominance of proinflammatory over anti‑inflammatory cytokine effects ultimately leads to the development of OA. CTE, which employs mesenchymal stem cells and scaffolding technology, may prevent OA by maintaining the homeostasis of pro‑ and anti‑inflammatory factors.

Many human birth defects and neurodevelopmental disorders are caused by loss-of-function mutations in a single copy of transcription factor (TF) and chromatin regulator genes. Although this dosage sensitivity has long been known, how and why haploinsufficiency (HI) of transcriptional regulators leads to developmental disorders (DDs) is unclear. Here I propose the hypothesis that such DDs result from defects in cell fate determination that are based on disrupted bistability in the underlying gene regulatory network (GRN). Bistability, a crucial systems biology concept to model binary choices such as cell fate decisions, requires both positive feedback and ultrasensitivity, the latter often achieved through TF cooperativity. The hypothesis explains why dosage sensitivity of transcriptional regulators is an inherent property of fate decisions, and why disruption of either positive feedback or cooperativity in the underlying GRN is sufficient to cause disease. I present empirical and theoretical evidence in support of this hypothesis and discuss several issues for which it increases our understanding of disease, such as incomplete penetrance. The proposed framework provides a mechanistic, systems-level explanation of HI of transcriptional regulators, thus unifying existing theories, and offers new insights into outstanding issues of human disease. This article has an associated Future Leader to Watch interview with the author of the paper.

Intravenous nanoparticle hemostats offer a potentially attractive approach to promote hemostasis, in particular for inaccessible wounds such as noncompressible torso hemorrhage (NCTH). In this work, particle size was tuned over a range of <100-500 nm, and its effect on nanoparticle-platelet interactions was systematically assessed using <i>in vitro</i> and <i>in vivo</i> experiments. Smaller particles bound a larger percentage of platelets per mass of particle delivered, while larger particles resulted in higher particle accumulation on a surface of platelets and collagen. Intermediate particles led to the greatest platelet content in platelet-nanoparticle aggregates, indicating that they may be able to recruit more platelets to the wound. In biodistribution studies, smaller and intermediate nanoparticles exhibited longer circulation lifetimes, while larger nanoparticles resulted in higher pulmonary accumulation. The particles were then challenged in a 2 h lethal inferior vena cava (IVC) puncture model, where intermediate nanoparticles significantly increased both survival and injury-specific targeting relative to saline and unfunctionalized particle controls. An increase in survival in the second hour was likewise observed in the smaller nanoparticles relative to saline controls, though no significant increase in survival was observed in the larger nanoparticle size. In conjunction with prior <i>in vitro</i> and <i>in vivo</i> experiments, these results suggest that platelet content in aggregates and extended nanoparticle circulation lifetimes are instrumental to enhancing hemostasis. Ultimately, this study elucidates the role of particle size in platelet-particle interactions, which can be a useful tool for engineering the performance of particulate hemostats and improving the design of these materials.

The role of circular RNAs in oncogenesis has begun to be widely studied in recent years, due to the significant impact that these molecules have in disease pathogenesis, as well as their potential for the future of innovative therapies. Moreover, due to their characteristically circular shape, circular RNAs are very resistant molecules to RNA degradation whose levels are easily assessed in body fluids. Accordingly, they represent an opportunity for the discovery of new diagnostic and prognostic markers in a wide range of diseases. Among circular RNAs, circPVT1 is a rather peculiar one that originates from the circularization of the exon 2 of the PVT1 gene that encodes a pro-tumorigenic long non-coding RNA named lncPVT1. There are a few examples of circular RNAs that derive from a locus producing another non-coding RNA. Despite their apparent transcriptional independence, which occurs using two different promoters, a possible synergistic effect in tumorigenesis cannot be excluded considering that both have been reported to correlate with the oncogenic phenotype. This complex mechanism of regulation appears to also be controlled by c-MYC. Indeed, the PVT1 locus is located only 53 Kb downstream c-MYC gene, a well-known oncogene that regulates the expression levels of about 15% of all genes. Here, we review circPVT1 origin and biogenesis highlighting the most important mechanisms through which it plays a fundamental role in oncogenesis, such as the well-known sponge activity on microRNAs, as well as its paradigmatic interactome link with lncPVT1 and c-MYC expression.

<h4>Background</h4>Diabetic nephropathy (DN) is a critical and the most common microvascular complication and its pathogenesis is still faintly understood. Thus, this study was performed to examine the long non-coding RNA ZNFX1 Antisense Gene Protein 1 (lncRNA ZFAS1) biological function and mechanism of regulation in DN.<h4>Method</h4>Human glomerular mesangial cells (HGMC) were induced with high glucose (HG, 25 mM) to establish HG-induced cell viability, pro-inflammation observed in DN. After, target miRNA and mRNA were predicted through Lncbase and Targetscan. Subsequently, the expression of ZFAS1, miR-588, and ROCK1 in DN clinical samples and cell-model was examined through qRT-PCR and western blot analysis. We upheld the targeted interaction between miR-588 and ZFAS1 or ROCK1 through a dual-luciferase reporter assay. The proliferation of the cell was also examined through CCK-8 assay, while the level of HG-induced oxidative stress was established by measuring reactive oxygen species (ROS) level, and also the activities of antioxidant enzymes in the cell. Lastly, the level of accumulated extracellular matrix (ECM) protein-fibronectin and collagen type IV, and inflammatory cytokines produced by the cell was analyzed through western blot analysis and ELISA.<h4>Results</h4>ZFAS1 was significantly upregulated in the DN blood samples and HG-induced HGMC. Prediction result revealed that the ZFAS1 endogenously targets the miR-588 seed sequence while miR-588 plays a role in post-transcriptional regulation of ROCK1 mRNA. Moreover, we found that miR-588 expression was significantly downregulated in DN blood samples and negatively correlates with ZFAS1 expression. Further results show that silencing ZFAS1 had a protective effect on HG-induced proliferation, oxidative stress, fibrosis, and inflammation in HGMC while miR-588 inhibition and ROCK1 overexpression reversed this effect.<h4>Conclusions</h4>Altogether, our data suggest that ZFAS1 regulates the proliferation, oxidative stress, fibrosis, and inflammation of high glucose-induced diabetic nephropathy through the miR-588/ROCK1 axis.

Synaptic abnormalities are a cardinal feature of Alzheimer's disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.

Five New World mammarenaviruses (NWMs) cause life-threatening hemorrhagic fever (HF). Cellular entry by these viruses is mediated by human transferrin receptor 1 (hTfR1). Here, we demonstrate that an antibody (ch128.1/IgG1) which binds the apical domain of hTfR1, potently inhibits infection of attenuated and pathogenic NWMs in vitro. Computational docking of the antibody Fab crystal structure onto the known structure of hTfR1 shows an overlapping receptor-binding region shared by the Fab and the viral envelope glycoprotein GP1 subunit that binds hTfR1, and we demonstrate competitive inhibition of NWM GP1 binding by ch128.1/IgG1 as the principal mechanism of action. Importantly, ch128.1/IgG1 protects hTfR1-expressing transgenic mice against lethal NWM challenge. Additionally, the antibody is well-tolerated and only partially reduces ferritin uptake. Our findings provide the basis for the development of a novel, host receptor-targeted antibody therapeutic broadly applicable to the treatment of HF of NWM etiology.

MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. Besides cytosol and nucleus, MATα1 also targets the mitochondria of hepatocytes to regulate their function. Here, we show that mitochondrial MATα1 is selectively depleted in alcohol-associated liver disease through a mechanism that involves the isomerase PIN1 and the kinase CK2. Alcohol activates CK2, which phosphorylates MATα1 at Ser114 facilitating interaction with PIN1, thereby inhibiting its mitochondrial localization. Blocking PIN1-MATα1 interaction increased mitochondrial MATα1 levels and protected against alcohol-induced mitochondrial dysfunction and fat accumulation. Normally, MATα1 interacts with mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and fatty acid β-oxidation. Preserving mitochondrial MATα1 content correlates with higher methylation and expression of mitochondrial proteins. Our study demonstrates a role of CK2 and PIN1 in reducing mitochondrial MATα1 content leading to mitochondrial dysfunction in alcohol-associated liver disease.

Schizophrenia is a severe, complex mental disorder characterized by a combination of positive symptoms, negative symptoms, and impaired cognitive function. Schizophrenia is highly heritable (~80%) with multifactorial etiology and complex polygenic genetic architecture. Despite the large number of genetic variants associated with schizophrenia, few causal variants have been established. Gaining insight into the mechanistic influences of these genetic variants may facilitate our ability to apply these findings to prevention and treatment. Though there have been more than 300 studies of gene expression in schizophrenia over the past 15 years, none of the studies have yielded consistent evidence for specific genes that contribute to schizophrenia risk. The aim of this work is to conduct a systematic review and synthesis of case-control studies of genome-wide gene expression in schizophrenia. Comprehensive literature searches were completed in PubMed, EmBase, and Web of Science, and after a systematic review of the studies, data were extracted from those that met the following inclusion criteria: human case-control studies comparing the genome-wide transcriptome of individuals diagnosed with schizophrenia to healthy controls published between January 1, 2000 and June 30, 2020 in the English language. Genes differentially expressed in cases were extracted from these studies, and overlapping genes were compared to previous research findings from the genome-wide association, structural variation, and tissue-expression studies. The transcriptome-wide analysis identified different genes than those previously reported in genome-wide association, exome sequencing, and structural variation studies of schizophrenia. Only one gene, GBP2, was replicated in five studies. Previous work has shown that this gene may play a role in immune function in the etiology of schizophrenia, which in turn could have implications for risk profiling, prevention, and treatment. This review highlights the methodological inconsistencies that impede valid meta-analyses and synthesis across studies. Standardization of the use of covariates, gene nomenclature, and methods for reporting results could enhance our understanding of the potential mechanisms through which genes exert their influence on the etiology of schizophrenia. Although these results are promising, collaborative efforts with harmonization of methodology will facilitate the identification of the role of genes underlying schizophrenia.

COVID-19-associated acute kidney injury (COVID-AKI) is a common complication of SARS-CoV-2 infection in hospitalized patients. The susceptibility of human kidneys to direct SARS-CoV-2 infection and modulation of the renin-angiotensin II signaling (RAS) pathway by viral infection remain poorly characterized. Using induced pluripotent stem cell-derived kidney organoids, SARS-CoV-1, SARS-CoV-2, and MERS-CoV tropism, defined by the paired expression of a host receptor (<i>ACE2</i>, <i>NRP1</i> or <i>DPP4</i>) and protease (<i>TMPRSS2</i>, <i>TMPRSS4</i>, <i>FURIN</i>, <i>CTSB</i> or <i>CTSL</i>), was identified primarily among proximal tubule cells. Losartan, an angiotensin II receptor blocker being tested in patients with COVID-19, inhibited angiotensin II-mediated internalization of ACE2, upregulated interferon-stimulated genes (<i>IFITM1</i> and <i>BST2</i>) known to restrict viral entry, and attenuated the infection of proximal tubule cells by SARS-CoV-2. Our work highlights the susceptibility of proximal tubule cells to SARS-CoV-2 and reveals a putative protective role for RAS inhibitors during SARS-CoV-2 infection.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the expression of mutant huntingtin (mHtt). One of the main features of HD is the degeneration of the striatum that leads to motor discoordination. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that acts through three receptors named PAC1R, VPAC1R, and VPAC2R. In the present study, we first investigated the effect of PACAP on STHdhQ7/Q7 and STHdhQ111/Q111 cells that express wild-type Htt with 7 and mHtt with 111 glutamines, respectively. Then we explored the capacity of PACAP to rescue motor symptoms in the R6/1, a murine model of HD. We found that PACAP treatment (10^-7 M) for 24 h protects STHdhQ111/Q111 cells from mHtt-induced apoptosis. This effect is associated with an increase in PAC1R transcription, phosphorylation of ERK and Akt, and an increase of intracellular c-fos, egr1, CBP, and BDNF protein content. Moreover, the use of pharmacological inhibitors revealed that activation of ERK and Akt mediates these antiapoptotic and neurotrophic effects of PACAP. To find out PAC1R implication, we treated STHdh cells with vasoactive intestinal peptide (VIP), which exhibits equal affinity for VPAC1R and VPAC2R, but lower affinity for PAC1R, in contrast to PACAP which has same affinity for the three receptors. VIP reduced cleaved caspase-3 protein level, without promoting the expression of c-fos, egr1, CBP, and the neurotrophin BDNF. We next measured the protein level of PACAP receptors in the striatum and cortex of R6/1 mice. We observed a specific reduction of PAC1R at the onset of motor symptoms. Importantly, the intranasal administration of PACAP to R6/1 animals restored the motor function and increased the striatal levels of PAC1R, CBP, and BDNF. In conclusion, PACAP exerts antiapoptotic and neurotrophic effects in striatal neurons mainly through PAC1R. This effect in HD striatum allows the recovery of motor function and point out PAC1R as a therapeutic target for treatment of HD.

Epithelial-mesenchymal transition (EMT) is thought to be involved in the tissue remodeling and long-term inflammatory process of chronic sinusitis (CRS), but the driving mechanism is still unclear. Using high-resolution mass spectrometry, we performed a proteomic screen of CRS nasal mucosal tissue to identify differentially expressed proteins. Data are available <i>via</i> ProteomeXchange with identifier PXD030884. Specifically, we identified S100 calcium binding protein A4 (S100A4), an effective factor in inflammation-related diseases, and its downstream protein closely related to tissue fibrosis collagen type I alpha 1 chain (COL1A1), which suggested its involvement in nasal mucosal tissue remodeling. In addition, stimulation of human nasal epithelial cells (HNEpCs) with lipopolysaccharide (LPS) mimicked the inflammatory environment of CRS and showed that S100A4 is involved in regulating EMT and thus accelerating tissue remodeling in the nasal mucosa, both in terms of increased cell motility and overexpression of mesenchymal-type proteins. Additionally, we further investigated the regulation mechanism of S100A4 involved in EMT in CRS. Our research results show that in the inflammatory environment of CRS nasal mucosal epithelial cells, TCF-4 will target to bind to S100A4 and regulate its transcription. The transcription of S100A4 in turn affects the execution of the important signaling pathway in EMT, the Wnt/GSK-3β/β-catenin pathway, through the TCF-4/β-catenin complex. In conclusion, this study confirmed that the expression of S100A4 was significantly increased during the progressive EMT process of CRS mucosal epithelial cells, and revealed that the transcriptional regulation of S100A4 plays an important role in the occurrence and development of EMT. This finding will help us to better understand the pathogenesis behind the remodeling in CRS patients, and identify target molecules for the treatment of CRS.

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with high recurrence and mortality rate. Chemotherapy, including 5-fluorouracil (5-FU), adriamycin (ADR), vincristine (VCR), paclitaxel (PTX), and platinum drugs, remains one of the fundamental methods of GC treatment and has efficiently improved patients' prognosis. However, most patients eventually develop resistance to chemotherapeutic agents, leading to the failure of clinical treatment and patients' death. Recent studies suggest that long non-coding RNAs (lncRNAs) are involved in the drug resistance of GC by modulating the expression of drug resistance-related genes <i>via</i> sponging microRNAs (miRNAs). Moreover, lncRNAs also play crucial roles in GC drug resistance <i>via</i> a variety of mechanisms, such as the regulation of the oncogenic signaling pathways, inhibition of apoptosis, induction of autophagy, modulation of cancer stem cells (CSCs), and promotion of the epithelial-to-mesenchymal transition (EMT) process. Some of lncRNAs exhibit great potential as diagnostic and prognostic biomarkers, as well as therapeutic targets for GC patients. Therefore, understanding the role of lncRNAs and their mechanisms in GC drug resistance may provide us with novel insights for developing strategies for individual diagnosis and therapy. In this review, we summarize the recent findings on the mechanisms underlying GC drug resistance regulated by lncRNAs. We also discuss the potential clinical applications of lncRNAs as biomarkers and therapeutic targets in GC.

<h4>Background</h4>The incidence of neurological disorders is increasing due to population growth and extended life expectancy. Despite advances in the understanding of these disorders, curative strategies for treatment have not yet eventuated. In part, this is due to the complexities of the disorders and a lack of identification of their specific underlying pathologies. <i>Dictyostelium discoideum</i> has provided a useful, simple model to aid in unraveling the complex pathological characteristics of neurological disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, neuronal ceroid lipofuscinoses and lissencephaly. In addition, <i>D. discoideum</i> has proven to be an innovative model for pharmaceutical research in the neurological field.<h4>Scope of review</h4>This review describes the contributions of <i>D. discoideum</i> in the field of neurological research. The continued exploration of proteins implicated in neurological disorders in <i>D. discoideum</i> may elucidate their pathological roles and fast-track curative therapeutics.

<h4>Background</h4>Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) constitute rare chronic inflammatory biliary diseases which likely comprise genetic, environmental and autoimmune factors. Specific inhibitory (auto-) antibodies against the muscarinic acetylcholine receptor type 3 (mAChR3 auto-ab) may contribute to the pathogenesis of chronic biliary inflammation by modulating mAChR3- mediated signaling.<h4>Aims</h4>The aim of this study was to analyze the prevalence and relevance of inhibitory mAChR3 auto-ab (mAChR3inh+ auto-ab) in a large cohort of PBC patients from two independent tertiary centers in Berlin and Leipzig in comparison to a large PSC cohort. Baseline parameters and response rates to standard treatment with ursodeoxycholic acid (UDCA) were characterized with respect to the individual mAChR3 auto-ab status.<h4>Methods</h4>In total, the study population comprised 437 PBC patients, 187 PSC patients and 80 healthy controls. Clinical and laboratory baseline characteristics were retrieved from medical records. The response to ursodeoxycholic acid (UDCA) therapy after 12 months of treatment was available in 176 PBC and 45 PSC patients.<h4>Results</h4>The prevalence of mAChR3inh+ auto-ab was significantly higher among PBC patients (11.2%, 49/437; <i>p</i> = 0.008 vs. healthy controls) and PSC patients (33.6%, 63/187; <i>p</i> < 0.0001 vs. healthy controls) compared to healthy controls (2.5%, 2/80), respectively. PBC patients with mAChR3inh+ auto-ab exhibited significantly higher levels of alkaline phosphatase (ALP) and bilirubin, which constitute established parameters for PBC risk stratification. Moreover, mAChR3inh+ PBC patients tended to show decreased response rates to UDCA therapy compared to PBC patients without mAChR3inh+ auto-ab (mAChR3- PBC). In contrast, PSC patients with mAChR3inh+ auto-ab showed no significant differences in laboratory findings compared to mAChR3 auto-ab negative (mAChR3-) PSC patients.<h4>Conclusion</h4>MAChR3inh+ auto-ab might be involved in the pathogenesis and treatment response of chronic biliary inflammation in patients with PBC but not in patients with PSC.

Cleft palate (CP) is one of the most common birth defects, presenting a multitude of negative impacts on the health of the patient. It also leads to increased mortality at all stages of life, economic costs and psychosocial effects. The embryological development of CP has been outlined thanks to the advances made in recent years due to biomolecular successions. The etiology is broad and combines certain environmental and genetic factors. Currently, all surgical interventions work off the principle of restoring the area of the fissure and aesthetics of the patient, making use of bone substitutes. These can involve biological products, such as a demineralized bone matrix, as well as natural-synthetic polymers, and can be supplemented with nutrients or growth factors. For this reason, the following review analyzes different biomaterials in which nutrients or biomolecules have been added to improve the bioactive properties of the tissue construct to regenerate new bone, taking into account the greatest limitations of this approach, which are its use for bone substitutes for large areas exclusively and the lack of vascularity. Bone tissue engineering is a promising field, since it favors the development of porous synthetic substitutes with the ability to promote rapid and extensive vascularization within their structures for the regeneration of the CP area.

Bone metabolism consists of a balance between bone formation and bone resorption, which is mediated by osteoblast and osteoclast activity, respectively. In order to ensure bone plasticity, the bone remodeling process needs to function properly. Mesenchymal stem cells differentiate into the osteoblast lineage by activating different signaling pathways, including transforming growth factor β (TGF-β)/bone morphogenic protein (BMP) and the Wingless/Int-1 (Wnt)/β-catenin pathways. Recent data indicate that bone remodeling processes are also epigenetically regulated by DNA methylation, histone post-translational modifications, and non-coding RNA expressions, such as micro-RNAs, long non-coding RNAs, and circular RNAs. Mutations and dysfunctions in pathways regulating the osteoblast differentiation might influence the bone remodeling process, ultimately leading to a large variety of metabolic bone diseases. In this review, we aim to summarize and describe the genetics and epigenetics of the bone remodeling process. Moreover, the current findings behind the genetics of metabolic bone diseases are also reported.

Pannexins (PANX) were cloned based on their sequence homology to innexins (Inx), invertebrate gap junction proteins. Although there is no sequence homology between PANX and connexins (Cx), these proteins exhibit similar configurations. The PANX family has three members, PANX1, PANX2 and PANX3. Among them, PANX1 has been the most extensively studied. The PANX1 channels are activated by many factors, including high extracellular K⁺ ([K⁺]_e), high intracellular Ca²⁺ ([Ca²⁺]_i), Src family kinase (SFK)-mediated phosphorylation, caspase cleavage and mechanical stimuli. However, the mechanisms mediating this mechanosensitivity of PANX1 remain unknown. Both force-from-lipids and force-from-filaments models are proposed to explain the gating mechanisms of PANX1 channel mechanosensitivity. Finally, both the physiological and pathological roles of mechanosensitive PANX1 are discussed.

The main aim of our research was to investigate antiadhesive and antibiofilm properties of nanocrystalline apatites doped and co-doped with noble metal ions (Ag⁺, Au⁺, and Pd²⁺) against selected drug-resistant strains of <i>Enterococcus faecalis</i> and <i>Staphylococcus aureus</i>. The materials with the structure of apatite (hydroxyapatite, nHAp; hydroxy-chlor-apatites, OH-Cl-Ap) containing 1 mol% and 2 mol% of dopants and co-dopants were successfully obtained by the wet chemistry method. The majority of them contained an additional phase of metallic nanoparticles, in particular, AuNPs and PdNPs, which was confirmed by the XRPD, FTIR, UV-Vis, and SEM-EDS techniques. Extensive microbiological tests of the nanoapatites were carried out determining their MIC, MBC value, and FICI. The antiadhesive and antibiofilm properties of the tested nanoapatites were determined in detail with the use of fluorescence microscopy and computer image analysis. The results showed that almost all tested nanoapatites strongly inhibit adhesion and biofilm production of the tested bacterial strains. Biomaterials have not shown any significant cytotoxic effect on fibroblasts and even increased their survival when co-incubated with bacterial biofilms. Performed analyses confirmed that the nanoapatites doped and co-doped with noble metal ions are safe and excellent antiadhesive and antibiofilm biomaterials with potential use in the future in medical sectors.

In this study, forchlorfenuron (CPPU) was coupled with succinic anhydride to yield a CPPU hapten (CPPU-COOH), and a high-affinity monoclonal antibody (mAb) that can specifically recognize CPPU was produced. Using this mAb as a recognition reagent, a sensitive indirect competitive enzyme-linked immunosorbent assay (icELISA) for CPPU was optimized, which exhibits an IC₅₀ of 1.04 ng/mL, a limit of detection of 0.16 ng/mL, and a linear range of 0.31-3.43 ng/mL for CPPU. Cross-reactivity percentages with six analogues were all below 6%. The average recovery rates for cucumber and orange samples were from 85.23% to 119.14%. The analysis results of this icELISA showed good consistency with those from liquid chromatography mass spectrometry. These results suggest that the proposed icELISA provides a sensitive, specific, and reliable strategy for CPPU detection in food samples.

<h4>Background</h4>Neoadjuvant chemotherapy (NACT) is an increasingly used approach for treatment of breast cancer. The pathological complete response (pCR) is considered a good predictor of disease-specific survival. This study investigated whether circulating exosomal microRNAs could predict pCR in breast cancer patients treated with NACT.<h4>Method</h4>Plasma samples of 20 breast cancer patients treated with NACT were collected prior to and after the first cycle. RNA sequencing was used to determine microRNA profiling. The Cancer Genome Atlas (TCGA) was used to explore the expression patterns and survivability of the candidate miRNAs, and their potential targets based on the expression levels and copy number variation (CNV) data.<h4>Results</h4>Three miRNAs before that NACT (miR-30b, miR-328 and miR-423) predicted pCR in all of the analyzed samples. Upregulation of miR-127 correlated with pCR in triple-negative breast cancer (TNBC). After the first NACT dose, pCR was predicted by exo-miR-141, while miR-34a, exo-miR182, and exo-miR-183 predicted non-pCR. A significant correlation between the candidate miRNAs and the overall survival, subtype, and metastasis in breast cancer, suggesting their potential role as predictive biomarkers of pCR.<h4>Conclusions</h4>If the miRNAs identified in this study are validated in a large cohort of patients, they might serve as predictive non-invasive liquid biopsy biomarkers for monitoring pCR to NACT in breast cancer.

Understanding the pathogenesis and carcinogenesis of gallbladder adenocarcinoma is important. The fifth edition of the World Health Organization's tumor classification of the digestive system indicates three types of preinvasive neoplasm of the gallbladder: pyloric gland adenoma (PGA), biliary intraepithelial neoplasia (BilIN), and intracholecystic papillary neoplasm (ICPN). New terminologies have also been introduced, such as intracholecystic papillary-tubular neoplasm, gastric pyloric, simple mucinous type, and intracholecystic tubular non-mucinous neoplasm (ICTN). Pancreatobiliary maljunction (PBM) poses a markedly high risk for bile duct carcinoma, which was analyzed and investigated mainly by Asian researchers in the past; however, recent studies have clarified a similar significance of biliary carcinogenesis in Western countries as well. In this study, we reviewed and summarized information on three gallbladder neoplastic precursors, PGA, BilIN, and ICPN, and gallbladder lesions in patients with PBM.

Arunachali yak, the only registered yak breed of India, is crucial for the economic sustainability of pastoralist Monpa community. This study intended to determine the genomic diversity and to identify signatures of selection in the breed. Previously available double digest restriction-site associated DNA (ddRAD) sequencing data of Arunachali yak animals was processed and 99,919 SNPs were considered for further analysis. The genomic diversity profiled based on nucleotide diversity, π (π = 0.041 in 200 bp windows), effective population size, Ne (Ne = 83) and Runs of homozygosity (ROH) (predominance of shorter length ROHs) was found to be optimum. Subsequently, 207 regions were identified to be under selective sweeps through de-correlated composite of multiple signals (DCMS) statistic which combined three individual test statistics viz. π, Tajima's D and |iHS| in non-overlapping 100 kb windows. Mapping of these regions revealed 611 protein-coding genes including <i>KIT</i>, <i>KITLG</i>, <i>CDH12</i>, <i>FGG</i>, <i>FGA</i>, <i>FGB</i>, <i>PDGFRA</i>, <i>PEAR1</i>, <i>STXBP3</i>, olfactory receptor genes (<i>OR5K3</i>, <i>OR5H6</i> and <i>OR1E1</i>) and taste receptor genes (<i>TAS2R1</i>, <i>TAS2R3</i> and <i>TAS2R4</i>). Functional annotation highlighted that biological processes like platelet aggregation and sensory perception were the most overrepresented and the associated regions could be considered as breed-specific signatures of selection in Arunachali yak. These findings point towards evolutionary role of natural selection in environmental adaptation of Arunachali yak population and provide useful insights for pursuing genome-wide association studies in future.

Synthetic bone graft substitutes have attracted increasing attention in tissue engineering. This study aimed to fabricate a novel, bioactive, porous scaffold that can be used as a bone substitute. Strontium and zinc doped nano-hydroxyapatite (Sr/Zn n-HAp) were synthesized by a water-based sol-gel technique. Sr/Zn n-HAp and poly (lactide-co-glycolide) (PLGA) were used to fabricate composite scaffolds by supercritical carbon dioxide technique. FTIR, XRD, TEM, SEM, and TGA were used to characterize Sr/Zn n-HAp and the composite scaffolds. The synthesized scaffolds were adequately porous with an average pore size range between 189 to 406 µm. The scaffolds demonstrated bioactive behavior by forming crystals when immersed in the simulated body fluid. The scaffolds after immersing in Tris/HCl buffer increased the pH value of the medium, establishing their favorable biodegradable behavior. ICP-MS study for the scaffolds detected the presence of Sr, Ca, and Zn ions in the SBF within the first week, which would augment osseointegration if implanted in the body. nHAp and their composites (PLGA-nHAp) showed ultimate compressive strength ranging between 0.4-19.8 MPa. A 2.5% Sr/Zn substituted nHAp-PLGA composite showed a compressive behavior resembling that of cancellous bone indicating it as a good candidate for cancellous bone substitute.

Maintaining neuronal integrity and functions requires precise mechanisms controlling organelle and protein quality. Alzheimer's disease (AD) is characterized by functional defects in the clearance and recycling of intracellular components. As such, neuronal homeostasis involves autophagy, mitophagy, and apoptosis. Compromised activity in these cellular processes may cause pathological phenotypes of AD. Dysfunction of mitochondria is one of the hallmarks of AD. Mitophagy is a critical mitochondria quality control system, and the impaired mitophagy is observed in AD. Myeloid cell leukemia 1 (MCL1), a member of the pro-survival B-cell lymphoma protein 2 (BCL2) family, is a mitochondria-targeted protein that contributes to maintaining mitochondrial integrity. <i>Mcl1</i> knockout mice display peri-implantation lethality. The studies on conditional <i>Mcl1</i> knockout mice demonstrate that MCL1 plays a central role in neurogenesis and neuronal survival during brain development. Accumulating evidence reveals the critical role of MCL1 as a regulator of neuronal autophagy, mitophagy, and survival. In this review, we discuss the emerging neuroprotective function of MCL1 and how dysregulation of MCL1 signaling is involved in the pathogenesis of AD. As the pro-survival BCL2 family of proteins are promising targets of pharmacological intervention with BH3 mimetic drugs, we also discuss the promise of MCL1-targeting therapy in AD.

<b>Introduction:</b> Cognitive decline, correlating with hippocampal atrophy, characterizes several neurodegenerative disorders having a background of low-level chronic inflammation and oxidative stress. <b>Methods:</b> In this cross-sectional study, we examined how cognitive decline and hippocampal subfields volume are associated with the expression of redox and inflammatory genes in peripheral blood. We analyzed 34 individuals with different cognitive scores according to Mini-Mental State Examination, corrected by age and education (adjMMSE). We identified a group presenting cognitive decline (CD) with adjMMSE<27 (n=14) and a normal cognition (NC) group with adjMMSE≥27 (n=20). A multiparametric approach, comprising structural magnetic resonance imaging measurement of different hippocampal segments and blood mRNA expression of redox and inflammatory genes was applied. <b>Results:</b> Our findings indicate that hippocampal segment volumes correlate positively with adjMMSE and negatively with the blood transcript levels of 19 genes, mostly redox genes correlating especially with the left subiculum and presubiculum. A strong negative correlation between hippocampal subfields atrophy and Sulfiredoxin-1 ( <i>SRXN1</i>) redox gene was emphasized. <b>Conclusions:</b> Concluding, these results suggest that <i>SRXN1</i> might be a valuable candidate blood biomarker for non-invasively monitoring the evolution of hippocampal atrophy in CD patients.

<h4>Introduction</h4>During open surgical dislocated hip reduction, several anatomical structures, such as the round ligament, are approached. However, there is controversy over both the possibility of preserving the ligament and its functional importance.<h4>Materials and methods</h4>This experimental study used skeletally immature rabbits as a model for congenital hip dislocation. Thirty-six rabbits comprised the sample that was submitted to the round ligament analysis. The sample was stratified for analysis (biomechanics, zymography, histology, and immunohistochemistry). Statistical analysis compared the unstable side to the control side of each rabbit.<h4>Results</h4>Biomechanical assays showed that the mean maximal strength of the round ligament on the unstable side was similar to that of the control side (p = 0.594), which was also the case with maximum deformation (p = 0.328). Histologically, there was a statistically significant increase in cellularity on the unstable side (p <0.001). Additionally, there was significantly greater collagen occupancy on the control side (p <0.001). Zymography revealed no significant difference in the amount of active metalloproteinase 2 (MMP-2) (p = 0.068).<h4>Conclusions</h4>Although histological analysis found evidence of significant changes in the RL in unstable hips, there were no significant differences in zymography, and no changes were observed in biomechanical tests. <i>Evidence Level V; Experimental study.</i>

X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ∼20->100 repeats and contractions of ∼20-40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington’s disease brains reveals similar brain region-specific profiles, indicating common trans -acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.

<h4>ABSTRACT</h4> The sharp increase in the number of new COVID-19 cases in late 2021 and early 2022, which is associated with the spread of a new strain of coronavirus - omicron - is of great concern and makes it necessary to make at least approximate forecasts for the pandemic dynamics of the epidemic. As this rapid growth occurs even in countries with high levels of vaccinations, the question arises as to their effectiveness. The smoothed daily number of new cases and deaths per capita and the ratio of these characteristics were used to reveal the appearance of new coronavirus strains and to estimate the effectiveness of quarantine, testing and vaccination. The third year of the pandemic allowed us to compare the pandemic dynamics in the period from September 2020 to January 2021 with the same period one year later for Ukraine, EU, the UK, USA, India, Brazil, South Africa, Argentina, Australia, and in the whole world. Record numbers of new cases registered in late 2021 and early 2022 once again proved that existing vaccines cannot prevent new infections, and vaccinated people can spread the infection as intensively as non-vaccinated ones. Fortunately, the daily number of new cases already diminishes in EU, the UK, USA, South Africa, and Australia. In late January - early February 2022,the maximum averaged numbers of new cases are expected in Brazil, India, EU, and worldwide. “Omicron” waves can increase the numbers of deaths per capita, but in highly vaccinated countries, the deaths per case ratio significantly decreases.

Altered microRNA (miRNA) expression is a common feature of Huntington’s disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin (mHTT) binds to Ago2, a central component of miRNA biogenesis, and disrupts mature miRNA levels. In this study, we sought to determine if miRNA maturation per se was compromised in HD. Towards this end, we characterized t major miRNA biogenesis pathway components and miRNA maturation products (pri-miRNA, pre-miRNA, and mature) in human HD (N=41, Vonsattel grades HD2-4) and healthy control (N=25) subjects. Notably, the striatum (putamen) and cortex (BA39) from the same individuals were analyzed in parallel. We show that Ago2, Drosha, and Dicer were strongly downregulated in human HD at early stages of disease. Using a panel of HD-related miRNAs (miR-10b, miR-196b, miR-132, miR-212, miR-127, miR-128), we uncovered various types of maturation defects in HD brain, the most prominent occurring at the pre-miRNA to mature miRNA maturation step. Consistent with earlier findings, we provide evidence that alterations in autophagy could participate in miRNA maturation defects. Notably, most changes occurred in the striatum, which is more prone to HTT aggregation and neurodegeneration. Likewise, we observed no significant alterations in miRNA biogenesis in human HD cortex and blood, strengthening tissue-specific effects. Overall, these data provide important clues into the underlying mechanisms behind miRNA alterations in HD-susceptible tissues. Further investigations are now required to understand the biological, diagnostic, and therapeutic implications of miRNA/RNAi biogenesis defects in HD and related neurodegenerative disorders.

Glutamatergic transmission prompts K⁺ efflux through postsynaptic NMDA receptors. The ensuing hotspot of extracellular K⁺ elevation depolarizes presynaptic terminal, boosting glutamate release, but whether this also affects glutamate uptake in local astroglia has remained an intriguing question. Here, we find that the pharmacological blockade, or conditional knockout, of postsynaptic NMDA receptors suppresses use-dependent increase in the amplitude and duration of the astrocytic glutamate transporter current (I_GluT ), whereas blocking astrocytic K⁺ channels prevents the duration increase only. Glutamate spot-uncaging reveals that astrocyte depolarization, rather than extracellular K⁺ rises per se, is required to reduce the amplitude and duration of I_GluT . Biophysical simulations confirm that local transient elevations of extracellular K⁺ can inhibit local glutamate uptake in fine astrocytic processes. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K⁺ efflux to enhanced extrasynaptic glutamate signaling. Thus, repetitive glutamatergic transmission triggers a feedback loop in which postsynaptic K⁺ efflux can transiently facilitate presynaptic release while reducing local glutamate uptake.

Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11-producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.

<h4>Objective</h4>To develop a quantitative ultrasound (QUS)- and elastography-based model to improve classification of steatosis grade, inflammation grade, and fibrosis stage in patients with chronic liver disease in comparison with shear wave elastography alone, using histopathology as the reference standard.<h4>Methods</h4>This ancillary study to a prospective institutional review-board approved study included 82 patients with non-alcoholic fatty liver disease, chronic hepatitis B or C virus, or autoimmune hepatitis. Elastography measurements, homodyned K-distribution parametric maps, and total attenuation coefficient slope were recorded. Random forests classification and bootstrapping were used to identify combinations of parameters that provided the highest diagnostic accuracy. Receiver operating characteristic (ROC) curves were computed.<h4>Results</h4>For classification of steatosis grade S0 vs. S1-3, S0-1 vs. S2-3, S0-2 vs. S3, area under the receiver operating characteristic curve (AUC) were respectively 0.60, 0.63, and 0.62 with elasticity alone, and 0.90, 0.81, and 0.78 with the best tested model combining QUS and elastography features. For classification of inflammation grade A0 vs. A1-3, A0-1 vs. A2-3, A0-2 vs. A3, AUCs were respectively 0.56, 0.62, and 0.64 with elasticity alone, and 0.75, 0.68, and 0.69 with the best model. For classification of liver fibrosis stage F0 vs. F1-4, F0-1 vs. F2-4, F0-2 vs. F3-4, F0-3 vs. F4, AUCs were respectively 0.66, 0.77, 0.72, and 0.74 with elasticity alone, and 0.72, 0.77, 0.77, and 0.75 with the best model.<h4>Conclusion</h4>Random forest models incorporating QUS and shear wave elastography increased the classification accuracy of liver steatosis, inflammation, and fibrosis when compared to shear wave elastography alone.

We report a computational study of the little-studied neutral bisulfite, bisulfate, dihydro-phosphite, and dihydro-phosphate radicals (HSO_<i>x</i>^•, H₂PO_<i>x</i>^•, <i>x</i> = 3,4), calling special attention to their various tautomeric structures together with p<i>K</i>_a values estimated from the Gibbs free energies of their dissociations (at the G4 and CAM-B3LYP levels of density functional theory). The energetics of microhydration clusters with up to four water molecules for the S-based species and up to eight water molecules for the P-based species were investigated. The number of microhydrating water molecules needed to induce spontaneous de-protonation is found to correlate the acid strength of each radical. According to the computed Gibbs free reaction and activation energies, S- and P-centered radicals preferentially add to the double bond of propene (a lipid model), whereas the O-centered radical tautomers prefer H-abstraction. The likely downstream reactions of these radicals in biological media are discussed.

<h4>Background</h4>Flowering signals are sensed in plant leaves and transmitted to the shoot apical meristems, where the formation of flowers is initiated. Searches for a diffusible hormone-like signaling entity ("florigen") went on for many decades, until a product of plant gene FT was identified as the key component of florigen in the 1990s, based on the analysis of mutants, genetic complementation evidence, and protein and RNA localization studies. Sequence homologs of FT protein are found throughout prokaryotes and eukaryotes; some eukaryotic family members appear to bind phospholipids or interact with the components of the signal transduction cascades. Most FT homologs are known to share a constellation of five charged residues, three of which, i.e., two histidines and an aspartic acid, are located at the rim of a well-defined cavity on the protein surface.<h4>Results</h4>We studied molecular features of the FT homologs in prokaryotes and analyzed their genome context, to find tentative evidence connecting the bacterial FT homologs with small molecule metabolism, often involving substrates that contain sugar or ribonucleoside moieties. We argue that the unifying feature of this protein family, i.e., a set of charged residues conserved at the sequence and structural levels, is more likely to be an enzymatic active center than a catalytically inert ligand-binding site.<h4>Conclusions</h4>We propose that most of FT-related proteins are enzymes operating on small diffusible molecules. Those metabolites may constitute an overlooked essential ingredient of the florigen signal.

Single-cell transcriptomic profiles analysis has proposed new insights for understanding the behavior of human gastric cancer (GC). GC offers a unique model of intratumoral heterogeneity. However, the specific classes of cells involved in carcinogenetic passage, and the tumor microenvironment of stromal cells was poorly understood. We characterized the heterogeneous cell population of precancerous lesions and gastric cancer at the single-cell resolution by RNA sequencing. We identified 10 gastric cell subtypes and showed the intestinal and diffuse-type cancer were characterized by different cell population. We found that the intestinal and diffuse-type cancer cells have the differential metaplastic cell lineages: intestinal-type cancer cells differentiated along the intestinal metaplasia lineage while diffuse-type cancer cells resemble de novo pathway. We observed an enriched CCND1 mutation in premalignant disease state and discovered cancer-associated fibroblast cells harboring pro-stemness properties. In particular, tumor cells could be categorized into previously proposed molecular subtypes and harbored specific subtype of malignant cell with high expression level of epithelial-myofibroblast transition which was correlated with poor clinical prognosis. In addition to intratumoral heterogeneity, the analysis revealed different cellular lineages were responsible for potential carcinogenetic pathways. Single-cell transcriptomes analysis of gastric pre-cancerous lesions and cancer may provide insights for understanding GC cell behavior, suggesting potential targets for the diagnosis and treatment of GC.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease involving symmetric joints and is generally characterized by persistent pain, tenderness, and destruction of joints. The vast majority of RA patients produce autoantibodies, and immune cell involvement in disease development is well recognized, as is the contribution of other types of cells in synovial tissue, like fibroblasts. It is known that there are major genetic associations with the HLA locus, while multiple non-HLA genetic variants display relatively low risk of RA. Both HLA and non-HLA associations suggest that the profiles of genetic associations for autoantibody-positive vs. autoantibody-negative RA are different. Several alleles of HLA-DRB1 are associated with high risk for autoantibody-positive RA, with the strongest risk characterized by valine at position 11 of the protein sequence (HLA-DRB1*04 and *10 alleles). There is a strong protective effect for the risk of autoantibody-positive RA associated with HLA-DRB1*13 alleles. Although major genetic associations have been known for several years, understanding of the specific mechanisms in the development of increased risk of RA for these variations is work in progress. Current studies focus on the binding of immune receptors involved in recognition of putative peptides in activation of T cells, as well as investigation of cell signaling mechanisms. At least a part of RA risk could be explained by gene-gene and gene-environment interactions. There are currently more than 150 candidate loci with polymorphisms that associate with RA, mainly related to seropositive disease, and new discoveries are anticipated in the future from investigation of diverse human populations. This new research will help create a strong foundation for the continuing process of integrating genetic, epigenetic, transcriptomic, and proteomic data in studies of RA.

Tuberculosis (TB) is the leading cause of death from a single infectious agent. The estimated total global TB deaths in 2019 were 1.4 million. The decline in TB incidence rate is very slow, while the burden of noncommunicable diseases (NCDs) is exponentially increasing in low- and middle-income countries, where the prevention and treatment of TB disease remains a great burden, and there is enough empirical evidence (scientific evidence) to justify a greater research emphasis on the syndemic interaction between TB and NCDs. The current study was proposed to build a disease-gene network based on overlapping TB with NCDs (overlapping means genes involved in TB and other/s NCDs), <i>such as</i> Parkinson's disease, cardiovascular disease, diabetes mellitus, rheumatoid arthritis, and lung cancer. We compared the TB-associated genes with genes of its overlapping NCDs to determine the gene-disease relationship. Next, we constructed the gene interaction network of disease-genes by integrating curated and experimentally validated interactions in humans and find the 13 highly clustered modules in the network, which contains a total of 86 hub genes that are commonly associated with TB and its overlapping NCDs, which are largely involved in the Inflammatory response, cellular response to cytokine stimulus, response to cytokine, cytokine-mediated signaling pathway, defense response, response to stress and immune system process. Moreover, the identified hub genes and their respective drugs were exploited to build a bipartite network that assists in deciphering the drug-target interaction, highlighting the influential roles of these drugs on apparently unrelated targets and pathways. Targeting these hub proteins by using drugs combination or drug repurposing approaches will improve the clinical conditions in comorbidity, enhance the potency of a few drugs, and give a synergistic effect with better outcomes. Thus, understanding the <i>Mycobacterium tuberculosis</i> (Mtb) infection and associated NCDs is a high priority to contain its short and long-term effects on human health. Our network-based analysis opens a new horizon for more personalized treatment, drug-repurposing opportunities, investigates new targets, multidrug treatment, and can uncover several side effects of unrelated drugs for TB and its overlapping NCDs.

<i>Colletotrichum scovillei</i> causes anthracnose of chili pepper in many countries. Three strains of this pathogen, Coll-524, Coll-153, and Coll-365, show varied virulence on chili pepper. Among the three strains, Coll-365 showed significant defects in growth and virulence. To decipher the genetic variations among these strains and identify genes contributing to growth and virulence, comparative genomic analysis and gene transformation to show gene function were applied in this study. Compared to Coll-524, Coll-153, and Coll-365 had numerous gene losses including 32 candidate effector genes that are mainly exist in acutatum species complex. A cluster of 14 genes in a 34-kb genomic fragment was lost in Coll-365. Through gene transformation, three genes in the 34-kb fragment were identified to have functions in growth and/or virulence of <i>C. scovillei. CsPLAA</i> encoding a phospholipase A2-activating protein enhanced the growth of Coll-365. A combination of CsPLAA with one transcription factor CsBZTF and one C6 zinc finger domain-containing protein CsCZCP was found to enhance the pathogenicity of Coll-365. Introduction of <i>CsGIP</i>, which encodes a hypothetical protein, into Coll-365 caused a reduction in the germination rate of Coll-365. In conclusion, the highest virulent strain Coll-524 had more genes and encoded more pathogenicity related proteins and transposable elements than the other two strains, which may contribute to the high virulence of Coll-524. In addition, the absence of the 34-kb fragment plays a critical role in the defects of growth and virulence of strain Coll-365.

<h4>Background</h4>Bladder cancer (BLCA) is a common malignant tumor of the urinary tract, which is the sixth most common cancer among men. Numerous studies suggested that pyroptosis and long noncoding RNAs (lncRNAs) played an essential role in the development of cancers. However, the role of pyroptosis-related lncRNAs in BLCA and their prognostic value are still unclear.<h4>Methods</h4>In this study, we constructed a signature model through least absolute shrinkage and selection operator (LASSO) Cox regression analysis and Cox univariate analysis based on The Cancer Genome Atlas (TCGA) database. The expression of 12 pyroptosis-related lncRNAs was also confirmed by qRT-PCR in BLCA cell lines. TIMER, XCELL, QUANTISEQ, MCPCOUNTER, EPIC, and CIBERSORT R script were applied to quantify the relative proportions of infiltrating immune cells. Correlation coefficients were computed by Spearman analyses. The Kaplan-Meier method, Cox regression model, and log-rank tests were used to evaluate the prognostic value. The R package of pRRophetic was used to predict IC50 of common chemotherapeutic agents.<h4>Results</h4>A total of 12 pyroptosis-related lncRNAs with great prognosis value were identified. The expression was investigated by qRT-PCR in four BLCA cell lines. Then, 126 cases were identified as high-risk group, and 277 cases were identified as low-risk group based on the cutoff point. Patients in the low-risk group showed a significant survival advantage. Furthermore, we found that clinical features were significantly related to the risk score. As well, based on the C-index values, a nomogram was constructed. The gene set enrichment analysis (GSEA) results showed that mitogen-activated protein kinase (MAPK) signaling, transforming growth factor (TGF)-β signaling, and WNT signaling were with important significance in the high-risk group. Moreover, we found that riskscore was positively correlated with M0 macrophages and M2 macrophages.<h4>Conclusions</h4>In conclusion, our study indicated that pyroptosis is closely connected to BLCA. The riskscore generated from the expression of 12 pyroptosis-related lncRNAs was evaluated by various clinical features including survival status, tumor microenvironment, clinicopathological characteristic, and chemotherapy. It may offer a significant basis for future studies.

Heterozygosity can effectively reflect the diverse models of population structure and demographic history. However, the genomic distribution of heterozygotes and the correlation between regions of heterozygosity (runs of heterozygosity, ROHet) and phenotypes are largely understudied in livestock. The objective of this study was to identify ROHet in the Duroc pig genome, and investigate the relationships between ROHet and eight important economic traits. Here, we genotyped 3,770 American Duroc (S21) and 2,096 Canadian Duroc (S22) pigs using 50 K single nucleotide polymorphism array to analyze heterozygosity. A total of 145,010 and 84,396 ROHets were characterized for S21 and S22 populations, respectively. ROHet segments were mostly enriched in 1-2 Mb length classification (75.48% in S21 and 72.25% in S22). The average genome length covered by ROHet was 66.53 ± 12.20 Mb in S21 and 73.32 ± 13.77 Mb in S22 pigs. Additionally, we detected 20 and 13 ROHet islands in S21 and S22 pigs. Genes in these genomic regions were mainly involved in the biological processes of immunity and reproduction. Finally, the genome-wide ROHet-phenotypes association analysis revealed that 130 ROHets of S21 and 84 ROHets of S22 were significantly associated with eight economic traits. Among the candidate genes in the significant ROHet regions, 16 genes related to growth, metabolism, and meat quality were considered as candidate genes for important economic traits of pigs. This work preliminarily explores the effect of heterozygosity-rich regions in the pig genome on production performance and provides new insights for subsequent research on pig genetic improvement.

Identifying cancer-related miRNAs (or microRNAs) that precisely target mRNAs is important for diagnosis and treatment of cancer. Creating novel methods to identify candidate miRNAs becomes an imminent Frontier of researches in the field. One major obstacle lies in the integration of the state-of-the-art databases. Here, we introduce a novel method, MIMRDA, which incorporates the <b>mi</b>RNA and <b>m</b>RNA expression profiles for predicting mi<b>R</b>NA-<b>d</b>isease <b>a</b>ssociations to identify key miRNAs. As a proof-of-principle study, we use the MIMRDA method to analyze TCGA datasets of 20 types (BLCA, BRCA, CESE, CHOL, COAD, ESCA, HNSC, KICH, KIRC, KIRP, LIHC, LUAD, LUSC, PAAD, PRAD, READ, SKCM, STAD, THCA and UCEC) of cancer, which identified hundreds of top-ranked miRNAs. Some (as Category 1) of them are endorsed by public databases including TCGA, miRTarBase, miR2Disease, HMDD, MISIM, ncDR and mTD; others (as Category 2) are supported by literature evidences. miR-21 (representing Category 1) and miR-1258 (representing Category 2) display the excellent characteristics of biomarkers in multi-dimensional assessments focusing on the function similarity analysis, overall survival analysis, and anti-cancer drugs' sensitivity or resistance analysis. We compare the performance of the MIMRDA method over the Limma and SPIA packages, and estimate the accuracy of the MIMRDA method in classifying top-ranked miRNAs via the Random Forest simulation test. Our results indicate the superiority and effectiveness of the MIMRDA method, and recommend some top-ranked key miRNAs be potential biomarkers that warrant experimental validations.

Long non-coding RNAs (lncRNAs) are non-protein coding RNAs with more than 200 nucleic acids in length. When lncRNAs are located in the nucleus, they regulate chromosome structure, participate in chromatin remodeling, and act as transcription regulators. When lncRNAs are exported to the cytoplasm, they regulate mRNA stability, regulate translation, and interfere with post-translational modification. In recent years, more and more evidences have shown that lncRNA can regulate the biological processes of tumor proliferation, apoptosis, invasion and metastasis, and can participate in a variety of tumor signaling pathways. Long-gene non-protein coding RNA641 (LINC00641), located on human chromosome 14q11.2, is differentially expressed in a variety of tumors and is related to overall survival and prognosis, etc. Interfering the expression of LINC00641 can lead to changes in tumor cell proliferation, invasion, metastasis, apoptosis and other biological behaviors. Therefore, LINC00641 is a promising new biomarker and potential clinical therapeutic target. In this review, the biological functions, related mechanisms and clinical significance of LINC00641 in many human cancers are described in detail.

Colorectal cancer stem cells (CRCSCs) can actively self-renew, as well as having multidirectional differentiation and tumor regeneration abilities. Because the high functional activities of CRCSCs are associated with low cure rates in patients with colorectal cancer, efforts have sought to determine the function and regulatory mechanisms of CRCSCs. To date, however, the potential regulatory mechanisms of CRCSCs remain incompletely understood. Many non-coding genes are involved in tumor invasion and spread through their regulation of CRCSCs, with long non-coding RNAs (lncRNAs) being important non-coding RNAs. LncRNAs may be involved in the colorectal cancer development and drug resistance through their regulation of CRCSCs. This review systematically evaluates the latest research on the ability of lncRNAs to regulate CRCSC signaling pathways and the involvement of these lncRNAs in colorectal cancer promotion and suppression. The regulatory network of lncRNAs in the CRCSC signaling pathway has been determined. Further analysis of the potential clinical applications of lncRNAs as novel clinical diagnostic and prognostic biomarkers and therapeutic targets for colorectal cancer may provide new ideas and protocols for the prevention and treatment of colorectal cancer.

Cognitive function is a crucial determinant of human capital. The Lancet Commission (2020) has recognized air pollution as a risk factor for dementia. However, the scientific evidence on the impact of air pollution on cognitive outcomes across the life course and across different income settings, with varying levels of air pollution, needs further exploration. A systematic review was conducted, using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Guidelines to assess the association between air pollution and cognitive outcomes across the life course with a plan to analyze findings as per the income status of the study population. The PubMed search included keywords related to cognition and to pollution (in their titles) to identify studies on human participants published in English until 10 July 2020. The search yielded 84 relevant studies that described associations between exposure to air pollutants and an increased risk of lower cognitive function among children and adolescents, cognitive impairment and decline among adults, and dementia among older adults with supportive evidence of neuroimaging and inflammatory biomarkers. No study from low- and middle-income countries (LMICs)was identified despite high levels of air pollutants and high rates of dementia. To conclude, air pollution may impair cognitive function across the life-course, but a paucity of studies from reLMICs is a major lacuna in research.

Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM), a metabolic disorder characterized by elevation in blood glucose level. The pathogenesis of DR includes vascular, neuronal, and inflammatory components leading to activation of complex cellular molecular signaling. If untreated, the disease can culminate in vision loss that eventually leads to blindness. Animal models mimicking different aspects of DM complications have been developed to study the development and progression of DR. Despite the significant contribution of the developed DR models to discovering the mechanisms of DR and the recent achievements in the research field, the sequence of cellular events in diabetic retinas is still under investigation. Partially, this is due to the complexity of molecular mechanisms, although the lack of availability of models that adequately mimic all the neurovascular pathobiological features observed in patients has also contributed to the delay in determining a precise molecular trigger. In this review, we provide an update on the status of animal models of DR to help investigators choose an appropriate system to validate their hypothesis. We also discuss the key cellular and physiological events of DR in these models.

Damage to organs by trauma, infection, diseases, congenital defects, aging, and other injuries causes organ malfunction and is life-threatening under serious conditions. Some of the lower order vertebrates such as zebrafish, salamanders, and chicks possess superior organ regenerative capacity over mammals. The extracellular signal-regulated kinases 1 and 2 (ERK1/2), as key members of the mitogen-activated protein kinase (MAPK) family, are serine/threonine protein kinases that are phylogenetically conserved among vertebrate taxa. MAPK/ERK signaling is an irreplaceable player participating in diverse biological activities through phosphorylating a broad variety of substrates in the cytoplasm as well as inside the nucleus. Current evidence supports a central role of the MAPK/ERK pathway during organ regeneration processes. MAPK/ERK signaling is rapidly excited in response to injury stimuli and coordinates essential pro-regenerative cellular events including cell survival, cell fate turnover, migration, proliferation, growth, and transcriptional and translational activities. In this literature review, we recapitulated the multifaceted MAPK/ERK signaling regulations, its dynamic spatio-temporal activities, and the profound roles during multiple organ regeneration, including appendages, heart, liver, eye, and peripheral/central nervous system, illuminating the possibility of MAPK/ERK signaling as a critical mechanism underlying the vastly differential regenerative capacities among vertebrate species, as well as its potential applications in tissue engineering and regenerative medicine.

Phosphoantigens (pAgs) are small organophosphorus compounds such as (<i>E</i>)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) that trigger an immune response. These molecules bind to butyrophilin 3A1 (part of the HMBPP receptor) and activate Vγ9Vδ2 T cells. To explore the structure-activity relationships underlying this process, we evaluated a series of novel diene analogs of HMBPP. Here we report that prodrug forms of [(1<i>E</i>)-4-methylpenta-1,3-dien-1-yl] phosphonic acid that lack the allylic alcohol of HMBPP but instead contained a diene scaffold exhibit mid-nanomolar potency for the activation of Vγ9Vδ2 T cells. The compounds also trigger the production of T-cell interferon γ upon exposure to loaded K562 cells. Although both the allylic alcohol and the diene scaffold boost pAg activity, the combination of the two decreases the activity and results in glutathione conjugation. Together, these data show that the diene scaffold results in intermediate pAgs that may have implications for the mechanisms regulating the HMBPP receptor.

Several biologic therapies that target inflammatory modulators are now used for treating patients with uncontrolled, severe asthma. Knowledge about how this type of treatment modifies the molecular milieu is rapidly increasing. Thus, this systematic review aimed to compile the reported effects of therapeutic antibodies on the transcriptome or proteome of asthma patients. Studies of asthmatic patients under biological treatment describing transcriptomic or proteomic changes upon treatment were included. Preclinical or single gene/protein studies were not considered. PubMed and Scopus search was performed in August and September 2021. Following PRISMA guidelines and GRADE recommendations, we selected 12 studies on gene or protein expression changes in patients treated with the antibodies currently approved by EMA and the FDA. All studies were at low risk of bias as per the RoB2 tool. Different gene clusters have been identified to change upon omalizumab treatment, found a reduction in eosinophil-associated gene signatures after benralizumab treatment, and protein profiles were different in patients treated with mepolizumab and in those treated with benralizumab. The main potential biomarkers proposed by the selected studies are shown. These results may contribute to discovering biomarkers of response and selecting the best therapy for each patient.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by a complex network of physiopathological events where oxidative stress plays a central role among other factors such as neuroinflammation and protein homeostasis. Nuclear factor-erythroid 2 p45-related factor 2 (NRF2) has a multitarget profile itself as it controls a plethora of cellular processes involved in the progression of the disease. In this line, we designed a novel family of 2-(1<i>H</i>-indol-3-yl)ethan-1-amine derivatives as NRF2 inducers with complementary activities. Novel compounds are based on melatonin scaffold and include, among other properties, selective monoamine oxidase B (MAO-B) inhibition activity. Novel multitarget compounds exhibited NRF2 induction activity and MAO-B selective inhibition, combined with anti-inflammatory, antioxidant, and blood-brain barrier permeation properties. Furthermore, they exert neuroprotective properties against oxidative stress toxicity in PD-related in vitro. Hit compound <b>14</b> reduced oxidative stress markers and exerted neuroprotection in rat striatal slices exposed to 6-hydroxydopamine or rotenone. In conclusion, we developed a promising family of dual NRF2 inducers and selective MAO-B inhibitors that could serve as a novel therapeutic strategy for PD treatment.

Interferons (IFNs) are a family of cytokines that play a pivotal role in orchestrating the innate immune response during viral infections, thus representing the first line of defense in the host. After binding to their respective receptors, they are able to elicit a plethora of biological activities, by initiating signaling cascades which lead to the transcription of genes involved in antiviral, anti-inflammatory, immunomodulatory and antitumoral effector mechanisms. In hindsight, it is not surprising that viruses have evolved multiple IFN escape strategies toward efficient replication in the host. Hence, in order to achieve insight into preventive and treatment strategies, it is essential to explore the mechanisms underlying the IFN response to viral infections and the constraints thereof. Accordingly, this review is focused on three RNA and three DNA viruses of major importance in the swine farming sector, aiming to provide essential data as to how the IFN system modulates the antiviral immune response, and is affected by diverse, virus-driven, immune escape mechanisms.

<b>Background:</b> iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. <b>Methods</b>: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. <b>Results</b>: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19.     <b>Conclusions</b>: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

Condensin is a multi-subunit structural maintenance of chromosomes (SMC) complex that binds to and compacts chromosomes. Here, we addressed the regulation of condensin binding dynamics using Caenorhabditis elegans condensin DC, which represses X chromosomes in hermaphrodites for dosage compensation. We established fluorescence recovery after photobleaching (FRAP) using the SMC4 homolog DPY-27 and showed that a well-characterized ATPase mutation abolishes DPY-27 binding to X chromosomes. Next, we performed FRAP in the background of several chromatin modifier mutants that cause varying degrees of X chromosome derepression. The greatest effect was in a null mutant of the H4K20me2 demethylase DPY-21, where the mobile fraction of condensin DC reduced from ∼30% to 10%. In contrast, a catalytic mutant of dpy-21 did not regulate condensin DC mobility. Hi-C sequencing data from the dpy-21 null mutant showed little change compared to wild-type data, uncoupling Hi-C-measured long-range DNA contacts from transcriptional repression of the X chromosomes. Taken together, our results indicate that DPY-21 has a non-catalytic role in regulating the dynamics of condensin DC binding, which is important for transcription repression.

<h4>Aim</h4>Obesity is a significant health issue for participants with type 1 diabetes undergoing intensive diabetes management. The temporal pattern and factors associated with weight gain after treatment initiation remain poorly understood including how weight gain in participants with and without type I diabetes compare. Our aim was to compare weight gain in those receiving intensive (INT) and conventional (CONV) type 1 diabetes treatment to a population without diabetes.<h4>Methods</h4>Participants included men and women of 18 years and older in the Diabetes Control and Complications Trial (DCCT) randomized to INT (n = 562) or CONV (n = 568) and a prospective, observational cohort without diabetes from the Coronary Artery Development in Young Adults (CARDIA, controls) study (n = 2446). Body mass index (BMI) trajectories and obesity prevalence were compared between groups and candidate metabolic and therapeutic moderators investigated.<h4>Results</h4>Annual weight gain with INT peaked 1.3 years after initiation and was greater than both CONV and controls before and after this peak. Obesity prevalence with INT was lower than controls at baseline, was similar to controls at 2 years and surpassed controls by 5 years. Obesity rates with CONV remained below controls at all time points. Greater annual weight gain in the DCCT was associated with lower haemoglobin A_1c , higher insulin dose and family history of type 2 diabetes.<h4>Conclusions</h4>Greater weight gain accompanying INT therapy occurs in two stages, leads to similar or greater obesity rates than controls after 2 years and is primarily modified by glucose control and family history, supportive of a therapeutic-genetic influence on weight trajectories.

Whether induced tissue-resident memory T (T_RM) cells in nonlymphoid organs alone can mediate allograft rejection is unknown. By grafting alloskin or heart into severe combined immunodeficient or Rag2KO mice in which a piece of induced CD4⁺ and/or CD8⁺ T_RM cell-containing MHC-matched or syngeneic skin was transplanted in advance, we addressed this issue. The induced CD4⁺ T_RM cells in the skin alone acutely rejected alloskin or heart grafts. RNA-seq analysis showed that induced CD4⁺ T_RM cells in skin favorably differentiated into T_H17-like polarization during the secondary immune response. Inhibition of the key T_H17 signaling molecule RORγt attenuated T_RM cell-mediated graft rejection. Thus, we offer a unique mouse model to specifically study T_RM cell-mediated allograft rejection without the involvement of lymphocytes in lymphoid organs and tissues. Our study provides strong evidence supporting the hypothesis that long-lived alloreactive T_RM cells resident in other organs/tissues substantially contribute to organ allograft rejection.

Tuberculosis constitutes a global emergency as it affects one-third of the world's inhabitants. Although Pulmonary tuberculosis (PTB) is curable, immunological responses to the infection induce several hematological derangements. This study evaluated the effect of PTB on natural anticoagulant activity and CBC indices. Ninety adults were recruited: 60 PTB patients and 30 non-TB controls. Blood specimens from each participant was tested for Proteins C and S, Antithrombin-III and CBC. Pulmonary TB was associated with significantly reduced Protein C activity (101.46 [87.61-128.3] vs 121.44 [99.50-149.8] IU/L, <i>p</i>= 0.038), RBC (<i>p</i>< 0.0001), HgB (<i>p</i>= 0.0019), HCT (<i>p</i>< 0.0001), MCV (<i>p</i>= 0.0133) and PDW (<i>p</i>< 0.0001) compared to controls. Conversely, PTB patients were associated with significantly increased MCH (<i>p</i>= 0.0086), TWBC (<i>p</i>= 0.0047), Abs. GRAN (<i>p</i>= 0.0226), RDW-CV (<i>p</i>< 0.0001), MCHC (<i>p</i>< 0.0001) and MPV (<i>p</i>= 0.0027) compared to controls. The PTB patients were disproportionately affected with anemia (91.7%, <i>p</i>= 0.001), erythrocytopenia (75.0%, <i>p</i>≤ 0.001) and reduced HCT (80.0%, <i>p</i>≤ 0.001). The frequency of thrombocytosis, leucocytosis, and granulocytosis (50.0%, <i>p</i>= 0.013; 23.3%, <i>p</i>= 0.013; 18.3%, <i>p</i>= 0.025; respectively) in PTB patients were significantly higher than in controls. PTB predisposes to hypercoagulability and causes derangements in erythrocytes, leucocytes, and thrombocytes, and disproportionately causes anemia. Measurement of Protein C activity and CBC indices are useful in the management of PTB patients.

Tau protein accumulation drives toxicity in several neurodegenerative disorders. To better understand the pathways regulating tau homeostasis in disease, we investigated the role of ubiquilins (UBQLNs)-a class of proteins linked to ubiquitin-mediated protein quality control (PQC) and various neurodegenerative diseases-in regulating tau. Cell-based assays identified UBQLN2 as the primary brain-expressed UBQLN to regulate tau. UBQLN2 efficiently lowered wild-type tau levels regardless of aggregation, suggesting that UBQLN2 interacts with and regulates tau protein under normal conditions or early in disease. Moreover, UBQLN2 itself proved to be prone to accumulation as insoluble protein in male and female tau transgenic mice and the human tauopathy progressive supranuclear palsy. Genetic manipulation of UBQLN2 in a tauopathy mouse model demonstrated that a physiological UBQLN2 balance is required for tau homeostasis. UBQLN2 overexpression exacerbated phosphorylated tau pathology and toxicity in mice expressing P301S mutant tau, whereas P301S mice lacking UBQLN2 showed significantly reduced phosphorylated tau. Further studies support the view that an imbalance of UBQLN2 perturbs ubiquitin-dependent PQC and autophagy. We conclude that changes in UBQLN2 levels, whether because of pathogenic mutations or secondary to disease states, such as tauopathy, contribute to proteostatic imbalances that exacerbate neurodegeneration.<b>SIGNIFICANCE STATEMENT</b> We defined a role for the protein quality control protein Ubiquilin-2 (UBQLN2), in age-related neurodegenerative tauopathies. This group of disorders is characterized by the accumulation of tau protein aggregates, which differ when UBQLN2 levels are altered. Given the lack of effective disease-modifying therapies for tauopathies and the function of UBQLN2 in handling various disease-linked proteins, we explored the role of UBQLN2 in regulating tau. We found that UBQLN2 reduced tau levels in cell models but behaved differently in mouse brain, where it accelerated mutant tau pathology and tau-mediated toxicity. A better understanding of the diverse functions of regulatory proteins like UBQLN2 can elucidate some of the causative factors in neurodegenerative disease and outline new routes to therapeutic intervention.

T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.

Protein aggregation is a hallmark of neurodegeneration. Here, we find that Huntington's disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while ALS-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis. Further exploring chaperone function as potential modifiers of pathological aggregation in these contexts, we reveal divergent effects of naturally-occurring chaperone isoforms on different aggregate types. We identify a complex of the full-length (FL) DNAJB14 and DNAJB12, that substantially protects from mutFUS aggregation, in an HSP70-dependent manner. Their naturally-occurring short isoforms, however, do not form a complex, and lose their ability to preclude mutFUS aggregation. In contrast, DNAJB12-short alleviates, while DNAJB12-FL aggravates, HTT-polyQ aggregation. DNAJB14-FL expression increases the mobility of mutFUS aggregates, and restores the deteriorated proteostasis in mutFUS aggregate-containing cells and primary neurons. Our results highlight a maladaptive cellular response to pathological aggregation, and reveal a layer of chaperone network complexity conferred by DNAJ isoforms, in regulation of different aggregate types.

<h4>Background</h4>Isolated Hypogonadotropic Hypogonadism (IHH) is a clinical syndrome that results from gonadal failure due to abnormal pituitary gonadotropin levels, in the presence of normal baseline and reserve testing of the remaining pituitary hormones.<h4>Case presentation</h4>An 18 years old female came with primary amenorrhea, accompanied by poor breast and pubic development, with low levels of estradiol and gonadotropins but normal levels of other anterior pituitary hormones. Imaging of the hypothalamic-pituitary region revealed hypophyseal hypoplasia due to ischemia. Sex steroids therapy was given to induce pubertal development. IHH represents a rare condition but with a good prognosis.<h4>Discussion</h4>Early diagnosis and treatment can prevent negative physical and psychological sequelae, and restore fertility in affected patients. Constant surveillance is required due to the possibility of gonadal axis reversal and/or relapse of gonadal axis failure and to identify any adverse effects related to therapy.<h4>Conclusion</h4>Early identification of IHH can help in treatment efficiency.

All brain functionality arises from the activity in neural circuits in different anatomical regions. These regions contain different circuits comprising unique cell types. An integral part to understanding neural circuits is a full census of the constituent parts, i.e., the neural cell types. This census can be based on different characteristics. Previously combinations of morphology and physiology, gene expression, and chromatin accessibility have been used in various cortical and subcortical regions. This has given an extensive yet incomplete overview of neural cell types. However, these techniques have not been applied to all brain regions. Here we apply single cell analysis of accessible chromatin on two similar but different cortical regions, the medial and the lateral entorhinal cortices. Even though these two regions are anatomically similar, their intrinsic and extrinsic connectivity are different. In 4,136 cells we identify 20 different clusters representing different cell types. As expected, excitatory cells show regionally specific clusters, whereas inhibitory neurons are shared between regions. We find that several deep layer excitatory neuronal cell types as defined by chromatin profile are also shared between the two different regions. Integration with a larger scRNA-seq dataset maintains this shared characteristic for cells in Layer Vb. Interestingly, this layer contains three clusters, two specific to either subregion and one shared between the two. These clusters can be putatively associated with particular functional and anatomical cell types found in this layer. This information is a step forwards into elucidating the cell types within the entorhinal circuit and by extension its functional underpinnings.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in translation by linking amino acids onto their cognate tRNAs during protein synthesis. During evolution, aaRSs develop numerous non-canonical functions that expand the roles of aaRSs in eukaryotic organisms. Although aaRSs have been implicated in viral infection, the function of aaRSs during infections with coronaviruses (CoVs) remains unclear. Here, we analyzed the data from transcriptomic and proteomic database on human cytoplasmic (cyto) and mitochondrial (mt) aaRSs across infections with three highly pathogenic human CoVs, with a particular focus on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We found an overall downregulation of <i>aaRSs</i> at mRNA levels, while the protein levels of some mt-aaRSs and the phosphorylation of certain aaRSs were increased in response to SARS-CoV-2 infection. Strikingly, interaction network between SARS-CoV-2 and human aaRSs displayed a strong involvement of mt-aaRSs. Further co-immunoprecipitation (co-IP) experiments confirmed the physical interaction between SARS-CoV-2 M protein and TARS2. In addition, we identified the intermediate nodes and potential pathways involved in SARS-CoV-2 infection. This study provides an unbiased, overarching perspective on the correlation between aaRSs and SARS-CoV-2. More importantly, this work identifies TARS2, HARS2, and EARS2 as potential key factors involved in COVID-19.

<h4>Background</h4>An increasing number of RNA modification types other than N⁶-methyladenosine (m⁶A) modification have been detected. Nonetheless, the probable functions of RNA modifications beyond m⁶A in the tumor microenvironment (TME), mesenchymal (MES) transition, immunotherapy, and drug sensitivity remain unclear.<h4>Methods</h4>We analyzed the characteristics of 32 non-m⁶A RNA modification regulators in 539 glioblastoma (GBM) patients and the TME cell infiltration and MES transition patterns. Using principal component analysis, a non-m⁶A epitranscriptome regulator score (RM score) model was established. We estimated the association between RM score and clinical characteristics, TME status, GBM subtypes, and drug and immunotherapy response.<h4>Results</h4>Three definite non-m⁶A RNA modification patterns associated with diverse biological pathways and clinical characteristics were identified. The high RM score group was characterized by a poor prognosis, enhanced immune infiltration, and MES subtype. Further analysis indicated that the high RM score group had a lower tumor mutation burden as well as a weaker response to immunotherapy. The higher RM score group may benefit more from drugs targeting the EGFR and WNT signaling pathways.<h4>Conclusion</h4>Our study exposed the potential relationship of non-m⁶A RNA modification regulators with clinical features, TME status, and GBM subtype and clarified its therapeutic value.

Gastric cancer has developed as a very common gastrointestinal tumors, with recent effective advancements in the diagnosis and treatment of early gastric cancer. However, the prognosis for gastric cancer remains poor. As a result, there is in sore need of better understanding the mechanisms of gastric cancer development and progression to improve existing diagnostic and treatment options. In recent years, epigenetics has been recognized as an important contributor on tumor progression. Epigenetic changes in cancer include chromatin remodeling, DNA methylation and histone modifications. An increasing number of studies demonstrated that noncoding RNAs (ncRNAs) are associated with epigenetic changes in gastric cancer. Herein, we describe the molecular interactions of histone modifications and ncRNAs in epigenetics. We focus on ncRNA-mediated histone modifications of gene expression associated with tumorigenesis and progression in gastric cancer. This molecular mechanism will contribute to our deeper understanding of gastric carcinogenesis and progression, thus providing innovations in gastric cancer diagnosis and treatment strategies.

The "writers" of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification "writers" in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification "writer" scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these "writers" essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.

Dual Energy X-ray Absorptiometry (DXA) is a tool that allows the assessment of bone density. It was first presented by Cameron and Sorenson in 1963 and was approved by the Food and Drug Administration. Misplacing the femoral neck box, placing a trochanteric line below the midland and improper placement of boundary lines are the most common errors made during a DXA diagnostic test made by auto analysis. Hydroxyapatite is the most important inorganic component of teeth and bone tissue. It is estimated to constitute up to 70% of human bone weight and up to 50% of its volume. Calcium phosphate comes in many forms; however, studies have shown that only tricalcium phosphate and hydroxyapatite have the characteristics that allow their use as bone-substituted materials. The purpose of this study is aimed at analyzing the results of hip densitometry and hydorxyapatite distribution in order to better assess the structure and mineral density of the femoral neck. However, a detailed analysis of the individual density curves shows some qualitative differences that may be important in assessing bone strength in the area under study. To draw more specific conclusions on the therapy applied for individual patients, we need to determine the correct orientation of the bone from the resulting density and document the trends in the density distribution change. The average results presented with the DXA method are insufficient.

T-cell intracellular antigen 1 (TIA1) is an RNA-binding protein that is expressed in many tissues and in the vast majority of species, although it was first discovered as a component of human cytotoxic T lymphocytes. TIA1 has a dual localization in the nucleus and cytoplasm, where it plays an important role as a regulator of gene-expression flux. As a multifunctional master modulator, TIA1 controls biological processes relevant to the physiological functioning of the organism and the development and/or progression of several human pathologies. This review summarizes our current knowledge of the molecular aspects and cellular processes involving TIA1, with relevance for human pathophysiology.

Glioblastoma is the most aggressive and invasive form of central nervous system tumors due to the complexity of the intracellular mechanisms and molecular alterations involved in its progression. Unfortunately, current therapies are unable to stop its neoplastic development. In this context, we previously identified and characterized AaTs-1, a tetrapeptide (IWKS) from <i>Androctonus autralis</i> scorpion venom, which displayed an anti-proliferative effect against U87 cells with an IC₅₀ value of 0.57 mM. This peptide affects the MAPK pathway, enhancing the expression of p53 and altering the cytosolic calcium concentration balance, likely via FPRL-1 receptor modulation. In this work, we designed and synthesized new dendrimers multi-branched molecules based on the sequence of AaTs-1 and showed that the di-branched (AaTs-1-2B), tetra-branched (AaTs-1-4B) and octo-branched (AaTs-1-8B) dendrimers displayed 10- to 25-fold higher effects on the proliferation of U87 cells than AaTs-1. We also found that the effects of the newly designed molecules are mediated by the enhancement of the ERK1/2 and AKT phosphorylated forms and by the increase in p53 expression. Unlike AaTs-1, AaTs-1-8B and especially AaTs-1-4B affected the migration of the U87 cells. Thus, the multi-branched peptide synthesis strategy allowed us to make molecules more active than the linear peptide against the proliferation of U87 glioblastoma cells.

<h4>Background</h4>The study provides real-world data on the impact of Huntington's disease (HD) from the perspective of individuals with HD (IHD) and care partners (HD-CP) and contextualizes these results relative to Parkinson's disease (PD) and the general population (GP).<h4>Methods</h4>Cross-sectional survey of IHD and HD-CP in the US (July 2019-August 2019) conducted using the Rare Patient Voice panel. Data for individuals with Parkinson's Disease (IPD), the general population (GP), and respective care partners (PD-CP; GP-CP) came from the 2018 US National Health and Wellness Survey. Outcomes included demographics, mental health, clinical characteristics, and health-related quality of life (HRQoL).<h4>Results</h4>IHD had greater comorbid anxiety (IHD = 51.2%, IPD = 28.8%, GP = 2.0%), and HD-CP had greater comorbid anxiety (HD-CP = 52.5%, PD-CP = 28.6%, GP-CP = 19.6%) and depression (HD-CP = 65.0%, PD-CP = 29.9%, GP-CP = 19.6%), relative to other cohorts (<i>p</i> < 0.05). Respective of their GP cohorts, IHD exhibited lower HRQoL (EQ-5D: 0.66 ± 0.21 vs. 0.81 ± 0.17) and greater depression (PHQ-9: 11.59 ± 7.20 vs. 5.85 ± 6.71), whereas HD-CP exhibited greater depression only (PHQ-9: 6.84 ± 6.38 vs. 4.15 ± 5.58) (<i>p</i> < 0.001). No differences were observed between HD/HD-CP and PD/PD-CP cohorts on PHQ-9 or HRQoL.<h4>Conclusions</h4>HD has a significant burden on patients and care partners, which is higher than GP. Notably, anxiety and depression were greater among HD vs. PD, despite similar HRQoL.

The raising prevalence of obesity is associated with an increased risk for cardiovascular diseases (CVDs), particularly coronary artery disease (CAD), and heart failure, including atrial fibrillation, ventricular arrhythmias and sudden death. Obesity contributes directly to incident cardiovascular risk factors, including hyperglycemia or diabetes, dyslipidemia, and hypertension, which are involved in atherosclerosis, including structural and functional cardiac alterations, which lead to cardiac dysfunction. CVDs are the main cause of morbidity and mortality worldwide. In obesity, visceral and epicardial adipose tissue generate inflammatory cytokines and reactive oxygen species (ROS), which induce oxidative stress and contribute to the pathogenesis of CVDs. Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by <i>Nfe2l2</i> gene) protects against oxidative stress and electrophilic stress. NRF2 participates in the regulation of cell inflammatory responses and lipid metabolism, including the expression of over 1000 genes in the cell under normal and stressed environments. NRF2 is downregulated in diabetes, hypertension, and inflammation. <i>Nfe2l2</i> knockout mice develop structural and functional cardiac alterations, and NRF2 deficiency in macrophages increases atherosclerosis. Given the endothelial and cardiac protective effects of NRF2 in experimental models, its activation using pharmacological or natural products is a promising therapeutic approach for obesity and CVDs. This review provides a comprehensive summary of the current knowledge on the role of NRF2 in obesity-associated cardiovascular risk factors.

The impact of germline variants on the regulation of the expression of tumor microenvironment (TME)-based immune response genes remains unclear. Expression quantitative trait loci (eQTL) provide insight into the effect of downstream target genes (eGenes) regulated by germline-associated variants (eVariants). Through eQTL analyses, we illustrated the relationships between germline eVariants, TME-based immune response eGenes, and clinical outcomes. In this study, both RNA sequencing data from primary tumor and germline whole-genome sequencing data were collected from patients with stage III colorectal cancer (CRC). Ninety-nine high-risk subjects were subjected to immune response gene expression analyses. Seventy-seven subjects remained for further analysis after quality control, of which twenty-two patients (28.5%) experienced tumor recurrence. We found that 65 eQTL, including 60 germline eVariants and 22 TME-based eGenes, impacted the survival of cancer patients. For the recurrence prediction model, 41 differentially expressed genes (DEGs) achieved the best area under the receiver operating characteristic curve of 0.93. In total, 19 survival-associated eGenes were identified among the DEGs. Most of these genes were related to the regulation of lymphocytes and cytokines. A high expression of <i>HGF</i>, <i>CCR5</i>, <i>IL18</i>, <i>FCER1G</i>, <i>TDO2</i>, <i>IFITM2</i>, and <i>LAPTM5</i> was significantly associated with a poor prognosis. In addition, the <i>FCER1G</i> eGene was associated with tumor invasion, tumor nodal stage, and tumor site. The eVariants that regulate the TME-based expression of <i>FCER1G</i>, including rs2118867 and rs12124509, were determined to influence survival and chromatin binding preferences. We also demonstrated that <i>FCER1G</i> and co-expressed genes in TME were related to the aggregation of leukocytes via pathway analysis. By analyzing the eQTL from the cancer genome using germline variants and TME-based RNA sequencing, we identified the eQTL in immune response genes that impact colorectal cancer characteristics and survival.

Over the past decade, the secondary analysis of existing DNA datasets for clinical resulting has become an established practice. However, this established practice is typically limited to only one category of secondary genomic findings, the identification of "disease risk". Diagnostic resulting has been left out of secondary genomic findings. In medical practice, diagnostic resulting is triggered when a test is ordered for a patient based on a recognizable clinical indication for evaluation; most genetic and genomic testing is carried out in support of diagnostic evaluations. The secondary analysis of existing DNA data has the potential to cost less and have more rapid turnaround times for <i>diagnostic results</i> compared to current DNA diagnostic approaches that typically generate a new dataset with every test ordered. Worldwide, innovative health systems could position themselves to deliver valid secondary genomic finding results in both the established category of <i>disease risk results</i>, as well as a new category of <i>diagnostic results</i>. To support the ongoing delivery of both categories of secondary findings, health systems will need comprehensive genomic datasets for patients and secure workflows that allow for repeated access to that data for on-demand secondary analysis.

Cartilage diseases currently affect a high percentage of the world's population. Almost all of these diseases, such as osteoarthritis (OA), cause inflammation of this soft tissue. However, this could be controlled with biomaterials that act as an anti-inflammatory delivery system, capable of dosing these drugs over time in a specific area. The objective of this study was to incorporate etanercept (ETA) into porous three-layer scaffolds to decrease the inflammatory process in this soft tissue. ETA is a blocker of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). For this reason, the scaffold was built based on natural polymers, including chitosan and type I collagen. The scaffold was grafted next to subchondral bone using hydroxyapatite as filler. One of the biomaterials obtained was also crosslinked to compare its mechanical properties with the non-treated one. Both samples' physicochemical properties were studied with SEM, micro-CT and photoacoustic imaging, and their rheological properties were also compared. The cell viability and proliferation of the human chondrocyte C28/I2 cell line were studied in vitro. An in vitro and in vivo controlled release study was evaluated in both specimens. The ETA anti-inflammatory effect was also studied by in vitro TNF-α and IL-6 production. The crosslinked and non-treated scaffolds had rheological properties suitable for this application. They were non-cytotoxic and favoured the in vitro growth of chondrocytes. The in vitro and in vivo ETA release showed desirable results for a drug delivery system. The TNF-α and IL-6 production assay showed that this drug was effective as an anti-inflammatory agent. In an in vivo OA mice model, safranin-O and fast green staining was carried out. The OA cartilage tissue improved when the scaffold with ETA was grafted in the damaged area. These results demonstrate that this type of biomaterial has high potential for clinical applications in tissue engineering and as a controlled drug delivery system in OA articular cartilage.

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression was enriched in the myogenic progenitors of the cardiac outflow tract. Moreover, subsets of the candidate genes were found in specific gene coexpression modules along the cardiomyocyte differentiation trajectory. These integrative functional analyses help dissect the pathogenesis of TOF, revealing cellular hotspots in early heart development resulting in cardiac malformations.

Design and synthesis of pseudo-natural products (PNPs) through recombination of natural product (NP) fragments in unprecedented arrangements enables the discovery of novel biologically relevant chemical matter. With a view to wider coverage of NP-inspired chemical and biological space, we describe the combination of this principle with macrocycle formation. PNP-macrocycles were synthesized efficiently in a stereoselective one-pot procedure including the 1,3-dipolar cycloadditions of different dipolarophiles with dimeric cinchona alkaloid-derived azomethine ylides formed in situ. The 20-membered bis-cycloadducts embody 18 stereocenters and an additional fragment-sized NP-structure. After further functionalization, a collection of 163 macrocyclic PNPs was obtained. Biological investigation revealed potent inducers of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy-related processes.

<h4>Background</h4>Proprotein convertase subtilisin/kexin type 9 (PCSK9) participates in the development of various cancers, including hepatocellular carcinoma (HCC). Here, we attempted to reveal the underlying mechanism of PCSK9 in HCC.<h4>Methods</h4>Tumor tissues and adjacent tissues were separated from HCC patients to detect PCSK9 expression. Then, PCSK9 was overexpressed or silenced in HCC cells (MHCC97H or Huh7), and then the cell supernatant was incubated with THP-1 macrophages. OX40L neutralizing antibody (nAb) was used to inhibit OX40L activity. The expression of macrophage markers was examined by immunohistochemical staining and flow cytometry. Finally, tumor-bearing mouse model was constructed by inoculation of LV-PCSK9 infected MHCC97H cells to verify the role of PCSK in HCC.<h4>Results</h4>PCSK9 expression was decreased in tumor tissues of HCC patient specimens. HCC patients displayed M2 macrophage infiltration in tumor tissues. Moreover, PCSK9-silenced Huh7 cell supernatant promoted cell migration, and enhanced the proportion of CD206-positive cells and the expression of M2 macrophage markers IL-10 and ARG-1 in THP-1 macrophages. PCSK9-overexpressing MHCC97H cell supernatant inhibited THP-1 macrophage migration and M2-like tumor-associated macrophage (TAM) polarization, which was abolished by OX40L nAb treatment. PCSK9 overexpression enhanced the expression of OX40L in MHCC97H cells. In tumor-bearing mouse models, PCSK9 overexpression inhibited tumor growth and M2 polarization of TAMs in HCC by promoting OX40L expression. Conclusion: This work demonstrated that PCSK9 suppressed M2-like TAM polarization by regulating the secretion of OX40L from hepatocellular carcinoma cells. This study suggests that PCSK9 may be a potential target for HCC treatment.

<h4>Background</h4>Virtual Reality (VR) training is emerging in the neurorehabilitation field. Technological advancement is often faster than clinical implementation. Previous reviews stressed the study design and methodological weaknesses of research in the field of VR for neurorehabilitation. Clinically relevant conclusions on implementation in particular patient groups are needed. The aim was to update the existing knowledge with the recent evidence on the effects of VR training on functional ability of patients with stroke and Parkinson's Disease (PD). Secondary objective was to analyze the aspects of usability of VR intervention in these populations.<h4>Methods</h4>Systematic literature search (via PubMed, CENTRAL) was conducted from inception to February 29, 2020 to identify suitable articles for two population subcategories. Randomized controlled trials published from 2016 to 2020, investigating the effectiveness of VR on a variety of outcomes contributing to the functional independence were included. Critical Appraisal Skills Programme (CASP) checklist was used for a methodological quality assessment of the primary studies. Given the heterogeneity in types of VR intervention and outcomes, a descriptive synthesis was conducted.<h4>Results</h4>A total of 18 randomized controlled trials were included (10 in stroke subcategory, 8 in PD). CASP grading ranged 9-11, suggesting high methodological quality. All studies concluded that overall VR might be as effective as the conventional training, but more motivating. In some studies, VR was found to have a greater effect, taking the high response to treatment and satisfaction into account.<h4>Conclusions</h4>VR training is suggested as an effective intervention to improve the functional ability in stroke and PD patients. Addition of VR into a rehabilitation program might facilitate patient's motivation, participation and improvement, as this method was generally well accepted, and the results of trials were promising. The consideration of disorder-specific aspects should take place during the decision-making of VR implementation.

<h4>Background</h4>Transcriptional regulation is primarily mediated by the binding of factors to non-coding regions in DNA. Identification of these binding regions enhances understanding of tissue formation and potentially facilitates the development of gene therapies. However, successful identification of binding regions is made difficult by the lack of a universal biological code for their characterisation.<h4>Results</h4>We extend an alignment-based method, changept, and identify clusters of biological significance, through ontology and de novo motif analysis. Further, we apply a Bayesian method to estimate and combine binary classifiers on the clusters we identify to produce a better performing composite.<h4>Conclusions</h4>The analysis we describe provides a computational method for identification of conserved binding sites in the human genome and facilitates an alternative interrogation of combinations of existing data sets with alignment data.

Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.

The cerebral cortex is formed by diverse neurons generated sequentially from neural stem cells (NSCs). A clock mechanism has been suggested to underlie the temporal progression of NSCs, which is mainly defined by the transcriptome and the epigenetic state. However, what drives such a developmental clock remains elusive. We show that translational control of histone H3 trimethylation in Lys27 (H3K27me3) modifiers is part of this clock. We find that depletion of Fbl, an rRNA methyltransferase, reduces translation of both Ezh2 methyltransferase and Kdm6b demethylase of H3K27me3 and delays the progression of the NSC state. These defects are partially phenocopied by simultaneous inhibition of H3K27me3 methyltransferase and demethylase, indicating the role of Fbl in the genome-wide H3K27me3 pattern. Therefore, we propose that Fbl drives the intrinsic clock through the translational enhancement of the H3K27me3 modifiers that predominantly define the NSC state.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe encephalopathy preceded by viral infections with high fever. AESD is a multifactorial disease, however, few disease susceptibility genes have previously been identified. Here, we conducted a genome-wide association study (GWAS) and assessed functional variants in non-coding regions to study genetic susceptibility in AESD using 254 Japanese children with AESD and 799 adult healthy controls. We also performed a microRNA enrichment analysis using GWAS statistics to search for candidate biomarkers in AESD. The variant with the lowest p-value, rs1850440, was located in the intron of serine/threonine kinase 39 gene (STK39) on chromosome 2q24.3 (p = 2.44 × 10^-7, odds ratio = 1.71). The minor allele T of rs1850440 correlated with the stronger expression of STK39 in peripheral blood. This variant possessed enhancer histone modification marks in STK39, the encoded protein of which activates the p38 mitogen-activated protein kinase (MAPK) pathway. In the replication study, the odds ratios of three SNPs, including rs1850440, showed the same direction of association with that in the discovery stage GWAS. One of the candidate microRNAs identified by the microRNA enrichment analysis was associated with inflammatory responses regulated by the MAPK pathway. This study identified STK39 as a novel susceptibility locus of AESD, found microRNAs as potential biomarkers, and implicated immune responses and the MAPK cascade in its pathogenesis.

Schizophrenia is a severe, disabling psychiatric disorder with unclear etiology. Family-based, twins, and adoption studies have shown that genetic factors have major contributions in schizophrenia occurrence. Until now, many studies have discovered the association of schizophrenia and its comorbid symptoms with functional polymorphisms that lie within serotonin reuptake pathway genes. Here, we aimed to investigate the association of three variable number tandem repeats (VNTR) functional polymorphisms in MAOA and SLC6A4 with schizophrenia in the Iranian population. Two hundred and forty-one subjects with schizophrenia and three hundred and seventy age and sex-matched healthy controls were genotyped for MAOA promoter uVNTR, 5-HTTLPR, and STin2 polymorphisms. Genotyping was performed by polymerase chain reaction (PCR) with locus-specific primers and running the PCR product on agarose 2.5% gel electrophoresis. Finally, the statistical inference was performed using R programming language and Haploview software. MAOA promoter uVNTR analysis of allele frequency showed no differences between schizophrenia subjects and healthy controls in both males and females and no significant differences were observed between female cases and female controls in MAOA promoter uVNTR 4 repeat frequency. Also, there were no differences between Schizophrenia and healthy control groups in 5-HTTLPR allele and genotype frequency but, 5-HTTLPR S allele carriers are significantly more frequent among cases. In addition, STin2.12 repeats were significantly more frequent among schizophrenia patients. Genotype comparison suggested that 5-HTTLPR S allele and STin2.12 repeat carriers were significantly more frequent among schizophrenia cases and being STin2.12 repeat carrier significantly increase the risk of schizophrenia occurrence. Besides, analysis of haplotype showed stronger linkage disequilibrium between 5-HTTLPR and STin2 haplotype block in cases than controls. These results suggest that SLC6A4 functional polymorphisms potentially could play a possible role as risk factors for the incidence of schizophrenia.

Both the genetic and environmental factors may affect aggression susceptibility. However, the conclusions of these associations remain discrepant. In addition, studies that explored the association between CREB1 and aggression were meager. The aim of our present study was to assess whether CREB1 polymorphisms were related to aggression and also to explore the interactive effects of CREB1 variants and childhood maltreatment on aggression. A total of 488 individuals with aggressive behavior and 488 controls were recruited. Aggression and childhood maltreatment were surveyed by standardized self-administered questionnaires. Buccal cells were also obtained and genotyping was conducted using SNPscan. Logistic regressions were applied to investigate both individual effects of CREB1 polymorphisms and the interactive influences with childhood maltreatment on aggression. We found that adolescents who carried the rs4675690 T allele in CREB1 showed a higher level of aggression compared with those who carried wildtype genotypes (CC) under the dominant model (OR = 1.67, 95% CI, 1.16-2.40) after controlling for age and childhood maltreatment. Moreover, we also found that rs4675690 T allele had a synergic additive interaction with childhood sexual abuse and emotional neglect on aggression. The significant interactive effects of CREB1 polymorphisms and childhood maltreatment on aggression were reported for the first time.

Interest in the cerebellum is expanding given evidence of its contributions to cognition and emotion, and dysfunction in various psychopathologies. However, research into its genetic architecture and shared influences with liability for mental disorders is lacking. We conducted a genome-wide association study (GWAS) of total cerebellar volume and underlying cerebellar lobe volumes in 33,265 UK-Biobank participants. Total cerebellar volume was heritable (h²_SNP = 50.6%), showing moderate genetic homogeneity across lobes (h²_SNP from 35.4% to 57.1%; mean genetic correlation between lobes r_g ≈ 0.44). We identified 33 GWAS signals associated with total cerebellar volume, of which 6 are known to alter protein-coding gene structure, while a further five mapped to genomic regions known to alter cerebellar tissue gene expression. Use of summary data-based Mendelian randomisation further prioritised genes whose change in expression appears to mediate the SNP-trait association. In total, we highlight 21 unique genes of greatest interest for follow-up analyses. Using LD-regression, we report significant genetic correlations between total cerebellar volume and brainstem, pallidum and thalamus volumes. While the same approach did not result in significant correlations with psychiatric phenotypes, we report enrichment of schizophrenia, bipolar disorder and autism spectrum disorder associated signals within total cerebellar GWAS results via conditional and conjunctional-FDR analysis. Via these methods and GWAS catalogue, we identify which of our cerebellar genomic regions also associate with psychiatric traits. Our results provide important insights into the common allele architecture of cerebellar volume and its overlap with other brain volumes and psychiatric phenotypes.

The ligand-bound (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) receptor (BTN3A1 and BTN2A1) is detectable by the T cell receptor (TCR) of Vγ9Vδ2 T cells. Although BTN3A1 binds to phosphoantigens (pAgs), the mechanisms resulting in receptor activation are not clear. We used CRISPR-Cas9, ELISA, nano-bioluminescence resonance energy transfer (BRET), and isothermal titration calorimetry (ITC) to evaluate the role of BTN2A1. Depletion of BTN2A1 and rescue experiments demonstrate that its internal domain is essential for pAg detection. Internal hetero-BRET signals are observed between BTN2A1 and BTN3A1 that are increased by pAg. ITC detects a direct interaction between the intracellular domains of BTN3A1 and BTN2A1 only in the presence of pAg. This interaction is abrogated by removal of the BTN2A1 juxtamembrane (JM) region but not by removal of the BTN3A1 JM region. Regional mutations between BTN2A1 316-326 clearly affect the interferon γ (IFNγ) response and hetero-BRET signal. Mutations to amino acids L318, W320, and L325 indicate that these amino acids are crucial. This study demonstrates a pAg-inducible interaction between BTN2A1 and BTN3A1 internal domains.

<h4>Objective</h4>To determine short-term outcomes of patients with alcohol-associated cirrhosis (ALC) admitted to the intensive care unit (ICU) compared with other etiologies of liver disease. In addition, we investigate whether quick sequential organ failure assessment accurately predicts presence of sepsis and in-hospital mortality in critically ill patients with various etiologies of cirrhosis.<h4>Methods</h4>A retrospective cohort of 1174 consecutive patients with cirrhosis admitted to the ICU between January of 2006 and December of 2015 was analyzed. Outcomes of interest included survival rates within the ICU, post-ICU in-hospital, or at 30 days post-ICU discharge.<h4>Results</h4>Five hundred seventy-eight patients were found to have ALC with 596 in the non-ALC group. There was no significant difference in ICU mortality rates in ALC versus non-ALC cohorts (10.2% vs 11.7%, P=.40). However, patients with ALC had significantly higher post-ICU in-hospital death (10.0% vs 6.5%, P=.04) as well as higher mortality at 30-day post-ICU discharge (18.7% vs 11.2%, P<.001). Sustained alcohol abstinence did not offer survival advantage over nonabstinence. The predictive power for quick sequential organ failure assessment for sepsis and in-hospital mortality for patients with cirrhosis was limited.<h4>Conclusion</h4>Critically ill patients with ALC have decreased survival after ICU discharge compared with patients with other etiologies of cirrhosis, independent of alcohol abstinence.

<b>Introduction</b>  There is a noticeable increase in the incidence of acute invasive fungal sinusitis which coincides with the ongoing coronavirus pandemic. It is a potentially-lethal fungal infection, with the most common form being the rhino-orbito-cerebral presentation. <b>Objectives</b>  The aim of the present study is to discuss the different epidemiological factors, risk factors, clinical presentations and outcomes of acute invasive fungal sinusitis which is noticeably related to the coronavirus disease 2019 (Covid-19) pandemic. <b>Methods</b>  The present cross-sectional cohort study included 22 adult patients who presented with Covid-19-related acute invasive fungal sinusitis. The diagnosis of acute invasive fungal sinusitis was confirmed by histopathological biopsy. All data, including demographics, risk factors, clinical findings, different lines of treatment and their outcomes, were recorded and analyzed. <b>Results</b>  All patients had diabetes mellitus (100%), and 17 (77.3%) had been submitted to systemic steroids. All patients (100%) had unilateral sinonasal disease. Proptosis was found in 15 patients (68.2%), ophthalmoplegia was observed in 12 patients (54.5%), and intracranial affection occurred in 10 patients (45.5%). A total of 20 patients (90.9%) received liposomal amphotericin B. Surgical debridement was performed in 18 patients (45.5%). Non-septated mycelia was present in 19 biopsies (86.4%), while 3 (13.6%)showed septated mycelia. Total improvement was achieved in 10 patients (45.5%), while the mortality rate was of 27.3% (6 out of 22 participants). <b>Conclusion</b>  Diabetes mellitus is the most common preexisting medical condition associated with Covid-19-related acute invasive fungal sinusitis. Systemic corticosteroid therapy is considered a predisposing factor. It is necessary to raise the level of awareness to diagnose this condition, especially in patients with Covid-19 infection or those who have recently recovered from it.

Nasopharyngeal carcinoma (NPC) has a 10-15% recurrence rate, while no long term or durable treatment options are currently available. Single-cell profiling in recurrent NPC (rNPC) may aid in designing effective anticancer therapies, including immunotherapies. For the first time, we profiled the transcriptomes of ∼60,000 cells from four primary NPC and two rNPC cases to provide deeper insights into the dynamic changes in rNPC within radiation fields. Heterogeneity of both immune cells (T, natural killer, B, and myeloid cells) and tumor cells was characterized. Recurrent samples showed increased infiltration of regulatory T cells in a highly immunosuppressive state and CD8⁺ T cells in a highly cytotoxic and dysfunctional state. Enrichment of M2-polarized macrophages and LAMP3⁺ dendritic cells conferred enhanced immune suppression to rNPC. Furthermore, malignant cells showed enhanced immune-related features, such as antigen presentation. Elevated regulatory T cell levels were associated with a worse prognosis, with certain receptor-ligand communication pairs identified in rNPC. Even with relatively limited samples, our study provides important clues to complement the exploitation of rNPC immune environment and will help advance targeted immunotherapy of rNPC.

Long noncoding RNA (LncRNA) is closely associated with the development of colorectal cancer (CRC). The chip data and clinical information of GSE104364 and GSE151021 were downloaded by GEOquery. Limma and Kaplan-Meier analysis were performed. Lnc-S100B-2 was obtained, and high expression of Lnc-S100B-2 was predicted to be associated with a lower survival rate. Online software was adopted to predict downstream regulatory genes, and miR-331-3p and Mixed Lineage Leukemia Translocated to 10 (MLLT10) were screened and verified. After silencing Lnc-S100B-2 and MLLT10, the proliferative activity of CRC cells decreased, and the apoptosis rate increased. At the gene and protein levels, the expressions of PCNA, Ki67, and Bcl-2 were decreased in the sh-Lnc-S100B-2 group, sh-MLLT10 group, and sh-Lnc-S100B-2 + sh-MLLT10 group, while the expressions of cleaved caspase 3, caspase 9, and Bax were increased. <i>In vivo</i>, the volume and mass of the tumor decreased in the sh-Lnc-S100B-2 + sh-MLLT10 group. Proliferation and apoptosis-related index (PCNA, Ki67, cleaved caspase 3, caspase 9, Bax, and Bcl-2) expression level was also altered. Meanwhile, the infiltration of immune cells (CD3 (-), CD16 (+), and CD11b (+) cells) decreased. The expressions of epithelial-mesenchymal transformation (EMT) related indicators (E-cadherin, N-cadherin, Vimentin, <i>β</i>-catenin, Snail, and Slug) were changed. E-cadherin and <i>β</i>-catenin were increased in the sh-Lnc-S100B-2 + sh-MLLT10 group, while N-cadherin, vimentin, snail, and slug were decreased. In conclusion, our study found that the expression of Lnc-S100B-2 was dysregulated in CRC. Lnc-S100B-2 could affect cell apoptosis and the microenvironment of CRC through regulating MLLT10.

The coexistence of alpha- and beta-thalassemia is not uncommon and neither is a single thalassemia subtype with a hemochromatosis H63D mutation, however the inheritance of all three diseases together has yet to be reported. We present this rare case of co-inherited alpha-thalassemia minor and beta-thalassemia minor initially misdiagnosed as iron deficiency anemia (IDA) in a reproductive aged female with a heterozygous H63D mutation. In our case report, a 27-year-old, Asian female presented with excessive lethargy and fatigue for the past 10 months. A year ago, she was prescribed Ferrous Sulfate 325 mg daily supplementation due to a suspicion of IDA secondary to a history of heavy menstruations. Although her reports displayed a low mean corpuscular volume (MCV) anemia, the patient declined therapy at that time due to abnormal labs, specifically regarding her urine and liver that subsequently lead to a hemochromatosis, heterozygous H63D diagnosis following genetic testing. Subsequently, the patient's anemia presenting in the setting of normal ferritin, high iron saturation, and elevated A2 fraction was most likely in accordance to carrying the alpha-thalassemia minor, beta-thalassemia minor, and heterozygous H63D gene mutations. Genetic testing further clarified two of the four alpha-globin genes were deleted, alpha3.7 and alpha4.2, consistent with alpha-thalassemia trait and a heterozygous, frameshift mutation of c.27dupG on the hemoglobin subunit beta (HBB) gene associated with beta-thalassemia minor. The initial diagnosis of IDA was inaccurate following the iron studies displaying normal ferritin levels. This is the first report of combined alpha- and beta-thalassemia with a hemochromatosis H63D mutation. Although the clinical presentation of our patient and laboratory values are stable, the course of inheriting all three diseases together is unknown and may inflate the risk of future complications beyond reported studies. Frequent monitorization of hemoglobin and iron studies will be conducted to follow this rare presentation and prevent life-threating iron overload.

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. <i>In vitro</i> and <i>in vivo</i> experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. <i>In vivo</i> transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions.

Restrictive cardiomyopathy (RCM) is the least frequent phenotype among pediatric heart muscle diseases, representing only 2.5-3% of all cardiomyopathies diagnosed during childhood. Pediatric RCM has a poor prognosis, high incidence of pulmonary hypertension (PH), thromboembolic events, and sudden death, is less amenable to medical or surgical treatment with high mortality rates. In this <i>scenario</i>, heart transplantation remains the only successful therapeutic option. Despite a shared hemodynamic profile, characterized by severe diastolic dysfunction and restrictive ventricular filling, with normal ventricle ejection fraction and wall thickness, RCM recognizes a broad etiological spectrum, consisting of genetic/familial and acquired causes, each of which has a distinct pathophysiology and natural course. Hence, the aim of this review is to cover the causes, clinical presentation, diagnostic evaluation, treatment, and prognosis of pediatric RCM.

<b>Background:</b> The regulatory role of ferroptosis in malignant tumours has been recently demonstrated. However, the potential roles of ferroptosis mediation patterns in bladder cancer remain elusive. <b>Materials and Methods:</b> The ferroptosis mediation patterns of 889 bladder cancer samples were comprehensively evaluated based on ferroptosis-related genes. The underlying correlations between these mediation patterns and multi-omic characteristics of bladder cancer were systematically analysed. The ferroptosis mediation patterns of individual samples were quantified by ferropscore using the principal component analysis algorithm. The typical ferroptosis-related genes with prognostic roles were further randomly validated using immunohistochemical staining, real-time polymerase chain reaction and western blotting. <b>Results:</b> Three different ferroptosis mediation patterns were identified. The abundance of infiltration of 23 immune cells was different among the three mediation patterns. The quantification of ferroptosis mediation patterns in individual samples served as a promising tool for predicting patient survival outcomes; immune cell infiltration abundance; tumour mutation burden; oncogenic mutation status and tumour grade, stage and molecular subtypes. Low ferropscore combined with high tumour mutation burden was associated with the best survival prognosis. Expressions of PD-L1 (<i>p</i> < 0.001), PD-1 (<i>p</i> = 0.002) and CTLA-4 (<i>p</i> = 0.003) were all significantly upregulated in the high ferropscore group. Low ferropscores also predicted good immunotherapy response for anti-CTLA4 strategy. The mRNA and protein levels of FADS2, a typical ferroptosis-related gene used in the study, were higher in bladder cancer cell lines than in controlled SV-HUC-1 cells. In addition, immunohistochemical staining revealed significantly higher expression levels of FADS2 in human bladder cancer tumour tissues than in normal tissues. <b>Conclusion:</b> This study identified three distinct ferroptosis mediation patterns in bladder cancer. Quantification of ferroptosis mediation patterns in individual samples may help to improve the understanding of multiomic characteristics and guide future immunotherapy responses to bladder cancer.

The role and mechanism of inflammation in breast cancer is unclear. This study aims to probe the relationship between inflammation and long non-coding RNAs (lncRNAs) and to stablish an inflammation-related competing endogenous RNA (ceRNA) network in breast cancer. Inflammation-related lncRNAs and target genes were screened based on the data from four single-cell RNA sequencing (scRNA-seq) studies and miRNAs were bioinformatically predicted according to ceRNA hypothesis. A series of <i>in silico</i> analyses were performed to construct an inflammation-related ceRNA network in breast cancer. Consequently, a total of seven inflammation-related lncRNAs were selected, after which LRRC75A-AS1 was identified as the most potential lncRNA in view of its expression and prognostic predictive value in breast cancer. Finally, an inflammation-related ceRNA network in breast cancer at the single cell level was established based on lncRNA LRRC75A-AS1, miR-3127-5p, miR-2114-3p, RPL36 and RPL27A mRNAs. Collectively, the lncRNA LRRC75A-AS1 and the LRRC75A-AS1-based on ceRNA network may exert crucial roles in modulating inflammation response during the initiation and progression of breast cancer.

<b>Background:</b> The role of ferroptosis in breast cancer brain metastasis (BCBM) is unclear. This study aimed to explore the ferroptosis-related genes (FRG) relations with the tumor microenvironment, as well as evaluate their values in predicting survival and drug sensitivity in patients with BCBM. <b>Materials and Methods:</b> Genes expression and clinical data were downloaded from Gene Expression Omnibus (GEO). Univariate and multivariate Cox regression analyses were performed to explore the independent prognostic factors. Consensus cluster principal component analysis (PCA) was used to establish the ferroptosis score. Immunological signatures were analyzed by the single-sample gene set enrichment analysis (ssGSEA). Drug sensitivity was evaluated through the estimated half-maximal inhibitory concentration (IC50). Finally, results were validated in external cohorts. <b>Results:</b> Fourteen significantly different FRG were identified between breast cancer (BC) and BCBM tissues. Survival analysis demonstrated HMOX1, PEBP1, KEAP1, and LPCAT3 were significantly associated with overall survival (OS) and relapse-free survival (RFS) (all <i>p</i> < 0.05). High ferroptosis score was correlated with iron ion homeostasis, iron metabolism, higher stromal cells and immune cells scores. Patients with high- and low-ferroptosis scores were characterized by different drug sensitivities. Following external validations, the ferroptosis had distinct expression profiles between the BC and BCBM, and could serve as biomarkers for OS and drug response. <b>Conclusion:</b> Our findings suggested that ferroptosis may be involved in the process of BCBM, and ferroptosis could serve as prognostic biomarkers. Evaluation of ferroptosis may deepen our understanding about the tumor microenvironment, and could help clinicians to make individualized therapy.

Dynamic profiling of changes in gene expression in response to stressors in specific microenvironments without requiring cellular destruction remains challenging. Current methodologies that seek to interrogate gene expression at a molecular level require sampling of cellular transcriptome and therefore lysis of the cell, preventing serial analysis of cellular transcriptome. To address this area of unmet need, we have recently developed a technology allowing transcriptomic analysis over time without cellular destruction. Our method, TRACE-seq (TRanscriptomic Analysis Captured in Extracellular vesicles using sequencing), is characterized by a cell-type specific transgene expression. It provides data on the transcriptome inside extracellular vesicles that provides an accurate representation of stress-responsive cellular transcriptomic changes. Thus, the transcriptome of cells expressing TRACE can be followed over time without destroying the source cell, which is a powerful tool for many fields of fundamental and translational biology research.

Human infertility is an important health problem that affects one in six couples worldwide. Half of these cases are due to male infertility. Oxidative stress is a common culprit of male infertility, promoting lipid peroxidation and the oxidation of proteins and DNA in spermatozoa, thereby impairing motility, capacitation and fertilization. Peroxiredoxin 6 (PRDX6) possesses peroxidase and Ca²⁺-independent-phospholipase-A₂ (iPLA₂) activities that scavenge ROS and repair oxidized sperm membranes, respectively. PRDX6 protects spermatozoa against oxidative stress. Infertile men's spermatozoa have impaired motility, elevated lipid peroxidation levels and DNA damage due to low PRDX6 levels. A lack of PRDX6 is associated with male-mouse infertility. Here, we determined the impact of the absence of PRDX6 peroxidase or iPLA₂ activities on male-mouse fertility. Two-month-old male C57Bl6/J (wild-type), <i>Prdx6^-/-</i>, C47S and D140A knock-in (peroxidase- and iPLA₂-deficient, respectively) male mice were challenged with an in vivo oxidative stress triggered by tert-butyl hydroperoxide (t-BHP). C47S and D140A males produced smaller litters compared to wild-type controls. The t-BHP treatment promoted a lower number of pups, high levels of lipid peroxidation, tyrosine nitration, and DNA oxidation in all mutant spermatozoa compared to wild-type controls. All mutant spermatozoa had impaired capacitation and motility. In summary, both PRDX6 peroxidase and iPLA₂ activities are essential to support male-mouse fertility.

Transposable elements (TEs), also known as jumping genes, are sequences able to move or copy themselves within a genome. As TEs move throughout genomes they often act as a source of genetic novelty, hence understanding TE evolution within lineages may help in understanding environmental adaptation. Studies into the TE content of lineages of mammals such as bats have uncovered horizontal transposon transfer (HTT) into these lineages, with squamates often also containing the same TEs. Despite the repeated finding of HTT into squamates, little comparative research has examined the evolution of TEs within squamates. Here we examine a diverse family of Australo-Melanesian snakes (Hydrophiinae) to examine if the previously identified, order-wide pattern of variable TE content and activity holds true on a smaller scale. Hydrophiinae diverged from Asian elapids ~30 Mya and have since rapidly diversified into six amphibious, ~60 marine and ~100 terrestrial species that fill a broad range of ecological niches. We find TE diversity and expansion differs between hydrophiines and their Asian relatives and identify multiple HTTs into Hydrophiinae, including three likely transferred into the ancestral hydrophiine from fish. These HTT events provide the first tangible evidence that Hydrophiinae reached Australia from Asia via a marine route.

Liver cirrhosis is the final stage of continuous hepatic inflammatory activity derived by viral, metabolic or autoimmune origin. In the last years, cirrhosis was considered a unique and static condition; recently was accepted some patients subgroups with different liver injury degrees that coexist under the same diagnosis, with implications about the natural disease history. The liver growth factor (LGF) is a potent <i>in vivo</i> and <i>in vitro</i> mitogenic agent and an inducer of hepatic regeneration (HR) through the hepatocytes DNA synthesis. The clinical implications of the LGF levels in cirrhosis, are not clear and even with having a fundamental role in the liver regeneration processes, the studies suggest that it could be a cirrhosis severity marker, in acute liver failure and in chronic hepatitis. Its role as predictor of mortality in fulminant hepatic insufficiency patients has been suggested. HR is one of the most enigmatic and fascinating biological phenomena. The rapid volume and liver function restoration after a major hepatectomy (>70%) or severe hepatocellular damage and its strict regulation of tissue damage response after the cessation, is an exclusive property of the liver. HR is the clinical applications fundament, such as extensive hepatic resections (>70% of the liver parenchyma), segmental transplantation or living donor transplantation, sequential hepatectomies, isolated portal embolization or associated with <i>in situ</i> hepatic transection, temporary artificial support in acute liver failure and the possible cell therapy clinical applications.

<title>Abstract</title> <p>Intrauterine hematopoietic cell transplantation (IUT), a promising therapy for congenital haematological disease, is limited by subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) trafficked into fetal IUT recipients may directly influence immune-mediated donor cell clearance. We investigated if maternal dendritic cell (DC) suppression reduces recipient alloresponsiveness to donor cells, improving DCC. IUT was performed at E14 in pregnancies resulting from crossing CD11c.DTR(B6) females and Balb/c males, with semiallogenic Balb/c or C57BL/6, or fully allogenic C3H donor cells, 24h after administering diphtheria toxin to the dam, transiently suppressing maternal DC. This resulted in reduced MMc in recipient fetuses, greatest after Balb/c transplantation, also associated with the highest DCC, and lowest with C3H. Maternal-derived T-cell receptor (TCR) clonotypes were enriched in IUT recipients and displayed substantially reduced diversity. Recipient pups with reduced MMc increased expression of regulatory T-cell subtypes, reduced expression of proinflammatory cytokines, and demonstrated enhanced TCR clonotype diversity. DCC was primarily related to donor cell type and not influenced by MMc. Our data indicate that donor cell origin and MMc are distinct factors determining IUT effectiveness. MMc independently influences DCC and recipient tolerance to donor cells and may present novel therapeutic targets to improve transplantation outcomes.</p>

Granular hydrogels have emerged as a new class of injectable and porous biomaterials that improve integration with host tissue when compared to solid hydrogels. Granular hydrogels are typically prepared using spherical particles and this study considers whether particle shape (i.e., isotropic spheres vs anisotropic rods) influences granular hydrogel properties and cellular invasion. Simulations predict that anisotropic rods influence pore shape and interconnectivity, as well as bead transport through granular assemblies. Photo-cross-linkable norbornene-modified hyaluronic acid is used to produce spherical and rod-shaped particles using microfluidic droplet generators and formed into shear-thinning and self-healing granular hydrogels, with particle shape influencing mechanics and injectability. Rod-shaped particles form granular hydrogels that have anisotropic and interconnected pores, with pore size and number influenced by particle shape and degree of packing. Robust in vitro sprouting of endothelial cells from embedded cellular spheroids is observed with rod-shaped particles, including higher sprouting densities and sprout lengths when compared to hydrogels with spherical particles. Cell and vessel invasion into granular hydrogels when injected subcutaneously in vivo are significantly greater with rod-shaped particles, whereas a gradient of cellularity is observed with spherical particles. Overall, this work demonstrates potentially superior functional properties of granular hydrogels with rod-shaped particles for tissue repair.

The purpose of this study was to establish associations between both serum levels and bone content of a wide range of elements (Na, K, P, Ca, Mg, Zn, Cu, Cr, Mn, Fe, and Pb), with hip strength (HS) indices derived from dual-energy X-ray absorptiometry (DXA). The study population consisted of a number of male patients aged 56-77 years following hip replacement due to osteoarthritis of the hip. Bone specimens were taken from the femoral head and neck during arthroplasty. The elemental analyses were carried out using coupled plasma optical emission spectrometry. The following DXA-HS parameters were assessed: buckling ratio (BR), cross-sectional area (CSA) and its moment of inertia (CSMI), section modulus, and Femoral Strength Index (FSI). Age was positively correlated with Na, K, and Cu in the bone. Ca in the bone was positively associated with BR and negatively with SM and CSMI. Of all the DXA-HS parameters, the weakest associations of elements in the bone were found with FSI and the strongest with BR. Among the elements in the serum, the strongest negative associations were found for K, Cr, Mn, and Zn with CSA, while the majority of bone elements were associated either positively (Ca, P, Mg, Zn, and Cu) or negatively (Mn, Fe, Pb, and Cr) with BR. In conclusion, the interactions between individual elements in blood serum and bone with DXA-HS could not be unequivocally established.

Mitochondria tailor their morphology to execute their specialized functions in different cell types and/or different environments. During spermatogenesis, mitochondria undergo continuous morphological and distributional changes with germ cell development. Deficiencies in these processes lead to mitochondrial dysfunction and abnormal spermatogenesis, thereby causing male infertility. In recent years, mitochondria have attracted considerable attention because of their unique role in the regulation of piRNA biogenesis in male germ cells. In this review, we describe the varied characters of mitochondria and focus on key mitochondrial factors that play pivotal roles in the regulation of spermatogenesis, from primordial germ cells to spermatozoa, especially concerning metabolic shift, stemness and reprogramming, mitochondrial transformation and rearrangement, and mitochondrial defects in human sperm. Further, we discuss the molecular mechanisms underlying these processes.

<h4>Introduction</h4>Use of risk scores for early assessment of patients with upper gastrointestinal bleeding (UGIB) is recommended by various guidelines. We compared Cologne-WATCH (C-WATCH) score with Glasgow-Blatchford score (GBS), Rockall score (RS), and pre-endoscopic RS (p-RS).<h4>Methods</h4>Patients with UGIB between January and December 2017 were retrospectively analyzed for 30-day mortality and composite endpoints risk of complications and need for intervention using areas under the receiver-operating characteristics curve (AUROC). Subgroup analysis was conducted for patients with UGIB on admission and in-hospital UGIB.<h4>Results</h4>A total of 252 patients were identified (67.5% men, mean age 63.8 ± 14.9 years). In-hospital UGIB occurred in 49.6%. AUROCs for 30-day mortality, risk of complications, and need for intervention (not applicable to RS) were 0.684 (95% confidence interval [CI]: 0.606-0.763), 0.665 (95% CI: 0.594-0.735), and 0.694 (95% CI: 0.612-0.775) for C-WATCH score, 0.724 (95% CI: 0.653-0.796) and 0.751 (95% CI: 0.687-0.815) for RS, 0.652 (95% CI: 0.57-0.735), 0.653 (95% CI: 0.579-0.727), and 0.673 (95% CI: 0.602-0.745) for p-RS and 0.652 (95% CI: 0.572-0.732), 0.663 (95% CI: 0.592-0.734), and 0.752 (95% CI: 0.683-0.821) for GBS. RS outperformed pre-endoscopic scores in predicting risk of complications, while there were no significant differences between pre-endoscopic scores except GBS outperforming p-RS in predicting need for intervention. The subgroup analysis obtained similar results. Positive predictive values for patients with estimated low risk for all three endpoints (C-WATCH score ≤1, RS ≤2, p-RS <1, and GBS ≤1) were 89%, 69%, 78%, and 92%.<h4>Conclusion</h4>C-WATCH score performed similar to the established pre-endoscopic risk scores in patients with UGIB regarding relevant patient-related endpoints with no significant differences between both the subgroups.

<h4>Background</h4>The domestication of goat (Capra hircus) started 11,000 years ago in the fertile crescent. Breed formation in the nineteenth century, establishment of herd books, and selection for specific traits resulted in 10 modern goat breeds in Switzerland. We analyzed whole-genome sequencing (WGS) data from 217 modern goats and nine wild Bezoar goats (Capra aegagrus). After quality control, 27,728,288 biallelic single nucleotide variants (SNVs) were used for the identification of runs of homozygosity (ROH) and the detection of ROH islands.<h4>Results</h4>Across the 226 caprine genomes from 11 populations, we detected 344 ROH islands that harbor 1220 annotated genes. We compared the ROH islands between the modern breeds and the Bezoar goats. As a proof of principle, we confirmed a signature of selection, which contains the ASIP gene that controls several breed-specific coat color patterns. In two other ROH islands, we identified two missense variants, STC1:p.Lys139Arg and TSHR:p.Ala239Thr, which might represent causative functional variants for domestication signatures.<h4>Conclusions</h4>We have shown that the information from ROH islands using WGS data is suitable for the analysis of signatures of selection and allowed the detection of protein coding variants that may have conferred beneficial phenotypes during goat domestication. We hypothesize that the TSHR:p.Ala239Thr variant may have played a role in changing the seasonality of reproduction in modern domesticated goats. The exact functional significance of the STC1:p.Lys139Arg variant remains unclear and requires further investigation. Nonetheless, STC1 might represent a new domestication gene affecting relevant traits such as body size and/or milk yield in goats.

Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by excessive lipid peroxidation and associated with a plethora of pathological conditions in the liver. Emerging evidence supports the notion that dysregulated metabolic pathways and impaired iron homeostasis play a role in the progression of liver disease via ferroptosis. Although the molecular mechanisms by which ferroptosis causes disease are poorly understood, several ferroptosis-associated genes and pathways have been implicated in liver disease. Here, we review the physiological role of the liver in processing nutrients, our current understanding of iron metabolism, the characteristics of ferroptosis, and the mechanisms that regulate ferroptosis. In addition, we summarize the role of ferroptosis in the pathogenesis of liver disease, including liver injury, non-alcoholic steatohepatitis, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Finally, we discuss the therapeutic potential of targeting ferroptosis for managing liver disease.

To identify predictors of neonatal ECMO circuit health, a retrospective analysis of circuit functional pressure and flow parameters as well as infant clotting values were collected 48 h prior to and 24 h post circuit change. Circuit impairment was defined as need for partial or total circuit change. Statistical analysis used multivariate statistics and non-parametric Mann-Whitney U-test with possible non-normality of measurements. A total of 9764 ECMO circuit and clotting values in 21 circuits were analyzed. Circuit delta-P mean, and maximum values increased from 8.62 to 48.59 mmHg (p < 0.011) and 16.00 to 53.00 mmHg (p < 0.0128) respectively prior to need for circuit change. Maximum and mean Pump Flow Revolutions per minute (RPM) increased by 75% (p < 0.0043) and 81% (p < 0.0057), respectively. Mean plasma free hemoglobin (pfHb) increased from 26.45 to 76.00 mg/dl, (p < 0.0209). Sweep, venous pressure, and clotting parameters were unaffected. ECMO circuit delta-P, RPM, and pfHb were early predictors of circuit impairment.

Human brain organoid models that recapitulate the physiology and complexity of the human brain have a great potential for in vitro disease modeling, in particular for neurodegenerative diseases, such as Parkinson disease. In the present study, we compare single-cell RNA-sequencing data of human midbrain organoids to the developing human embryonic midbrain. We demonstrate that the in vitro model is comparable to its in vivo equivalents in terms of developmental path and cellular composition. Moreover, we investigate the potential of midbrain organoids for modeling early developmental changes in Parkinson disease. Therefore, we compare the single-cell RNA-sequencing data of healthy-individual-derived midbrain organoids to their isogenic LRRK2-p.Gly2019Ser-mutant counterparts. We show that the LRRK2 p.Gly2019Ser variant alters neurodevelopment, resulting in an untimely and incomplete differentiation with reduced cellular variability. Finally, we present four candidate genes, APP, DNAJC6, GATA3, and PTN, that might contribute to the LRRK2-p.Gly2019Ser-associated transcriptome changes that occur during early neurodevelopment.

<h4>Purpose of review</h4>This review highlights major studies across a broad array of topics presented at the virtual 2021 American Heart Association (AHA) Scientific Sessions.<h4>Recent findings</h4>Assessed studies examine a remotely delivered hypertension and lipid program in 10,000 patients across a diverse healthcare network; a cluster-randomized trial of a village doctor-led intervention for hypertension control; empagliflozin in heart failure with preserved ejection fraction (EMPEROR-Preserved); efficacy and safety of empagliflozin in hospitalized heart failure patients (EMPULSE); icosapent ethyl versus placebo in outpatients with coronavirus disease 2019 (PREPARE-IT 2); clinical safety, pharmacokinetics, and low-density lipoprotein cholesterol-lowering efficacy of MK-0161, an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor; and effects of aspirin on dementia and cognitive impairment in the ASCEND trial. Research presented at the 2021 AHA Scientific Sessions emphasized the importance of interventions for cardiovascular disease prevention.

Neck pain can be very bothersome for patients, and most will seek analgesic relief as soon as possible. We present a case of crystal deposition in the cervical spine where a frail patient admitted for pneumonia developed severe neck pain raising suspicion of discitis, and did not respond to standard analgesic medications. Investigations revealed crystal deposition around the dens and alar ligaments (C₁ and C₂ Spine) suggestive of crowned dens syndrome, which responded promptly to steroid therapy and averting the patient from invasive investigations and intense treatment with antibiotics.

Tardive dyskinesia is a severe motor adverse event of antipsychotic medication, characterized by involuntary athetoid movements of the trunk, limbs, and/or orofacial areas. It affects two to ten patients under long-term administration of antipsychotics that do not subside for years even after the drug is stopped. Dopamine, serotonin, cannabinoid receptors, oxidative stress, plasticity factors, signaling cascades, as well as CYP isoenzymes and transporters have been associated with tardive dyskinesia (TD) occurrence in terms of genetic variability and metabolic capacity. Besides the factors related to the drug and the dose and patients' clinical characteristics, a very crucial variable of TD development is individual susceptibility and genetic predisposition. This review summarizes the studies in experimental animal models and clinical studies focusing on the impact of genetic variations on TD occurrence. We identified eight genes emerging from preclinical findings that also reached statistical significance in at least one clinical study. The results of clinical studies are often conflicting and non-conclusive enough to support implementation in clinical practice.

Post-stroke depression (PSD) is the most common non-cognitive neuropsychiatric complication after stroke, and about a third of patients with stroke have depression. Although a great deal of effort has been made to treat PSD, the efficacy thereof has not been satisfactory, due to the complex pathological mechanism underlying PSD. In Traditional Chinese Medicine (TCM) theory, PSD is considered to be a combination of "stroke" and "Yu Zheng<i>.</i>" The holistic, multi-drug, and multi-objective nature of TCM is consistent with the treatment concept of systems medicine for PSD. TCM has a very long history of being used to treat depression, and various TCM prescriptions have been clinically proven to be effective in improving depression. Among the numerous prescriptions for treating depression, Shugan Jieyu capsule (SG) is one of the classic prescriptions. Additionally, clinical studies have increasingly confirmed that using SG alone or in combination with Western medicine can significantly improve the psychiatric symptoms of PSD patients. Here, we reviewed the mechanism of antidepressant action of SG and its targets in PSD pathologic systems. This review provides further insights into the pharmacological mechanism, drug interaction, and clinical application of TCM prescriptions, as well as a basis for the development of new drugs to treat PSD.

In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; <i>SOX5, CCDC26/GSDMC</i> and <i>DCC</i>. This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); <i>SOX5</i> rs34616559, <i>CCDC26/GSDMC</i> rs7833174 and <i>DCC</i> rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months (<i>n</i> = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; <i>SOX5</i> rs34616559, <i>CCDC26/GSDMC</i> rs7833174 and <i>DCC</i> rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.

<b>Background:</b> From previous studies, we found that there are more than 100 types of RNA modifications in RNA molecules. m⁶A methylation is the most common. The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) at home and abroad has increased faster than that of stomach cancer at other sites in recent years. Here, we systematically analyze the modification pattern of m⁶A mRNA in adenocarcinoma at the esophagogastric junction. <b>Methods:</b> m⁶A sequencing, RNA sequencing, and bioinformatics analysis were used to describe the m⁶A modification pattern in adenocarcinoma and normal tissues at the esophagogastric junction. <b>Results:</b> In AEG samples, a total of 4,775 new m⁶A peaks appeared, and 3,054 peaks disappeared. The unique m6A-related genes in AEG are related to cancer-related pathways. There are hypermethylated or hypomethylated m⁶A peaks in AEG in differentially expressed mRNA transcripts. <b>Conclusion:</b> This study preliminarily constructed the first m⁶A full transcriptome map of human AEG. This has a guiding role in revealing the mechanism of m⁶A-mediated gene expression regulation.

State-of-the-art treatment for sensorineural hearing loss is based on electrical stimulation of residual spiral ganglion neurons (SGNs) with cochlear implants (CIs). Due to the anatomical gap between the electrode contacts of the CI and the residual afferent fibers of the SGNs, spatial spreading of the stimulation signal hampers focused neuronal stimulation. Also, the efficiency of a CI is limited because SGNs degenerate over time due to loss of trophic support. A promising option to close the anatomical gap is to install fibers as artificial nerve guidance structures on the surface of the implant and install on these fibers drug delivery systems releasing neuroprotective agents. Here, we describe the first steps in this direction. In the present study, suture yarns made of biodegradable polymers (polyglycolide/poly-ε-caprolactone) serve as the basic fiber material. In addition to the unmodified fiber, also fibers modified with amine groups were employed. Cell culture investigations with NIH 3T3 fibroblasts attested good cytocompatibility to both types of fibers. The fibers were then coated with the extracellular matrix component heparan sulfate (HS) as a biomimetic of the extracellular matrix. HS is known to bind, stabilize, modulate, and sustainably release growth factors. Here, we loaded the HS-carrying fibers with the brain-derived neurotrophic factor (BDNF) which is known to act neuroprotectively. Release of this neurotrophic factor from the fibers was followed over a period of 110 days. Cell culture investigations with spiral ganglion cells, using the supernatants from the release studies, showed that the BDNF delivered from the fibers drastically increased the survival rate of SGNs <i>in vitro</i>. Thus, biodegradable polymer fibers with attached HS and loaded with BDNF are suitable for the protection and support of SGNs. Moreover, they present a promising base material for the further development towards a future neuronal guiding scaffold.

<h4>Background</h4>Aging is significantly associated with the incidence and progression of atrial fibrillation (AF) incidence. This study aimed to evaluate the potential predictive value of leukocyte telomere length (LTL) for progression from paroxysmal AF (PAF) to persistent AF (PsAF) after catheter ablation.<h4>Methods and results</h4>A total of 269 patients with AF (154 patients with PAF and 115 patients with PsAF, respectively) were prospectively enrolled, and all patients with PAF at baseline were regularly followed up to determine whether and when they should progress to PsAF after catheter ablation therapy. Baseline relative LTL was measured by quantitative real-time PCR (rt-PCT). There was a significant negative association between LTL and age (<i>r</i> = -0.23, <i>p</i> < 0.001). Patients with PsAF had significantly shorter LTL than those with PAF. After a mean follow-up of 854.9 ± 18.7 d, progression events occurred in 35 out of the 154 patients with PAF. Those progressed patients with PAF were older (70.9 ± 8.0 vs. 62.3 ± 10.3, <i>p</i> < 0.001) and had shorter LTL (1.2 ± 0.3 vs. 1.5 ± 0.3, <i>p</i> < 0.001) than those who did not. The receiver operating characteristic (ROC) curve analysis showed a significant value of LTL in distinguishing patients with PAF from patients with PsAF, with an area under the ROC curve (AUC) of 0.63 (95% CI 0.56-0.70, <i>p</i> < 0.001), and the optimal cut-off value of LTL was 1.175, with a sensitivity and specificity of 56.03 and 82.04%, respectively. All patients with PAF were divided into two subgroups according to the optimal cut-off point of LTL calculated by the ROC curve analysis: high LTL group (≥1.175) and low LTL group (<1.175). Kaplan-Meier curve analysis showed that PAF patients with shorter LTL had a significantly higher rate of progression after catheter ablation (40.5% vs. 18.8%, log-rank test <i>p</i> < 0.001). Multivariate Cox proportional-hazards model indicated that LTL [hazard ratio (HR): 2.71, 95% CI 1.36-5.42, <i>p</i> = 0.005] was an independent predictor for progression from PAF to PsAF after catheter ablation therapy, but HATCH score was not (HR: 1.02, 95% CI: 0.68-1.52, <i>p</i> = 0.923).<h4>Conclusion</h4>Leukocyte telomere length was significantly associated with AF types. LTL was independently associated with progression from PAF to PsAF after catheter ablation therapy.<b>Chinese Clinical Trial Registry, Registration Number:</b> ChiCTR1900021341.

The preparation, characterization, and controlled release of hydroxyapatite (HAp) nanoparticles loaded with streptomycin (STR) was studied. These nanoparticles are highly appropriate for the treatment of bacterial infections and are also promising for the treatment of cancer cells. The analyses involved scanning electron microscopy, dynamic light scattering (DLS) and Z-potential measurements, as well as infrared spectroscopy and X-ray diffraction. Both amorphous (ACP) and crystalline (cHAp) hydroxyapatite nanoparticles were considered since they differ in their release behavior (faster and slower for amorphous and crystalline particles, respectively). The encapsulated nanoparticles were finally incorporated into biodegradable and biocompatible polylactide (PLA) scaffolds. The STR load was carried out following different pathways during the synthesis/precipitation of the nanoparticles (i.e., nucleation steps) and also by simple adsorption once the nanoparticles were formed. The loaded nanoparticles were biocompatible according to the study of the cytotoxicity of extracts using different cell lines. FTIR microspectroscopy was also employed to evaluate the cytotoxic effect on cancer cell lines of nanoparticles internalized by endocytosis. The results were promising when amorphous nanoparticles were employed. The nanoparticles loaded with STR increased their size and changed their superficial negative charge to positive. The nanoparticles' crystallinity decreased, with the consequence that their crystal sizes reduced, when STR was incorporated into their structure. STR maintained its antibacterial activity, although it was reduced during the adsorption into the nanoparticles formed. The STR release was faster from the amorphous ACP nanoparticles and slower from the crystalline cHAp nanoparticles. However, in both cases, the STR release was slower when incorporated in calcium and phosphate during the synthesis. The biocompatibility of these nanoparticles was assayed by two approximations. When extracts from the nanoparticles were evaluated in cultures of cell lines, no cytotoxic damage was observed at concentrations of less than 10 mg/mL. This demonstrated their biocompatibility. Another experiment using FTIR microspectroscopy evaluated the cytotoxic effect of nanoparticles internalized by endocytosis in cancer cells. The results demonstrated slight damage to the biomacromolecules when the cells were treated with ACP nanoparticles. Both ACP and cHAp nanoparticles were efficiently encapsulated in PLA electrospun matrices, providing functionality and bioactive properties.

Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.

Biallelic pathogenic variants in the <i>SEC23B</i> gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in <i>SEC23B</i>, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for <i>SEC23B</i>. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for <i>SEC23B</i>. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of <i>SEC23B</i> pathogenic variants at hepatic level. Finally, we demonstrated the ability of <i>SEC23B</i> paralog, i.e., <i>SEC23A</i>, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells.

Sepsis is a clinical syndrome with high mortality and morbidity rates. In sepsis, the abrupt release of cytokines by the innate immune system may cause multiorgan failure, leading to septic shock and associated complications. In the presence of a number of systemic disorders, such as sepsis, infections, diabetes, and systemic lupus erythematosus (SLE), cardiorenal syndrome (CRS) type 5 is defined by concomitant cardiac and renal dysfunctions Thus, our study suggests that certain mRNAs and unexplored pathways may pave a way to unravel critical therapeutic targets in three debilitating and interrelated illnesses, namely, sepsis, SLE, and CRS. Sepsis, SLE, and CRS are closely interrelated complex diseases likely sharing an overlapping pathogenesis caused by erroneous gene network activities. We sought to identify the shared gene networks and the key genes for sepsis, SLE, and CRS by completing an integrative analysis. Initially, 868 DEGs were identified in 16 GSE datasets. Based on degree centrality, 27 hub genes were revealed. The gProfiler webtool was used to perform functional annotations and enriched molecular pathway analyses. Finally, core hub genes (<i>EGR1, MMP9</i>, and <i>CD44</i>) were validated using RT-PCR analysis. Our comprehensive multiplex network approach to hub gene discovery is effective, as evidenced by the findings. This work provides a novel research path for a new research direction in multi-omics biological data analysis.

The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.

<h4>Background/aims</h4>Gut-barrier dysfunction is well recognized in pathogenesis of both non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). However, comparison of components of this dysfunction between the two etiologies remains unexplored especially in early stages of NAFLD.<h4>Methods</h4>Components of gut-barrier dysfunction like alterations in intestinal permeability (IP) by lactulose mannitol ratio (LMR) in urine, systemic endotoxemia (IgG and IgM anti-endotoxin antibodies), systemic inflammation (serum tumor necrosis factor alpha [TNF-α] and interleukin-1 [IL-1] levels), tight junction (TJ) proteins expression in duodenal biopsy and stool microbiota composition using Oxford Nanopore MinION device were prospectively evaluated in patients with NAFLD (n = 34) with no cirrhosis, ALD (n = 28) and were compared with disease free controls (n = 20).<h4>Results</h4>Patients with ALD had more advanced disease than those with NAFLD (median liver stiffness -NAFLD:7.1 kPa [5.9-8.9] vs. ALD:14.3 kPa [9.6-24], <i>P</i> < 0.001]. Median LMR was significantly higher in NAFLD and ALD group when compared to controls (NAFLD 0.054 [0.037-0.17] vs. controls 0.027 [0.021-0.045] (<i>P</i> = 0.001)) and ALD 0.043 [0.03-0.068] vs. controls 0.027 [0.021-0.045] (<i>P</i> = 0.019)]. Anti-endotoxin antibody titer (IgM) (MMU/mL) was lowest in NAFLD 72.9 [3.2-1089.5] compared to ALD 120.6 [20.1-728]) (<i>P</i> = 0.042) and controls 155.3 [23.8-442.9]) (<i>P</i> = 0.021). Median TNF-α (pg/mL) levels were elevated in patients with NAFLD (53.3 [24.5-115]) compared to controls (16.1 [10.8-33.3]) (<i>P</i> < 0.001) and ALD (12.3 [10.1-42.7]) (<i>P</i> < 0.001). Expression of zonulin-1 and claudin-3 in duodenal mucosa was lowest in NAFLD. On principal co-ordinate analysis (PCoA), the global bacterial composition was significantly different across the three groups (PERMANOVA test, <i>P</i> < 0.001).<h4>Conclusion</h4>While remaining activated in both etiologies, gut-barrier dysfunction abnormalities were more pronounced in NAFLD at early stages compared to ALD despite more advanced disease in the latter.

Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the huntingtin ( HTT ) gene. Although the pathogenesis of HD remains complex, the CAG-expanded (CAG EX ) HTT mRNA and protein ultimately causes disease through a toxic gain-of-function mechanism. As the reduction of pathogenic mutant HTT mRNA is beneficial as a treatment, we developed a CAG EX RNA-eliminating CRISPR-Cas13d system (Cas13d/CAG EX ) that binds and eliminates toxic CAG EX RNA in HD patient iPSC-derived striatal neurons. We show that intrastriatal delivery of Cas13d/CAG EX via a single adeno-associated viral vector, serotype 9 (AAV9) mediates significant and selective reduction of mutant HTT mRNA and protein levels within the striatum of heterozygous zQ175 mice, an established mouse model of HD. Moreover, the reduction of mutant HTT mRNA renders a sustained reversal of HD phenotypes, including improved motor coordination, attenuated striatal atrophy, and reduction of mutant HTT protein aggregates. Importantly, phenotypic improvements were durable for at least 8 months without gross or behavioral adverse effects, and with minimal off-target interactions of Cas13d/CAG EX in the mouse transcriptome. Taken together, we demonstrate a proof-of-principle of an RNA-targeting CRISPR/Cas13d system as a therapeutic approach for HD, a strategy with broad implications for the treatment of other dominantly inherited neurodegenerative disorders.

<h4>Background</h4>Human hepcidin, produced by hepatocytes, regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic storage. Recent studies indicate that hepcidin deficiency is the underlying cause of the most known form of hereditary hemochromatosis.<h4>Case presentation</h4>A 44-year-old Asian man who developed type 2 diabetes mellitus had elevated serum ferritin levels (10,191 ng/mL). Liver biopsy revealed remarkable iron deposition in the hepatocytes and relatively advanced fibrosis (F3). Chromosomal analysis confirmed the presence of transferrin receptor type 2 mutations (c.1100T>G, c.2008_9delAC, hereditary hemochromatosis type 3 analyzed by Kawabata). The patient received intravenous infusions of Laennec (672 mg/day, three times/week) or oral administration with Porcine (3.87 g/day) for 84 months as an alternative to repeated phlebotomy. At the end of the treatment period, serum ferritin level decreased to 428.4 ng/mL (below the baseline level of 536.8 ng/mL). Hemoglobin A1c levels also improved after treatment with the same or lower dose of insulin (8.8% before versus 6.8% after). Plural liver biopsies revealed remarkable improvements in the grade of iron deposition and fibrosis (F3 before versus F1 after) of the liver tissue.<h4>Conclusion</h4>The discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis. Laennec (parenteral) and Porcine (oral), which act as hepcidin inducers, actually improved iron overload in this hereditary hemochromatosis patient, without utilizing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis (types 1, 2, and 3) but also ameliorating complications, such as type 2 diabetes, liver fibrosis, and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with venesection and may improve other iron-overloading disorders caused by hepcidin deficiency.

This review summarizes the current understanding of the development of the neuroendocrine gonadotropin-releasing hormone (GnRH) system, including discussion on open questions regarding (1) transcriptional regulation of the Gnrh1 gene; (2) prenatal development of the GnRH1 system in rodents and humans; and (3) paracrine and synaptic communication during migration of the GnRH cells.

Peripheral nerve and spinal cord injuries are potentially devastating traumatic conditions with major consequences for patients' lives. Severe cases of these conditions are currently incurable. In both the peripheral nerves and the spinal cord, disruption and degeneration of axons is the main cause of neurological deficits. Biomaterials offer experimental solutions to improve these conditions. They can be engineered as scaffolds that mimic the nerve tissue extracellular matrix and, upon implantation, encourage axonal regeneration. Furthermore, biomaterial scaffolds can be designed to deliver therapeutic agents to the lesion site. This article presents the principles and recent advances in the use of biomaterials for axonal regeneration and nervous system repair.

Pod color is a major economic trait of snap beans (<i>Phaseolus vulgaris</i> L.), among which the pod with a purple stripe is more attractive to people. A stable purple mutant with purple stripes on the pods was obtained by artificial mutagenesis with the high generation snap bean inbred line 'A18-1'. In order to reveal the genetic factors and pathways responsible for the purple appearance in snap bean, we performed transcriptome and metabolome analyses using the green stem and yellow pod cultivar 'A18-1' and its purple mutant '<i>pv-pur</i>' via ⁶⁰Co-γ radiation. Transcriptome analysis showed that three genes in the anthocyanin biosynthetic pathway were differentially expressed, among which the expression level of <i>F3'5'H</i> (<i>Phvul.006G018800</i>) was increased in the mutant '<i>pv-pur</i>', while expression of <i>F3'H</i> (<i>Phvul.004G021200</i>) and <i>ANS</i> (<i>Phvul.002G152700</i>) was downregulated. Anthocyanin-targeted metabonomics analysis showed significant differences in the contents of 10 metabolites between the wild type and mutant plants. Combined analysis of transcriptome and metabolomics showed that one differential metabolite, delphinidin, was related to the differential expression of <i>Phvul.006G024700</i>, <i>Phvul.002G152700</i>, and <i>Phvul.006G018800</i>. Based on the levels of six anthocyanins in wild type and mutant plants, we speculative that the purple appearance of the mutant '<i>pv-pur</i>' is caused by the increased expression of <i>F3'5'H</i> (<i>Phvul.006G018800</i>), the key enzyme in the transformation from dihydroflavanol (DHK) to dihydromyricetone (DHM) in the anthocyanin biosynthetic pathway. The results lay a foundation for further studies on the molecular mechanism of anthocyanin synthesis in snap bean, and provide a framework for breeding different colors of snap bean.

Little is known about differentially expressed genes (DEGs) and alternative splicing (AS) landscapes in congenital lung malformations (CLMs). We applied reference-based assembly of sequencing reads from RNA sequencing (RNA-seq) libraries to identify DEGs and AS landscapes in the lesions and normal lung tissue from the most common types of CLMs, including congenital pulmonary airway malformation-Ⅰ (CPAM-Ⅰ), CPAM-Ⅱ, intralobar sequestration (ILS), and ILS with CPAM (ILS-CPAM). We analyzed the expression profiles and related biological functions of AS events (ASEs). We further constructed a co-expression regulatory network between RNA binding protein (RBP) genes and corresponding ASEs to explore the related pathways in the regulated network. Ten DEGs were identified in the four types of CLMs, including eight upregulated genes and two downregulated genes. Additionally, 16 differential ASEs were detected, including the genes MACF1, RFX2, and FBXL4. Gene ontology (GO) enrichment was mainly observed in embryonic visual malformation and apoptotic process, and the KEGG pathway mainly enriched in the PI3K/AKT signaling pathway. We also detected 13 differentially expressed RBPs among 1979 DEGs in CPAM-I, in which ASEs in the MACF1 gene and RBP genes TLR8 and PTRH1 were closely associated. Moreover, we confirmed that the expression levels of PTRH1, NSUN7, and DZIP1L abundantly increased and the expression levels of TLR8, MEF2A, and NIPBL decreased in the CPAM-I lung tissue compared with the controls. It is suggested that ASEs in different types of CLMs is prominently different from normal controls, and ASEs differences occurring in CPAM-I malformation tissue are dramatically different from other types, which demonstrates the complex pathogenesis of CLMs and provides foundations for future studies to elucidate the mechanisms of developing CLMs.

Gastric cancer (GC) is one of the most common types of tumors and the most common cause of cancer mortality worldwide. The diagnosis of GC is critical to its prevention and treatment. Available tumor markers are the crucial step for GC diagnosis. Recent studies have shown that proteins in exosomes are potential diagnostic and prognostic markers for GC. Exosomes, secreted by cells, are cup-shaped with a diameter of 30-150 nm under the electron microscope. They are also surrounded by lipid bilayers and are widely found in various body fluids. Exosomes contain proteins, lipids and nucleic acid. The examination of exosomal proteins has the advantages of quickness, easy sampling, and low pain and cost, as compared with the routine inspection method of GC, which may lead to marked developments in GC diagnosis. This article summarized the exosomal proteins with a diagnostic and prognostic potential in GC, as well as exosomal proteins involved in GC progression.

Neurocognitive consequences of blast-induced traumatic brain injury (bTBI) pose significant concerns for military service members and veterans with the majority of "invisible injury." However, the underlying mechanism of such mild bTBI by low-intensity blast (LIB) exposure for long-term cognitive and mental deficits remains elusive. Our previous studies have shown that mice exposed to LIB result in nanoscale ultrastructural abnormalities in the absence of gross or apparent cellular damage in the brain. Here we tested the hypothesis that glutamatergic hyperexcitability may contribute to long-term learning deficits. Using brain slice electrophysiological recordings, we found an increase in averaged frequencies with a burst pattern of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal CA3 neurons in LIB-exposed mice at 1- and 7-days post injury, which was blocked by a specific NMDA receptor antagonist AP5. In addition, cognitive function assessed at 3-months post LIB exposure by automated home-cage monitoring showed deficits in dynamic patterns of discrimination learning and cognitive flexibility in LIB-exposed mice. Collected hippocampal tissue was further processed for quantitative global-proteomic analysis. Advanced data-independent acquisition for quantitative tandem mass spectrometry analysis identified altered expression of proteins involved in synaptic plasticity and serine protease inhibitors in LIB-exposed mice. Some were correlated with the ability of discrimination learning and cognitive flexibility. These findings show that acute glutamatergic hyperexcitability in the hippocampus induced by LIB may contribute to long-term cognitive dysfunction and protein alterations. Studies using this military-relevant mouse model of mild bTBI provide valuable insights into developing a potential therapeutic strategy to ameliorate hyperexcitability-modulated LIB injuries.

<h4>Purpose</h4>The incidence of hepatocellular carcinoma (HCC) in the United Kingdom has increased 60% in the past 10 years. The epidemics of obesity and type 2 diabetes are contributing factors. In this article, we examine the impact of diabetes and glucose-lowering treatments on HCC incidence and overall survival (OS).<h4>Methods</h4>Data from 1064 patients diagnosed with chronic liver disease (CLD) (n = 340) or HCC (n = 724) were collected from 2007 to 2012. Patients with HCC were followed up prospectively. Univariate and multivariate logistic regression determined HCC risk factors. Kaplan-Meier curves were used to examine survival and Cox proportional hazards analysis estimated hazard ratios (HRs) for death according to use of glucose-lowering therapies.<h4>Findings</h4>Diabetes prevalence was 39.6% and 10.6% within the HCC and CLD cohorts, respectively. The odds ratio for having HCC in patients with diabetes was 5.55 (P < 0.001). Univariate analysis found an increased association of HCC with age, sex, cirrhosis, hemochromatosis, alcohol abuse, diabetes, and Child's Pugh score. In multivariate analysis age, sex, cirrhosis, Child's Pugh score, diabetes status, and insulin use retained significance. Diabetes status did not significantly affect OS in HCC; however, in people with diabetes and HCC, metformin treatment was associated with improved OS (mean survival, 31 vs 24 months; P =0.016; HR for death = 0.75; P = 0.032).<h4>Implications</h4>Diabetes is significantly associated with HCC in the United Kingdom. Metformin treatment is associated with improved OS after HCC diagnosis. Treatment of diabetes should be appropriately reviewed in high-risk populations, with specific consideration of the potential hepatoprotective effects of metformin in HCC.

As the worldwide average life expectancy has grown, the prevalence of age-related neurodegenerative diseases (NDDs) has risen dramatically. A progressive loss of neuronal function characterizes NDDs, usually followed by neuronal death. Inflammation, apoptosis, oxidative stress, and protein misfolding are critical dysregulated signaling pathways that mainly orchestrate neuronal damage from a mechanistic point. Furthermore, in afflicted families with genetic anomalies, mutations and multiplications of α-synuclein and amyloid-related genes produce some kinds of NDDs. Overproduction of such proteins, and their excessive aggregation, have been proven in various models of neuronal malfunction and death. In this line, providing multi-target therapies carried by novel delivery systems would pave the road to control NDDs through simultaneous modulation of such dysregulated pathways. Phytochemicals are multi-target therapeutic agents, which employ several mechanisms towards neuroprotection. Besides, the blood-brain barrier (BBB) is a critical issue in managing NDDs since it inhibits the accessibility of drugs to the brain in sufficient concentration. Besides, discovering novel delivery systems is vital to improving the efficacy, bioavailability, and pharmacokinetic of therapeutic agents. Such novel formulations are also employed to improve the drug's biodistribution, allow for the co-delivery of several medicines, and offer targeted intracellular delivery against NDDs. The present review proposes nanoformulations of phytochemicals and synthetic agents to combat NDDs by modulating neuroinflammation, neuroapoptosis, neuronal oxidative stress pathways and protein misfolding.

Hypertension and coronary heart disease are the most common cardiovascular diseases, and traditional Chinese medicine is applied as an auxiliary treatment for common cardiovascular diseases. This study is based on 3 years of electronic medical record data from the Affiliated Hospital of Shandong University of Traditional Chinese Medicine. A complex network and machine learning algorithm were used to establish a screening model of coupled herbs for the treatment of hypertension complicated with coronary heart disease. A total of 5688 electronic medical records were collected to establish the prescription network and symptom database. The hierarchical network extraction algorithm was used to obtain core herbs. Biological features of herbs were collected from public databases. At the same time, five supervised machine learning models were established based on the biological features of the coupled herbs. Finally, the K-nearest neighbor model was established as a screening model with an AUROC of 91.0%. Seventy coupled herbs for adjuvant treatment of hypertension complicated with coronary heart disease were obtained. It was found that the coupled herbs achieved the purpose of adjuvant therapy mainly by interfering with cytokines and regulating inflammatory and metabolic pathways. These results show that this model can integrate the molecular biological characteristics of herbs, preliminarily screen combinations of herbs, and provide ideas for explaining the value in clinical applications.

Deacetylated chitin derivatives have been widely studied for tissue engineering purposes. This study aimed to compare the efficacy of an injectable product containing a 50% deacetylated chitin derivative (BoneReg-Inject™) and an existing product (chronOS Inject^®) serving as a predicate device. A sheep model with a critical size drill hole in the tibial plateau was used. Holes of 8 mm diameter and 30 mm length were drilled bilaterally into the proximal area of the tibia and BoneReg-Inject™ or chronOS Inject^® were injected into the right leg holes. Comparison of resorption and bone formation in vivo was made by X-ray micro-CT and histological evaluation after a live phase of 12 weeks. Long-term effects of BoneReg-Inject™ were studied using a 13-month live period. Significant differences were observed in (1) amount of new bone within implant (<i>p</i> < 0.001), higher in BoneReg-Inject^TM, (2) signs of cartilage tissue (<i>p</i> = 0.003), more pronounced in BoneReg-Inject^TM, and (3) signs of fibrous tissue (<i>p</i> < 0.001), less pronounced in BoneReg-Inject^TM. Mineral content at 13 months postoperative was significantly higher than at 12 weeks (<i>p</i> < 0.001 and <i>p</i> < 0.05, for implant core and rim, respectively). The data demonstrate the potential of deacetylated chitin derivatives to stimulate bone formation.

piRNAs (PIWI-interacting RNAs) are small non-coding RNAs capable of regulation of transposon and gene expression. piRNAs utilise multiple mechanisms to affect gene expression, which makes them potentially more powerful regulators than microRNAs. The mechanisms by which piRNAs regulate transposon and gene expression include DNA methylation, histone modifications, and mRNA degradation. Genitourinary cancers (GC) are a large group of neoplasms that differ by their incidence, clinical course, biology, and prognosis for patients. Regardless of the GC type, metastatic disease remains a key therapeutic challenge, largely affecting patients' survival rates. Recent studies indicate that piRNAs could serve as potentially useful biomarkers allowing for early cancer detection and therapeutic interventions at the stage of non-advanced tumour, improving patient's outcomes. Furthermore, studies in prostate cancer show that piRNAs contribute to cancer progression by affecting key oncogenic pathways such as PI3K/AKT. Here, we discuss recent findings on biogenesis, mechanisms of action and the role of piRNAs and the associated PIWI proteins in GC. We also present tools that may be useful for studies on the functioning of piRNAs in cancers.

Pigs are strategically important animals for the agricultural industry. An assessment of genetic differentiation between pigs, undergone and not undergone to selection intensification, is of particular interest. Our research was conducted on two groups of Large White pigs grown on the same farm but in different years. A total of 165 samples were selected with 78 LW_А (<i>n</i> = 78, the Russian selection) and LW_B (<i>n</i> = 87, a commercial livestock). For genotyping, we used GeneSeek^® GGP Porcine HD Genomic Profiler v1 (Illumina Inc, San Diego, CA, USA). To define breeding characteristics of selection, we used smoothing FST and segment identification of HBD (Homozygous-by-Descent). The results of smoothing FST showed 20 areas of a genome with strong ejection regions of the genome located on all chromosomes except SSC2, SSC3, and SSC8. The average realized autozygosity in Large White pigs of native selection was in (LW_A)-0.21, in LW_В-0.29. LW_А showed 13,338 HBD segments, 171 per one animal, and LW_B-15,747 HBD segments, 181 per one animal. The ejections found by the smoothing FST method were partially localized in the HBD regions. In these areas, the genes ((NCBP1, PLPPR1, GRIN3A, NBEA, TRPC4, HS6ST3, NALCN, SMG6, TTC3, KCNJ6, IKZF2, OBSL1, CARD10, ETV6, VWF, CCND2, TSPAN9, CDH13, CEP128, SERPINA11, PIK3CG, COG5, BCAP29, SLC26A4) were defined. The revealed genes can be of special interest for further studying their influence on an organism of an animal since they can act as candidate genes for selection-significant traits.

Following the first proof of concept of using small nucleic acids to modulate gene expression, a long period of maturation led, at the end of the last century, to the first marketing authorization of an oligonucleotide-based therapy. Since then, 12 more compounds have hit the market and many more are in late clinical development. Many companies were founded to exploit their therapeutic potential and Big Pharma was quickly convinced that oligonucleotides could represent credible alternatives to protein-targeting products. Many technologies have been developed to improve oligonucleotide pharmacokinetics and pharmacodynamics. Initially targeting rare diseases and niche markets, oligonucleotides are now able to benefit large patient populations. However, there is still room for oligonucleotide improvement and further breakthroughs are likely to emerge in the coming years. In this review we provide an overview of therapeutic oligonucleotides. We present in particular the different types of oligonucleotides and their modes of action, the tissues they target and the routes by which they are administered to patients, and the therapeutic areas in which they are used. In addition, we present the different ways of patenting oligonucleotides. We finally discuss future challenges and opportunities for this drug-discovery platform.

<h4>Objective</h4>Very few clinical predictors of descending thoracic aorta dissection have been determined. Although aneurysms can dissect in a size-dependent process, most descending dissections will occur without prior enlargement. We compared the proteomic profiles of normal, dissected, aneurysm, and both aneurysm and dissected descending thoracic aortas to identify novel biomarkers and further understand the molecular pathways that lead to tissue at risk of dissection.<h4>Methods</h4>We performed proteomic profiling of descending thoracic aortas with four phenotypes: normal (n = 46), aneurysm (n = 22), dissected (n = 12), and combined aneurysm and dissection (n = 8). Pairwise differential protein expression analyses using a Bayesian approach were then performed to identify common proteins that were dysregulated between each diseased tissue type and control aorta and to uncover unique proteins between aneurysmal and dissected aortas. Network and Markov cluster algorithms of differentially expressed proteins were used to find enriched ontology processes. A convex analysis of mixtures was also performed to identify the molecular subtypes within the different tissue types.<h4>Results</h4>The diseased aortas had 71 common differentially expressed proteins compared with the control, including higher amounts of the protein thrombospondin 1. We found 42 differentially expressed proteins between the aneurysm and dissected tissue, with an abundance of apolipoproteins in the former and higher quantities of extracellular matrix proteins in the latter. The convex analysis of mixtures showed enhancement of a molecular subtype enriched in contractile proteins within the control tissue compared with the diseased tissue, in addition to increased proportions of molecular subtypes enriched in inflammation and red blood cell expression in the aneurysmal compared with the dissected tissue.<h4>Conclusions</h4>We found some overlapping differentially expressed proteins in aneurysmal and nonaneurysmal descending thoracic aortas at risk of dissection compared with normal aortas. However, we also found uniquely altered molecular pathways that might uncover mechanisms for dissection.

Ferroptosis is a regulated iron-dependent cell death mechanism accompanied by the accumulation of peroxidized phospholipids, particularly phosphatidylethanolamine, in the cell. It occurs due to the disbalance between production and elimination of oxidized phospholipids in response to ferroptotic stimuli. A growing body of recent studies indicates that ferroptosis is involved in the pathogenesis of various human diseases leading to organ/tissue abnormalities. Due to their central role in ATP synthesis, ROS production, iron homeostasis, and redox status, mitochondria have been proposed to mediate ferroptotic signaling pathways. However, precise mechanisms underlying the potential role of mitochondria in ferroptosis remain unrevealed. This review summarizes and discusses previous studies on the contribution of mitochondria to ferroptotic cell death and highlights future directions elucidating the mitochondria as a promising target to prevent cell death through blocking ferroptosis.

<i><b>Introduction:</b></i> Pompe disease (PD) is a disease caused by pathogenic variations in the GAA gene known as glycogen storage disease type II, characterized by heart hypertrophy, respiratory failure, and muscle hypotonia, leading to premature death if not treated early. The only treatment option, enzyme replacement therapy (ERT), significantly improves the prognosis for some patients while failing to help others. In this study, the determination of key genes involved in the response to ERT and potential molecular mechanisms were investigated. <i><b>Methods:</b> </i> Gene Expression Omnibus (GEO) data, accession number GSE38680, containing samples of biceps and quadriceps muscles was used. Expression array data were analyzed using BRB-Array Tools. Biceps group patients did not receive ERT, while quadriceps received treatment with rhGAA at 0, 12, and 52 weeks. Differentially expressed genes (DEGs) were deeply analyzed by DAVID, GO, KEGG and STRING online analyses, respectively. <i><b>Results:</b> </i> A total of 1727 genes in the biceps group and 1198 genes in the quadriceps group are expressed differently. It was observed that DEGs were enriched in the group that responded poorly to ERT in the 52nd week. Genes frequently changed in the weak response group; the expression of 530 genes increased and 1245 genes decreased compared to 0 and 12 weeks. The GO analysis demonstrated that the DEGs were mainly involved in vascular smooth muscle contraction, lysosomes, autophagy, regulation of actin cytoskeleton, inflammatory response, and the WNT signaling pathway. We also discovered that the WNT signaling pathway is highly correlated with DEGs. Several DEGs, such as <i>WNT11, WNT5A, CTNNB1, M6PR, MYL12A, VCL, TLN, FYN, YES1</i>, and <i>BCL2</i>, may be important in elucidating the mechanisms underlying poor response to ERT. <i><b>Conclusion:</b> </i> Early diagnosis and treatment of PD are very important for the clinic of the disease. As a result, it suggests that the enriched genes and new pathways emerging as a result of the analysis may help identify the group that responds poorly to treatment and the outcome of the treatment. Obtained genes and pathways in neonatal screening will guide diagnosis and treatment.

<h4>Background</h4>Pulmonary arteriovenous malformations are mostly caused by congenitally abnormal shunts between pulmonary arteries and pulmonary veins.<h4>Case presentation</h4>A 74-year-old Japanese woman with a history of bronchiectasis was admitted to our hospital because of dyspnea on exertion. Pulmonary angiography and reconstructed three-dimensional contrast-enhanced computed tomography images showed shunts between pulmonary arteries and pulmonary veins, indicating a diagnosis of pulmonary arteriovenous malformations. Coil embolization of the shunts was successful.<h4>Conclusions</h4>Our findings imply that bronchiectasis can cause pulmonary arteriovenous malformations, and thus patients who present with hypoxemia with bronchiectasis should be carefully evaluated.

The highly heterogeneous symptomatology and unpredictable progress of COVID‑19 triggered unprecedented intensive biomedical research and a number of clinical research projects. Although the pathophysiology of the disease is being progressively clarified, its complexity remains vast. Moreover, some extremely infrequent cases of thrombotic thrombocytopenia following vaccination against SARS‑CoV‑2 infection have been observed. The present study aimed to map the signaling pathways of thrombocytopenia implicated in COVID‑19, as well as in vaccine‑induced thrombotic thrombocytopenia (VITT). The biomedical literature database, MEDLINE/PubMed, was thoroughly searched using artificial intelligence techniques for the semantic relations among the top 50 similar words (>0.9) implicated in COVID‑19‑mediated human infection or VITT. Additionally, STRING, a database of primary and predicted associations among genes and proteins (collected from diverse resources, such as documented pathway knowledge, high‑throughput experimental studies, cross‑species extrapolated information, automated text mining results, computationally predicted interactions, etc.), was employed, with the confidence threshold set at 0.7. In addition, two interactomes were constructed: i) A network including 119 and 56 nodes relevant to COVID‑19 and thrombocytopenia, respectively; and ii) a second network containing 60 nodes relevant to VITT. Although thrombocytopenia is a dominant morbidity in both entities, three nodes were observed that corresponded to genes (AURKA, CD46 and CD19) expressed only in VITT, whilst ADAM10, CDC20, SHC1 and STXBP2 are silenced in VITT, but are commonly expressed in both COVID‑19 and thrombocytopenia. The calculated average node degree was immense (11.9 in COVID‑19 and 6.43 in VITT), illustrating the complexity of COVID‑19 and VITT pathologies and confirming the importance of cytokines, as well as of pathways activated following hypoxic events. In addition, PYCARD, NLP3 and P2RX7 are key potential therapeutic targets for all three morbid entities, meriting further research. This interactome was based on wild‑type genes, revealing the predisposition of the body to hypoxia‑induced thrombosis, leading to the acute COVID‑19 phenotype, the 'long‑COVID syndrome', and/or VITT. Thus, common nodes appear to be key players in illness prevention, progression and treatment.

SUMOylation is a ubiquitination-like post-translational modification that plays an essential role in the regulation of protein function. Recent studies have shown that proteins from both RNA and DNA virus families can be modified by SUMO conjugation, which facilitates viral replication. Viruses can manipulate the entire process of SUMOylation through interplay with the SUMO pathway. By contrast, SUMOylation can eliminate viral infection by regulating host antiviral immune components. A deeper understanding of how SUMOylation regulates viral proteins and cellular antiviral components is necessary for the development of effective antiviral therapies. In the present review, the regulatory mechanism of SUMOylation in viral replication and infection and the antiviral immune response, and the consequences of this regulation for viral replication and engagement with antiviral innate immunity are summarized. The potential therapeutic applications of SUMOylation in diseases caused by viruses are also discussed.

<h4>Background</h4>Patients with Huntington's disease (HD) exhibit a variable predominance of cognitive, behavioral and motor symptoms. A specific instrument focusing on the impact of cognitive impairment in HD over functional capacity is lacking.<h4>Objective</h4>To address the need for a brief and specifically developed HD questionnaire able to capture functional aspects suspected to be sensitive to cognitive impairment.<h4>Methods</h4>We developed and validated the "Huntington's Disease-Cognitive Functional Rating Scale" (HD-CFRS) in 78 symptomatic carriers of the Huntington's disease mutation. We also administered the HD-CFRS to a knowledgeable informant to measure the level of agreement. To explore the association between HD-CFRS scores and participants' cognitive status, we administered objective measures of cognition. Participants were classified as cognitively preserved (HD-NC), as having mild cognitive impairment (HD-MCI), or as having dementia (HD-Dem).<h4>Results</h4>The HD-CFRS showed concurrent validity and internal consistency in the three groups. HD carriers and informants in the HD-NC group obtained similar HD-CFRS scores. However, in patients with mild cognitive impairment and dementia, informers reported greater functional impairment than HD participants. The HD-CFRS total score showed strong correlations with measures assessing cognition.<h4>Conclusions</h4>These findings support the utility of the HD-CFRS as a brief and reliable instrument to measure functional defects associated with cognitive impairment in HD. We believe this questionnaire could be a useful tool both for clinical practice and research.

Heart failure (HF) is a clinical condition distinguished by structural and functional defects in the myocardium, which genetic and environmental factors can induce. HF is caused by various genetic factors that are both heterogeneous and complex. The incidence of HF varies depending on the definition and area, but it is calculated to be between 1 and 2% in developed countries. There are several factors associated with the progression of HF, ranging from coronary artery disease to hypertension, of which observed the most common genetic cause to be cardiomyopathy. The main objective of this study is to investigate heart failure and its association with cardiomyopathy with their genetic variants. The selected novel genes that have been linked to human inherited cardiomyopathy play a critical role in the pathogenesis and progression of HF. Research sources collected from the human gene mutation and several databases revealed that numerous genes are linked to cardiomyopathy and thus explained the hereditary influence of such a condition. Our findings support the understanding of the genetics aspect of HF and will provide more accurate evidence of the role of changing disease accuracy. Furthermore, a better knowledge of the molecular pathophysiology of genetically caused HF could contribute to the emergence of personalized therapeutics in future.

Injectable hydrogels are desired in many biomedical applications due to their minimally invasive deployment to the body and their ability to introduce drugs. However, current injectables suffer from mechanical mismatch with tissue, fragility, water expulsion, and high viscosity. To address these issues, we design brush-like macromolecules that concurrently provide softness, firmness, strength, fluidity, and swellability. The synthesized linear-bottlebrush-linear (LBL) copolymers facilitate improved injectability as the compact conformation of bottlebrush blocks results in low solution viscosity, while the thermoresponsive linear blocks permit prompt gelation at 37°C. The resulting hydrogels mimic the deformation response of supersoft tissues such as adipose and brain while withstanding deformations of 700% and precluding water expulsion upon gelation. Given their low cytotoxicity and mild inflammation in vivo, the developed materials will have vital implications for reconstructive surgery, tissue engineering, and drug delivery applications.

Hemophilia is a hereditary disease that remains incurable. Although innovative treatments such as gene therapy or bispecific antibody therapy have been introduced, substantial unmet needs still exist with respect to achieving long-lasting therapeutic effects and treatment options for inhibitor patients. Antithrombin (AT), an endogenous negative regulator of thrombin generation, is a potent genome editing target for sustainable treatment of patients with hemophilia A and B. In this study, we developed and optimized lipid nanoparticles (LNPs) to deliver Cas9 mRNA along with single guide RNA that targeted AT in the mouse liver. The LNP-mediated CRISPR-Cas9 delivery resulted in the inhibition of AT that led to improvement in thrombin generation. Bleeding-associated phenotypes were recovered in both hemophilia A and B mice. No active off-targets, liver-induced toxicity, and substantial anti-Cas9 immune responses were detected, indicating that the LNP-mediated CRISPR-Cas9 delivery was a safe and efficient approach for hemophilia therapy.

<h4>Background</h4>Knowledge of factors that influence the outcome of infection are crucial for determining the risk of severe disease and requires the characterisation of pathogen-host interactions that have evolved to confer variable susceptibility to infection. Cattle infected by Theileria annulata show a wide range in disease severity. Native (Bos indicus) Sahiwal cattle are tolerant to infection, whereas exotic (Bos taurus) Holstein cattle are susceptible to acute disease.<h4>Methodology/principal findings</h4>We used RNA-seq to assess whether Theileria infected cell lines from Sahiwal cattle display a different transcriptome profile compared to Holstein and screened for altered expression of parasite factors that could generate differences in host cell gene expression. Significant differences (<0.1 FDR) in the expression level of a large number (2211) of bovine genes were identified, with enrichment of genes associated with Type I IFN, cholesterol biosynthesis, oncogenesis and parasite infection. A screen for parasite factors found limited evidence for differential expression. However, the number and location of DNA motifs bound by the TashAT2 factor (TA20095) were found to differ between the genomes of B. indicus vs. B. taurus, and divergent motif patterns were identified in infection-associated genes differentially expressed between Sahiwal and Holstein infected cells.<h4>Conclusions/significance</h4>We conclude that divergent pathogen-host molecular interactions that influence chromatin architecture of the infected cell are a major determinant in the generation of gene expression differences linked to disease susceptibility.

Zebrafish possess the ability to completely regenerate the retina following injury, however little is understood about the damage signals that contribute to inducing Müller glia reprogramming and proliferation to regenerate lost neurons. Multiple studies demonstrated that iron contributes to various retinal injuries, however no link has been shown between iron and zebrafish retinal regeneration. Here we demonstrate that Müller glia exhibit transcriptional changes following injury to regulate iron levels within the retina, allowing for increased iron uptake and decreased export. The response of the zebrafish retina to intravitreal iron injection was then characterized, showing that ferrous, and not ferric, iron induces retinal cell death. Additionally, iron chelation resulted in decreased numbers of TUNEL-positive photoreceptors and fewer proliferating Müller glia. Despite the contribution of iron to retinal cell death, inhibition of ferroptosis did not significantly reduce cell death following light treatment. Finally, we demonstrate that both the anti-ferroptotic protein Glutathione peroxidase 4b and the Transferrin receptor 1b are required for Müller glia proliferation following light damage. Together these findings show that iron contributes to cell death in the light-damaged retina and is essential for inducing the Müller glia regeneration response.

Antibodies and T cells specific for tumor-associated antigens (TAA) are found in individuals without cancer but with a history of infections and are associated with lowered cancer risk. We hypothesized that those immune responses were generated to transiently abnormally expressed self-antigens on infected cells (disease-associated antigens, DAA) and later on tumor cells as TAA. We tested this hypothesis in mice with a history of infection with lymphocytic choriomeningitis virus (LCMV) Armstrong strain (Arm) that causes acute infection when injected intraperitoneally or CL-13 strain that establishes chronic infection when injected intravenously. Both elicited antibodies and T cells that recognized DAA/TAA on infected cells and on mouse tumors. When challenged with those tumors, Arm-experienced mice controlled tumors better than CL-13-experienced mice or infection-naïve mice. We characterized 7 DAA/TAA that were targets of LCMV-elicited antitumor immunity. We then vaccinated mice with tumor-derived gp96, a heat shock protein that binds a variety of TAA peptides, including those expressed on virus-infected cells as DAA. Tumor-gp96 vaccine induced DAA/TAA-specific immunity. When challenged with Cl-13, the mice showed lower viral copy numbers both early (day 7) and late (day 70) in infection. DAA/TAA may be immunogenic and safe candidates to develop vaccines to control both infections and cancer.

The protein kinase, GSK-3, participates in diverse biological processes and is now recognized a promising drug discovery target in treating multiple pathological conditions. Over the last decade, a range of newly developed GSK-3 inhibitors of diverse chemotypes and inhibition modes has been developed. Even more conspicuous is the dramatic increase in the indications that were tested from mood and behavior disorders, autism and cognitive disabilities, to neurodegeneration, brain injury and pain. Indeed, clinical and pre-clinical studies were largely expanded uncovering new mechanisms and novel insights into the contribution of GSK-3 to neurodegeneration and central nerve system (CNS)-related disorders. In this review we summarize new developments in the field and describe the use of GSK-3 inhibitors in the variety of CNS disorders. This remarkable volume of information being generated undoubtedly reflects the great interest, as well as the intense hope, in developing potent and safe GSK-3 inhibitors in clinical practice.

Prostate cancer invokes major shifts in gene transcription and metabolic signaling to mediate alterations in nutrient acquisition and metabolic substrate selection when compared to normal tissues. Exploiting such metabolic reprogramming is proposed to enable the development of targeted therapies for prostate cancer, yet there are several challenges to overcome before this becomes a reality. Herein, we outline the role of several nutrients known to contribute to prostate tumorigenesis, including fatty acids, glucose, lactate and glutamine, and discuss the major factors contributing to variability in prostate cancer metabolism, including cellular heterogeneity, genetic drivers and mutations, as well as complexity in the tumor microenvironment. The review draws from original studies employing immortalized prostate cancer cells, as well as more complex experimental models, including animals and humans, that more accurately reflect the complexity of the <i>in vivo</i> tumor microenvironment. In synthesizing this information, we consider the feasibility and potential limitations of implementing metabolic therapies for prostate cancer management.

Gastrointestinal (GI) cancer represents a major global health problem due to its aggressive characteristics and poor prognosis. Despite the progress achieved in the development of treatment regimens, the clinical outcomes and therapeutic responses of patients with GI cancer remain unsatisfactory. Chemoresistance arising throughout the clinical intervention is undoubtedly a critical barrier for the successful treatment of GI cancer. However, the precise mechanisms associated with chemoresistance in GI cancer remain unclear. In the past decade, accumulating evidence has indicated that circular RNAs (circRNAs) play a key role in regulating cancer progression and chemoresistance. Notably, circRNAs function as molecular sponges that sequester microRNAs (miRNAs) and/or proteins, and thus indirectly control the expression of specific genes, which eventually promote or suppress drug resistance in GI cancer. Therefore, circRNAs may represent potential therapeutic targets for overcoming drug resistance in patients with GI cancer. This review comprehensively summarizes the regulatory roles of circRNAs in the development of chemoresistance in different GI cancers, including colorectal cancer, gastric cancer and esophageal cancer, as well as deciphers the underlying mechanisms and key molecules involved. Increasing knowledge of the important functions of circRNAs underlying drug resistance will provide new opportunities for developing efficacious therapeutic strategies against GI cancer.

Aneuploidy is widely identified as a remarkable feature of malignancy genomes. Increasing evidences suggested aneuploidy was involved in the progression and metastasis of prostate cancer (PCa). Nevertheless, no comprehensive analysis was conducted in PCa about the effects of aneuploidy on different omics and, especially, about the driver genes of aneuploidy. Here, we validated the association of aneuploidy with the progression and prognosis of PCa and performed a systematic analysis in mutation profile, methylation profile, and gene expression profile, which detailed the molecular process aneuploidy implicated. By multi-omics analysis, we managed to identify 11 potential aneuploidy driver genes (GSTM2, HAAO, C2orf88, CYP27A1, FAXDC2, HFE, C8orf88, GSTP1, EFS, HIF3A, and WFDC2), all of which were related to the development and metastasis of PCa. Meanwhile, we also found aneuploidy and its driver genes were correlated with the immune microenvironment of PCa. Our findings could shed light on the tumorigenesis of PCa and provide a better understanding of the development and metastasis of PCa; additionally, the driver genes could be promising and actionable therapeutic targets pointing to aneuploidy.

Owing to the limitations of traditional systemic drug delivery in the treatment of bone diseases with side effects on normal cells, the selection of materials with high affinities for bones, as targeting ligands to modify drug carriers, has become an important research topic. Tetracyclines (TCs) have an adsorption effect on hydroxyapatite (HAp). Thus, they can be used as bone-targeting ligands and combined with drug carriers. In this study, density functional theory is used to analyze the interaction mechanism of TC, oxytetracycline (OTC), chlortetracycline, and HAp. We calculate the electrostatic potential (ESP) and molecular orbitals to predict the possible binding sites of TCs on the HAp surface. The adsorption energy is used to compare the affinities of the three TCs to HAp. An independent gradient model analysis is performed to study the weak interaction between TCs and HAp. The coordination bond between TCs and the HAp surface is evaluated by conducting a charge density difference analysis. The results show that OTC has the highest affinity to HAp because the introduction of hydroxyl groups change the adsorption configuration of OTC. Thus, OTC adsorbed on HAp in a broken-line shape exposes more binding sites. This study provides a theoretical basis for TCs as bone-targeting ligands in treating bone diseases and in improving the safety of treatment by selecting different bone-targeting ligands.

The need for the repair of bone defects has been increasing due to various causes of loss of skeletal tissue. High density polyethylenes (HDPE) have been used as bone substitutes due to their excellent biocompatibility and mechanical strength. In the present study, we investigated the preosteoblast cell proliferation and differentiation on the adding nano-hydroxyapatite (n-HAp) particles into HDPE scaffold and treating HDPE/n-HAp scaffolds with nitrogen (N₂) plasma. The three-dimensional (3D) HDPE/n-HAp scaffolds were prepared by fused modeling deposition 3D printer. The HDPE/n-HAp was blended with 10 wt% of n-HAp particle. The scaffold surface was reactive ion etched with nitrogen plasma to improve the preosteoblast biological response in vitro. After N₂ plasma treatment, surfaces characterizations were investigated using Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy. The proliferation and differentiation of preosteoblast (MC3T3-E1) cells were evaluated by MTT assay and alkaline phosphatase (ALP) activity. The incorporation of n-HAp particles and N₂ plasma surface treatment showed the improvement of biological responses of MC3T3-E1 cells in the HDPE scaffolds.

To obtain a more detailed picture of macrophage (MΦ) biology, in the current study, we analyzed the transcriptome of mouse peritoneal MΦs by RNA-seq and PCR-based transcriptomics. The results show that peritoneal MΦs, based on mRNA content, under non-inflammatory conditions produce large amounts of a number of antimicrobial proteins such as lysozyme and several complement components. They were also found to be potent producers of several chemokines, including platelet factor 4 (PF4), Ccl6, Ccl9, Cxcl13, and Ccl24, and to express high levels of both TGF-β1 and TGF-β2. The liver is considered to be the main producer of most complement and coagulation components. However, we can now show that MΦs are also important sources of such compounds including C1qA, C1qB, C1qC, properdin, C4a, factor H, ficolin, and coagulation factor FV. In addition, FX, FVII, and complement factor B were expressed by the MΦs, altogether indicating that MΦs are important local players in both the complement and coagulation systems. For comparison, we analyzed human peripheral blood monocytes. We show that the human monocytes shared many characteristics with the mouse peritoneal MΦs but that there were also many major differences. Similar to the mouse peritoneal MΦs, the most highly expressed transcript in the monocytes was lysozyme, and high levels of both properdin and ficolin were observed. However, with regard to connective tissue components, such as fibronectin, lubricin, syndecan 3, and extracellular matrix protein 1, which were highly expressed by the peritoneal MΦs, the monocytes almost totally lacked transcripts. In contrast, monocytes expressed high levels of MHC Class II, whereas the peritoneal MΦs showed very low levels of these antigen-presenting molecules. Altogether, the present study provides a novel view of the phenotype of the major MΦ subpopulation in the mouse peritoneum and the large peritoneal MΦs and places the transcriptome profile of the peritoneal MΦs in a broader context, including a comparison of the peritoneal MΦ transcriptome with that of human peripheral blood monocytes and the liver.

A deficiency of vitamin A (VAD) and iron is the most common nutritional problem affecting people worldwide. Given the scale of the problem, the interactions between vitamin A and iron levels are widely studied. However, the exact mechanism of the impact of vitamin A on the regulation of iron metabolism remains unclear. An extremely significant issue becomes a better understanding of the nature of the studied biological phenomenon, which is possible by using a systems approach through developing and analyzing a mathematical model based on a Petri net. To study the considered system, the t-cluster analysis, the significance analysis, and the analysis of the average number of transition firings were performed. The used analyses have allowed distinguishing the most important mechanisms (both subprocesses and elementary processes) positively and negatively regulating an expression of hepcidin and allowed to distinguish elementary processes with a higher frequency of occurrence compared to others. The analysis also allowed to resolve doubts about the discrepancy in literature reports, where VAD leads to positive regulation of hepcidin expression or to negative regulation of hepcidin expression. The more detailed analyses have shown that VAD more frequently positively stimulates hepcidin expression and this mechanism is more significant than the mechanism inhibiting hepcidin expression indirectly by VAD.

Anti-CD133 monoclonal antibody (Ab)-conjugated poly(lactide-co-glycolide) (PLGA) nanocarriers, for the targeted delivery of oxaliplatin (OXA) and superparamagnetic nanoparticles (IO-OA) to colorectal cancer cells (CaCo-2), were designed, synthesized, characterized, and evaluated in this study. The co-encapsulation of OXA and IO-OA was achieved in two types of polymeric carriers, namely, PLGA and poly(lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) by double emulsion. PLGA_IO-OA_OXA and PEGylated PLGA_IO-OA_OXA nanoparticles displayed a comparable mean diameter of 207 ± 70 nm and 185 ± 119 nm, respectively. The concentration of the released OXA from the PEGylated PLGA_IO-OA_OXA increased very rapidly, reaching ~100% release after only 2 h, while the PLGA_IO-OA_OXA displayed a slower and sustained drug release. Therefore, for a controlled OXA release, non-PEGylated PLGA nanoparticles were more convenient. Interestingly, preservation of the superparamagnetic behavior of the IO-OA, without magnetic hysteresis all along the dissolution process, was observed. The non-PEGylated nanoparticles (PLGA_OXA, PLGA_IO-OA_OXA) were selected for the anti-CD133 Ab conjugation. The affinity of Ab-coated nanoparticles for CD133-positive cells was examined using fluorescence microscopy in CaCo-2 cells, which was followed by a viability assay.

Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well-known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector. First, 14 analogues of this compound were evaluated to check whether extending the parent structure with linkers of different lengths would not deteriorate the NK1R binding. The tested analogues had affinity similar to or better than the parent compound, and none of the linkers had a negative impact on the binding. Next, five DOTA conjugates were synthesized and used for labelling with ⁶⁸Ga and ¹⁷⁷Lu. The obtained radioconjugates turned out to be fairly lipophilic but showed rather limited stability in human plasma. Evaluation of the receptor affinity of the (radio)conjugates showed that neither the chelator nor the metal negatively impacts the NK1R binding. The ¹⁷⁷Lu-radioconjugates exhibited the binding characteristics towards NK1R similar or better than that of the ¹⁷⁷Lu-labelled derivative of Substance P, which is in current clinical use. The experimental results presented herein, along with their structural rationalization provided by modelling, give insight for the further molecular design of small molecular NK1R-targeting vectors.

Iron is a trace element that is important for many vital processes, including oxygen transport, oxidative metabolism, cellular proliferation, and catalytic reactions. Iron supports these functions mainly as part of the heme molecule. Heme synthesis is an eight-step process which, when defective at the level of one of the eight enzymes involved, can cause the development of a group of diseases, either inherited or acquired, called porphyrias. Despite the strict link between iron and heme, the role of iron in the different types of porphyrias, particularly as a risk factor for disease development/progression or as a potential therapeutic target or molecule, is still being debated, since contrasting results have emerged from clinical observations, in vitro studies and animal models. In this review we aim to deepen such aspects by drawing attention to the current evidence on the role of iron in porphyrias and its potential implication. Testing for iron status and its metabolic pathways through blood tests, imaging techniques or genetic studies on patients affected by porphyrias can provide additional diagnostic and prognostic value to the clinical care, leading to a more tailored and effective management.

To improve the survival rate of cancer patients, biomarkers for both early diagnosis and patient stratification for appropriate therapeutics play crucial roles in precision oncology. Investigation of altered gene expression and the relevant molecular pathways in cancer cells are helpful for discovering such biomarkers. In this study, we explore the potential prognostic biomarkers for oral cancer patients through systematically analyzing five oral cancer transcriptomic data sets (TCGA, GSE23558, GSE30784, GSE37991, and GSE138206). Gene Set Enrichment Analysis (GSEA) was individually applied to each data set and the upregulated Hallmark molecular pathways of each data set were intersected to generate 13 common pathways including interferon-α/γ pathways. Among the 5 oral cancer data sets, 43 interferon pathway genes were commonly upregulated and 17 genes exhibited prognostic values in TCGA cohort. After validating in another oral cancer cohort (GSE65858), high expressions of C-X-C motif chemokine ligand 10 (CXCL10) and Signal transducer and activator of transcription 2 (STAT2) were confirmed to be good prognostic biomarkers. GSEA of oral cancers stratified by CXCL10/STAT2 expression showed that activation of T-cell pathways and increased tumor infiltration scores of Type 1 T helper (Th1) and CD8+ T cells were associated with high CXCL10/STAT2 expression. These results suggest that high CXCL10/STAT2 expression can predict a favorable outcome in oral cancer patients.

Ferroptosis is a newly discovered type of cell-regulated death. It is characterized by the accumulation of iron-dependent lipid peroxidation and can be distinguished from other forms of cell-regulated death by different morphology, biochemistry, and genetics. Recently, studies have shown that ferroptosis is associated with a variety of diseases, including liver, kidney and neurological diseases, as well as cancer. Ferroptosis has been shown to be associated with colorectal epithelial disorders, which can lead to cancerous changes in the gut. However, the potential role of ferroptosis in the occurrence and development of colorectal cancer (CRC) is still controversial. To elucidate the underlying mechanisms of ferroptosis in CRC, this article systematically reviews ferroptosis, and its cellular functions in CRC, for furthering the understanding of the pathogenesis of CRC to aid clinical treatment.

Progress in the development of salivary gland regenerative strategies is limited by poor maintenance of the secretory function of salivary gland cells (SGCs) in vitro. To reduce the precipitous loss of secretory function, a modified approach to isolate intact acinar cell clusters and intercalated ducts (AIDUCs), rather than commonly used single cell suspension, is investigated. This isolation approach yields AIDUCs that maintain many of the cell-cell and cell-matrix interactions of intact glands. Encapsulation of AIDUCs in matrix metalloproteinase (MMP)-degradable PEG hydrogels promotes self-assembly into salivary gland mimetics (SGm) with acinar-like structure. Expression of Mist1, a transcription factor associated with secretory function, is detectable throughout the in vitro culture period up to 14 days. Immunohistochemistry also confirms expression of acinar cell markers (NKCC1, PIP and AQP5), duct cell markers (K7 and K5), and myoepithelial cell markers (SMA). Robust carbachol and ATP-stimulated calcium flux is observed within the SGm for up to 14 days after encapsulation, indicating that secretory function is maintained. Though some acinar-to-ductal metaplasia is observed within SGm, it is reduced compared to previous reports. In conclusion, cell-cell interactions maintained within AIDUCs together with the hydrogel microenvironment may be a promising platform for salivary gland regenerative strategies.

MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c-Myc protein has been a challenge for >30 years. Here, WBC100, a novel oral active molecule glue that selectively degrades c-Myc protein over other proteins and potently kills c-Myc overexpressing cancer cells is reported. WBC100 targets the nuclear localization signal 1 (NLS1)-Basic-nuclear localization signal 2 (NLS2) region of c-Myc and induces c-Myc protein degradation through ubiquitin E3 ligase CHIP mediated 26S proteasome pathway, leading to apoptosis of cancer cells. In vivo, WBC100 potently regresses multiple lethal c-Myc overexpressing tumors such as acute myeloid leukemia, pancreatic, and gastric cancers with good tolerability in multiple xenograft mouse models. Identification of the NLS1-Basic-NLS2 region as a druggable pocket for targeting the "undruggable" c-Myc protein and that single-agent WBC100 potently regresses c-Myc overexpressing tumors through selective c-Myc proteolysis opens new perspectives for pharmacologically intervening c-Myc in human cancers.

<h4>Background</h4>In the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of KIT mutations in exons 9 and 11. In this retrospective, exploratory analysis of the GRID trial, we investigated whether a more comprehensive KIT mutation analysis could identify mutations that impact treatment outcome with regorafenib and a regorafenib-induced mutation pattern.<h4>Methods</h4>Archived tumor samples, collected at any time prior to enrollment in GRID, were analyzed by Sanger sequencing (n = 102) and next-generation sequencing (FoundationONE; n = 47). Plasma samples collected at baseline were analyzed by BEAMing (n = 163) and SafeSEQ (n = 96).<h4>Results</h4>In archived tumor samples, 67% (68/102) had a KIT mutation; 61% (62/102) had primary KIT mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). At baseline, 81% of samples (78/96) had KIT mutations by SafeSEQ, including the M541L polymorphism (sole event in 6 patients). Coexisting mutations in other oncogenes were rare, as were mutations in PDGFR, KRAS, and BRAF. Regorafenib showed PFS benefit across all primary and secondary KIT mutational subgroups examined. Available patient-matched samples taken at baseline and end of treatment (n = 41; SafeSEQ), revealed heterogeneous KIT mutational changes with no specific mutation pattern emerging upon regorafenib treatment.<h4>Conclusion</h4>These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.

<h4>Purpose</h4>To investigate whether co-administration of antiarrhythmic dronedarone and anticoagulant rivaroxaban would increase the risks of hemorrhage after atrial fibrillation (AF) ablation.<h4>Methods</h4>A total of 100 patients with AF who underwent radiofrequency catheter ablation (CA) in the Department of Cardiology, the Affiliated Hospital of Qingdao University from 2019-12 to 2020-11 were included. Patients were divided into an oral dronedarone and rivaroxaban group (D-R group, N = 50) and an oral amiodarone and rivaroxaban group (A-R group, N = 50) according to the postoperative antiarrhythmic and anticoagulation strategies. Patients in 2 groups were given propensity score matching (PSM) to obtain a sample with balanced inter-group covariates. A retrospective observational study was conducted. After 3 months of follow-up, the incidence of clinically relevant non-major bleeding (CRNMB), major hemorrhages, and early AF recurrence was observed.<h4>Results</h4>After PSM, 41 patients were included in each group. With similarly distributed baseline characteristics and ablation characteristics after PSM, the CRNMB rate after AF ablation was significantly higher in the D-R group than in the A-R group (26.8% versus 7.3%, P = 0.02), and no major hemorrhages were detected in both groups. No significant difference was observed in the sinus rhythm maintenance rate between the D-R group and the A-R group (26.8% vs. 22.0%, P = 0.43).<h4>Conclusions</h4>Compared to co-administration of amiodarone and rivaroxaban, co-administration of dronedarone and rivaroxaban increases the risk of CRNMB but it does not increase the risk of major hemorrhages in blanking period after AF ablation.

There is a rising interest in biotechnology for the compartmentalization of biochemical reactions in water droplets. Several applications, such as the widely used digital PCR, seek to encapsulate a single molecule in a droplet to be amplified. Directed evolution, another technology with growing popularity, seeks to replicate what happens in nature by encapsulating a single gene and the protein encoded by this gene, linking genotype with phenotype. Compartmentalizing reactions in droplets also allows the experimentalist to run millions of different reactions in parallel. Compartmentalization requires a fluid that is immiscible with water and a surfactant to stabilize the droplets. While there are fluids and surfactants on the market that have been used to accomplish encapsulation, there are reported concerns with these. Span® 80, for example, a commonly used surfactant, has contaminants that interfere with various biochemical reactions. Similarly, synthetic fluids distributed by the cosmetic industry allow some researchers to produce experimental results that can be published, but then other researchers fail to reproduce some of these protocols due to the unreliable nature of these products, which are not manufactured with the intent of being used in biotechnology. The most reliable fluids, immiscible with water and suitable for biochemical reactions, are fluorinated fluids. Fluorinated compounds have the peculiar characteristic of being immiscible with water while at the same time not mixing with hydrophobic molecules. This peculiar characteristic has made fluorinated fluids attractive because it seems to be the basis of their being biologically inert. However, commercially available fluorinated fluids have densities between 1.4 to 1.6 g/mL. The higher-than-water density of fluorinated oils complicates handling of the droplets since these would float on the fluid since the water droplets would be less dense. This can cause aggregation and coalescence of the droplets. Here, we report the synthesis, characterization, and use of fluorinated polysiloxane oils that have densities similar to the one of water at room temperature, and when mixed with non-ionic fluorinated surfactants, can produce droplets encapsulating biochemical reactions. We show how droplets in these emulsions can host many biological processes, including PCR, DNA origami, rolling circle amplification (RCA), and Taqman® assays. Some of these use unnatural DNA built from an Artificially Expanded Genetic Information System (AEGIS) with six nucleotide "letters".

The debilitating psychomotor symptoms of Huntington's disease (HD) are linked partly to degeneration of the basal ganglia indirect pathway. At early symptomatic stages, before major cell loss, indirect pathway neurons exhibit numerous cellular and synaptic changes in HD and its models. However, the impact of these alterations on circuit activity remains poorly understood. To address this gap, optogenetic- and reporter-guided electrophysiological interrogation was used in early symptomatic male and female <i>Q175</i> HD mice. D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs) were hypoactive during synchronous cortical slow-wave activity, consistent with known reductions in dendritic excitability and cortical input strength. Downstream prototypic parvalbumin-expressing external globus pallidus (PV⁺ GPe) neurons discharged at 2-3 times their normal rate, even during periods of D2-SPN inactivity, arguing that defective striatopallidal inhibition was not the only cause of their hyperactivity. Indeed, PV⁺ GPe neurons also exhibited abnormally elevated autonomous firing <i>ex vivo</i> Optogenetic inhibition of PV⁺ GPe neurons <i>in vivo</i> partially and fully ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative PV^- GPe neurons, respectively. In contrast to STN neurons whose autonomous firing is impaired in HD mice, putative PV^- GPe neuron activity was unaffected <i>ex vivo</i>, implying that excessive inhibition was responsible for their hypoactivity <i>in vivo</i> Together with previous studies, these data demonstrate that (1) indirect pathway nuclei are dysregulated in <i>Q175</i> mice through changes in presynaptic activity and/or intrinsic cellular and synaptic properties; and (2) prototypic PV⁺ GPe neuron hyperactivity and excessive target inhibition are prominent features of early HD pathophysiology.<b>SIGNIFICANCE STATEMENT</b> The early symptoms of Huntington's disease (HD) are linked to degenerative changes in the action-suppressing indirect pathway of the basal ganglia. Consistent with this linkage, the intrinsic properties of cells in this pathway exhibit complex alterations in HD and its models. However, the impact of these changes on activity is poorly understood. Using electrophysiological and optogenetic approaches, we demonstrate that the indirect pathway is highly dysregulated in early symptomatic HD mice through changes in upstream activity and/or intrinsic properties. Furthermore, we reveal that hyperactivity of external globus pallidus neurons and excessive inhibition of their targets are key features of early HD pathophysiology. Together, these findings could help to inform the development and targeting of viral-based, gene therapeutic approaches for HD.

Microglia play a role in the emergence and preservation of a healthy brain microenvironment. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative disorders. Investigating the function of human microglia in health and disease has been challenging due to the limited models of the human brain available. Here, we develop a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs). We apply this system to study the role of microglia during inflammation induced by amyloid-β (Aβ). The overexpression of the myeloid-specific transcription factor PU.1 generates microglia-like cells in hCOs, producing mhCOs (microglia-containing hCOs), that we engraft in the mouse brain. Single-cell transcriptomics reveals that mhCOs acquire a microglia cell cluster with an intact complement and chemokine system. Functionally, microglia in mhCOs protect parenchyma from cellular and molecular damage caused by Aβ. Furthermore, in mhCOs, we observed reduced expression of Aβ-induced expression of genes associated with apoptosis, ferroptosis, and Alzheimer's disease (AD) stage III. Finally, we assess the function of AD-associated genes highly expressed in microglia in response to Aβ using pooled CRISPRi coupled with single-cell RNA sequencing in mhCOs. In summary, we provide a protocol to generate mhCOs that can be used in fundamental and translational studies as a model to investigate the role of microglia in neurodevelopmental and neurodegenerative disorders.

<h4>Background</h4>Radiotherapy impacts the local immune response to cancers. Prostate Stereotactic Body Radiotherapy (SBRT) is a highly focused method to deliver radiotherapy often used to treat prostate cancer. This is the first direct comparison of immune cells within prostate cancers before and after SBRT in patients.<h4>Methods</h4>Prostate cancers before and 2 weeks after SBRT are interrogated by multiplex immune fluorescence targeting various T cells and macrophages markers and analyzed by cell and pixel density, as part of a clinical trial of SBRT neoadjuvant to radical prostatectomy.<h4>Results</h4>Two weeks after SBRT, CD68, and CD163 macrophages are significantly increased while CD8 T cells are decreased. SBRT markedly alters the immune environment within prostate cancers.

Efficient and regulated nucleocytoplasmic trafficking of macromolecules to the correct subcellular compartment is critical for proper functions of the eukaryotic cell. The majority of the macromolecular traffic across the nuclear pores is mediated by the Karyopherin-β (or Kap) family of nuclear transport receptors. Work over more than two decades has shed considerable light on how the different Kap family members bring their respective cargoes into the nucleus or the cytoplasm in efficient and highly regulated manners. In this Review, we overview the main features and established functions of Kap family members, describe how Kaps recognize their cargoes and discuss the different ways in which these Kap-cargo interactions can be regulated, highlighting new findings and open questions. We also describe current knowledge of the import and export of the components of three large gene expression machines - the core replisome, RNA polymerase II and the ribosome - pointing out the questions that persist about how such large macromolecular complexes are trafficked to serve their function in a designated subcellular location.

<h4>Purpose of review</h4>Sinonasal tumors are rare and heterogeneous diseases which pose challenges in diagnosis and treatment. Despite significant progress made in surgical, oncological, and radiotherapy fields, their prognosis still remains poor. Therefore, alternative strategies should be studied in order to refine diagnosis and improve patient care.<h4>Recent findings</h4>In recent years, in-depth molecular studies have identified new biological markers, such as genetic abnormalities and epigenetic variations, which have allowed to refine diagnosis and predict prognosis. As a consequence, new histological entities have been described and specific subgroup stratifications within the well-known histotypes have been made possible. These discoveries have expanded indications for immunotherapy and targeted therapies in order to reduce tumor spread, thus representing a valuable implementation of standard treatments. Recent findings in molecular biology have paved the way for better understanding and managing such rare and aggressive tumors. Although further efforts need to be made in this direction, expectations are promising.

No abstract available.