Biology subjects

Zhu, Z.

Publications and source records attributed to Zhu, Z..

At least 253 records · Page 14Linked to original sources

bioRxiv2020

Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models.

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

microbiology↗

bioRxiv2020

Comparative genomics of Exiguobacterium reveals what makes a cosmopolitan bacterium

Although the adaptation strategies of bacteria to specific environmental conditions are widely reported, fewer studies have addressed how microbe with cosmopolitan distribution adapted to diverse habitats. Exiguobacterium is a versatile genus whose members have been commonly found in great variety of habitats. To understand the mechanism behind the universally of Exiguobacterium, we isolated 103 strains from diverse environments, and performed large-scale metabolic and adaptive ability tests. We found that the capacities of survival in a wide range of temperature, salinity and pH are common for most Exiguobacterium members. According to the core genome based phylogeny and ANI analysis, 26 putative species including 13 putative new ones were identified and two genetic groups were classified as Group I and II. Comparative genomic analysis revealed that Exiguobacterium members can not only utilize a variety of complex polysaccharides and proteins that are ubiquitous in both terrestrial and marine environments, but also have a number of chaperonins and transporters which could support them to survive in different extreme environments. In addition, we found that the species from Group I can be found in more diverse environments with larger genome size compared to those of Group II. Twenty-five transporter families involved in transport of organic or inorganic substrates and environments stresses resistance were predicted to be enriched in Group I strains. This study provided the comprehensive insight into general genetic basis of the cosmopolitan distribution of a bacteria genus and deciphered putative determinants behind the ecological difference of different groups belonging to the same genus. IMPORTANCEThe wide distribution characteristics make Exiguobacterium a valuable model for studying adaptive strategy of bacteria adapted to multiple habitats. In this study, we found that comprehensive capacity of diverse polysaccharides utilization and environmental stress resistance is the important basis for survival, and selective expansion of transporters is an evolution and adaptation strategy for extensive distribution. Our findings are significant for understanding the adaptation and evolution mechanisms of cosmopolitan bacteria and explaining the vital genomic traits that facilitate niches adaptation.

microbiology↗

bioRxiv2020

Metformin prevented high glucose-induced endothelial reactive oxygen species via OGG1 in an AMPKα-Lin-28 dependent pathway

Metformin improved vascular function in obese type 2 diabetic patients. 8-oxoguanine glycosylase (OGG1), a main DNA glycosylase, was involved in vascular complications in diverse diseases. However, whether metformin suppressed endothelial ROS via OGG1 pathway was unclear. Human umbilical vein endothelial cells (HUVECs) were exposed to HG (high glucose) or HG with metformin. OGG1 and AMPf levels were measured after metformin treatment while HG-caused ROS was measured by DHE prober. Diabetic mice were induced by daily intraperitoneal injections of streptozotocin (STZ). Metformin reduced Endothelial ROS caused by HG via upregulating OGG1. Additionally, OGG1 protein expression was dependent on its mRNA stability, which was reversed by genetic inhibition of AMPK and Lin-28. The role of OGG1 on ROS stimulated by HG was partially dependent on NFKB/NOX4 pathway in HUVECs. These results suggested that metformin contacted HG-induced endothelial ROS via AMPK/Lin-28/OGG1 pathway.

cell biology↗

bioRxiv2020

Investigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases

An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well-established, but whether this reflects a shared genetic aetiology, and whether consistent genetic relationships exist between MS and the two predominant subtypes of IBD, ulcerative colitis (UC) and Crohns disease (CD), remains unclear. Here, we used genome-wide association study (GWAS) summary data to estimate genetic correlations (rg) between MS and each of IBD, UC and CD, finding that the rg between MS and UC was approximately twice that between MS and CD. On the basis of these genetic correlations, we performed cross-trait meta-analysis of GWAS summary data for MS and each of IBD, UC and CD, identifying a total of 42 novel SNPs shared between MS and IBD (N=19), UC (N=14), and CD (N=18). We then used multiple Mendelian randomization (MR) methods to investigate causal relationships between these diseases, finding suggestive but inconclusive evidence for a causal effect of MS on UC and IBD, and no or weak and inconsistent evidence for a causal effect of IBD or UC on MS. There was also no evidence for causality in bidirectional analyses of MS and CD. We also investigated tissue- and cell-type-specific enrichment of SNP heritability for each disease using stratified LD score regression. At the tissue level, we observed largely consistent patterns of enrichment for all four diseases in immune system-related tissues, including lung, spleen and whole blood, and in contrast to prior studies, small intestine. At the cell-type level, we identified significant enrichment for all diseases in CD4+ T cells in lung, and for MS, IBD and CD in CD8+ cytotoxic T cells in both lung and spleen, and regulatory T cells in lung. Our study sheds new insights into the biological basis of comorbidity between MS and both UC and CD.

genetics↗

bioRxiv2020

EARLY FLOWERING 3 controls temperature responsiveness of the circadian clock

Predictable changes in light and temperature during a diurnal cycle are major entrainment cues that enable the circadian clock to generate internal biological rhythms that are synchronized with the external environment. With the average global temperature predicted to keep increasing, the intricate light-temperature coordination that is necessary for clock functionality is expected to be seriously affected. Hence, understanding how temperature signals are perceived by the circadian clock has become an important issue, especially in light of climate change scenarios. In Arabidopsis, the clock component EARLY FLOWERING 3 (ELF3) not only serves as an essential light Zeitnehmer, but also functions as a thermosensor participating in thermomorphogenesis. However, the role of ELF3 in temperature entrainment of the circadian clock is not fully understood. Here, we report that ELF3 is essential for delivering temperature input to the clock. We demonstrate that in the absence of ELF3, the oscillator was unable to properly respond to temperature changes, resulting in an impaired gating of thermoresponses. Consequently, clock-controlled physiological processes such as rhythmic growth and cotyledon movement were disturbed. Together, our results reveal that ELF3 is an essential Zeitnehmer for temperature sensing of the oscillator, and thereby for coordinating the rhythmic control of thermoresponsive physiological outputs.

plant biology↗

bioRxiv2020

Activated Expression of Master Regulator MYB31 and of Capsaicinoid Biosynthesis Genes Results in Capsaicinoid Biosynthesis and Accumulation in the Pericarp of the Extremely Pungent Capsicum chinense

Capsaicinoids confer pungency in Capsicum fruits, and the capsaicinoid content varies greatly among the five domesticated Capsicum species. Although it is generally recognized that capsaicinoid biosynthesis occurs exclusively in the placenta, few studies have focused on capsaicinoid biosynthesis gene (CBG) expression in the pericarp. Therefore, the transcriptional regulation mechanisms of capsaicinoid biosynthesis in the pericarp remain elusive. Here, the capsaicinoid contents of 32 accessions from five domesticated Capsicum species were analyzed. The results showed that the capsaicinoid contents of C. chinense accessions are significantly higher than those of the other four Capsicum species due to the increased accumulation of capsaicinoids, especially in the pericarp. Compared to that in accessions with low pericarp capsaicinoid content, the expression of the master regulator MYB31 is significantly upregulated in the pericarp in C. chinense accessions, which leads to high levels of CBG expression. Moreover, in fruits of the extremely pungent Trinidad Moruga Scorpion (C. chinense) and low-pungency 59 inbred line (C. annuum) at different developmental stages, the capsaicinoid accumulation patterns were consistent with the MYB31 and CBG expression levels in the pericarp. Taken together, our results provide novel insights into the molecular mechanism arising from the expression of a master regulator in the pericarp that results in exceedingly hot peppers. The genetic resources identified in this study could be used as genetic resources for the genetic improvement of pepper pungency.

plant biology↗

bioRxiv2020

Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability

Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, such as cancer, ischemic stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema and sepsis, which often leads to acute lung injury, including acute respiratory distress syndrome. However, after initially stimulating permeability, VEGF subsequently mediates angiogenesis to repair damaged tissue. Consequently, understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics that achieve the delicate balance of inhibiting vascular permeability while preserving tissue repair. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. Specifically, we show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9 generated genomic STAT3 knockout zebrafish. Importantly, STAT3 deficiency does not impair vascular development and function in vivo. We identify intercellular adhesion molecule 1 (ICAM-1) as a STAT3-dependent transcriptional regulator and show VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved anti-microbial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse, and human endothelium. Indeed, pharmacologically targeting STAT3 increases vascular barrier integrity using two additional compounds, atovaquone and C188-9. Collectively, our findings suggest that the VEGF, VEGFR-2, JAK2, and STAT3 signaling cascade regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability in vertebrate models. Key PointsO_LIGenetic STAT3 deficiency in VEGF-inducible zebrafish and mice reveals that VEGF signals through STAT3 to promote vascular permeability C_LIO_LIPyrimethamine, a clinically available agent that inhibits STAT3 activity, reduces VEGF-induced vascular permeability in preclinical models C_LI

molecular biology↗

bioRxiv2020

Deciphering the mechanism underlying circRNA-mediated immune responses of western honeybees to Nosema ceranae infection

Nosema ceranae is a widespread fungal parasite for adult honeybees, severely damaging bee health and sustainable development of apiculture. Circular RNAs (circRNAs) are a class of newly discovered noncoding RNAs (ncRNAs) that regulate a number of biological processes such as immune defense and development. In this current work, based on previously obtained whole transcriptome data, 8 199 and 8 711 circRNAs were predicted from the midguts of Apis mellifera ligustica workers at 7 days (AmT1) and 10 days (AmT2) post inoculation (dpi) with N. ceranae using bioinformatics. Additionally, in combination with transcriptome data from uninfected midguts (AmCK1 and AmCK2) (Xiong et al., 2018), 4 464 circRNAs were found to be shared by the aforementioned four groups, whereas the numbers of specifically transcribed circRNAs in each group were 1 389, 1 696, 1 019 and 1 871, respectively. Furthermore, 10 226 circRNAs were homologous to Apis cerana cerana circRNAs, while 20 circRNAs had homology with Homo sapiens circRNAs; in addition, 16 circRNAs were highly conserved in these three species. Differential expression analysis showed that 168 (306) differentially expressed circRNAs (DEcircRNAs) were identified in AmCK1 vs AmT1 (AmCK2 vs AmT2) comparison group, including 61 (143) upregulated circRNAs and 107 (163) downregulated circRNAs. Moreover, RT-qPCR results showed that the expression trend of eight DEcircRNAs was consistent with that of the transcriptome dataset. Based on GO database annotation, we observed that source genes of DEcircRNAs in AmCK1 vs AmT1 (AmCK2 vs AmT2) were engaged in 27 (35) functional terms, including two (two) cell renewal-associated terms, seven (seven) cell structure-associated terms, and one (one) immunity-associated terms. Additionally, DEcircRNA source genes in AmCK1 vs AmT1 were involved in two cell renewal-related pathways, Hippo and Wnt signaling pathways, and three carbohydrate metabolism-related pathways, galactose metabolism, starch and sucrose metabolism, fructose and mannose metabolism, only one energy metabolism-related pathway (oxidative phosphorylation pathway), three cellular immune-related pathways, endocytosis, phagosome, and lysosome, and a humoral immune-related pathway (FoxO signaling pathway). In AmCK2 vs AmT2 comparison group, more source genes of DEcircRNAs were associated with the abovementioned pathways relative to cell renewal, carbohydrate metabolism, and cellular and humoral immune pathways. In addition, 122 (234) DEcircRNAs in the host midgut at 7 dpi (10 dpi) with N. ceranae targeted 82 (106) miRNAs. Furthermore, 75 (103) miRNAs targeted by 86 (178) DEcircRNAs in AmCK1 vs AmT1 (AmCK2 vs AmT2) further bound to 215 (305) mRNAs. These targets could be annotated as an array of functional terms and pathways related to cellular renewal, cellular structure, carbohydrate and energy metabolism, and cellular and humoral immunity. In a word, we for the first time explored immune responses mediated by DEcircRNAs in the midguts of A. m. ligustica workers to N. ceranae infection. Our data provide a foundation for clarifying the molecular mechanism underlying immune response of western honeybee to N. ceranae invasion, but also a new insight into further understanding the host-pathogen interaction during bee microsporidiosis.

genomics↗

bioRxiv2020

Defining a Global Map of Functional Group Based 3D Ligand-binding Motifs

Uncovering conserved 3D protein-ligand binding patterns at the basis of functional groups (FGs) shared by a variety of small molecules can greatly expand our knowledge of protein-ligand interactions. Despite that conserved binding patterns for a few commonly used FGs have been reported in the literature, large-scale identification and evaluation of FG-based 3D binding motifs are still lacking. Here, we developed AFTME, an alignment-free method for automatic mapping of 3D motifs to different FGs of a specific ligand through two-dimensional clustering. Applying our method to 233 nature-existing ligands, we defined 481 FG-binding motifs that are highly conserved across different ligand-binding pockets. Systematic analysis further reveals four main classes of binding motifs corresponding to distinct sets of FGs. Combinations of FG-binding motifs facilitate proteins to bind a wide spectrum of ligands with various binding affinities. Finally, we showed that these general binding patterns are also applicable to target-drug interactions, providing new insights into structure-based drug design.

bioinformatics↗

bioRxiv2020

Identification of Lysine Isobutyrylation as A New Histone Modification Mark

Short-chain acylation of lysine residues in eukaryotic proteins are recognized as essential posttranslational chemical modifications (PTMs) that regulate cellular processes from transcription, cell cycle, metabolism, to signal transduction. Lysine butyrylation was initially discovered as a normal straight chain butyrylation (Knbu). Here we report its structural isomer, branched chain butyrylation, i.e. lysine isobutyrylation (Kibu), existing as a new PTM on nuclear histones. Uniquely, isobutyryl-CoA is derived from valine catabolism and branched chain fatty acid oxidation which is distinct from the metabolism of n-butyryl-CoA. Several histone acetyltransferases were found to possess lysine isobutyryltransferase activity, especially p300 and HAT1. We resolved the X-ray crystal structures of HAT1 in complex with isobutyryl-CoA that gleaned an atomic level insight into HAT-catalyzed isobutyrylation. RNA-Seq profiling revealed that isobutyrate greatly affected the expression of genes associated with many pivotal biological pathways. Our findings identify Kibu as a novel chemical modification mark in histones and suggest its extensive role in regulating epigenetics and cellular physiology.

biochemistry↗

bioRxiv2020

Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases

RNA helicases and ubiquitin E3 ligases mediate many critical functions within cells, but their actions have been studied largely in distinct biological contexts. Here, we uncover evolutionarily conserved rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immunity. Using cryo-electron microscopy and biochemistry, we show that RIG-I-like receptors (RLRs), viral RNA receptors with helicase domains, interact with their cognate TRIM/TRIM-like E3 ligases through similar epitopes in the helicase domains. Their interactions are avidity-driven, restricting the actions of TRIM/TRIM-like proteins and consequent immune activation to RLR multimers. Mass-spectrometry and phylogeny-guided biochemical analyses further reveal that similar rules of engagement apply to diverse RNA helicases and TRIM/TRIM-like proteins. Our analyses thus reveal not only conserved substrates for TRIM proteins but also unexpectedly deep evolutionary connections between TRIM proteins and RNA helicases, thereby linking ubiquitin and RNA biology throughout animal evolution.

biochemistry↗

bioRxiv2020

Low XIST expression in Sertoli cells of Klinefelter syndrome patients caused the high susceptibility of these cells to an extra X chromosome

Klinefelter syndrome (KS) is the most common genetic cause of human male infertility. Patients suffer from heterogeneous testicular atrophy with loss of both germ cells and Sertoli cells. However, the mechanism by which the extra X chromosome causes failure of spermatogenesis remains poorly understood. Here, we profiled testicular single-cell transcriptomes from three KS patients and compared the results with those of healthy donors. Among different somatic cells, Sertoli cells showed the greatest changes in KS patients. Further analysis showed that XIST, a key long intergenic non-coding RNA that inactivates one X chromosome in female mammals, was widely expressed in somatic cells, except for Sertoli cells, leading to an increase in X-inactivation genes in these cells, which may cause Sertoli cells death and disruption of the spermatogenic microenvironment. Our study proposed a new mechanism to explain the unique pathological manifestations of KS in the testes and provided a theoretical basis for subsequent research and related treatment.

genomics↗

bioRxiv2020

Histone demethylase complexes KDM3A and KDM3B cooperate with OCT4/SOX2 to construct pluripotency gene regulatory network

The pluripotency gene regulatory network of porcine-induced pluripotent stem cells (piPSCs), especially in epigenetics, remains elusive. To determine this biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs. SummaryErasure of H3K9 methylation in porcine pluripotent stem cells depends on the complex of transcription factors OCT4/SOX2 and histone demethylase KDM3A/KDM3B.

cell biology↗

bioRxiv2020

Common variants contribute to intrinsic functional architecture of human brain

The human brain remains active in the absence of explicit tasks and forms networks of correlated activity. Resting-state functional magnetic resonance imaging (rsfMRI) measures brain activity at rest, which has been linked with both cognitive and clinical outcomes. The genetic variants influencing human brain function are largely unknown. Here we utilized rsfMRI from 44,190 individuals of multiple ancestries (37,339 in the UK Biobank) to discover and validate the common genetic variants influencing intrinsic brain activity. We identified hundreds of novel genetic loci associated with intrinsic functional signatures (P < 2.8 x 10-11), including associations to the central executive, default mode, and salience networks involved in the triple network model of psychopathology. A number of intrinsic brain activity associated loci colocalized with brain disorder GWAS (e.g., Alzheimers disease, Parkinsons disease, schizophrenia) and cognition, such as 19q13.32, 17q21.31, and 2p16.1. Particularly, we detected a colocalization between one (rs429358) of the two variants in the APOE {varepsilon}4 locus and function of the default mode, central executive, attention, and visual networks. Genetic correlation analysis demonstrated shared genetic influences between brain function and brain structure in the same regions. We also detected significant genetic correlations with 26 other complex traits, such as ADHD, major depressive disorder, schizophrenia, intelligence, education, sleep, subjective well-being, and neuroticism. Common variants associated with intrinsic brain activity were enriched within regulatory element in brain tissues.

genetics↗

bioRxiv2020

Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin

Severe 1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant 1-antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high throughput screen to identify small molecules that bind to, and stabilise Z 1-antitrypsin. The lead compound blocks Z 1-antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z 1-antitrypsin three-fold in mammalian cells including an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerization pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z 1-antitrypsin into the plasma by 7-fold. There was no observable clearance of hepatic inclusions with respect to controls. This study provides proof-of-principle that mutation ameliorating small molecules are a viable approach to treat protein conformational diseases.

pharmacology and toxicology↗

bioRxiv2020

The comprehensive genetic architecture of brain white matter

Brain regions communicate with each other via tracts of myelinated axons, commonly referred to as white matter. White matter microstructure can be measured in the living human brain using diffusion based magnetic resonance imaging (dMRI), and has been found to be altered in patients with neuropsychiatric disorders. Although under strong genetic control, few genetic variants influencing white matter microstructure have ever been identified. Here we identified common genetic variants influencing white matter microstructure using dMRI in 42,919 individuals (35,741 in the UK Biobank). The dMRIs were summarized into 215 white matter microstructure traits, including 105 measures from tract-specific functional principal component analysis. Genome-wide association analysis identified many novel white matter microstructure associated loci (P < 2.3 x 10-10). We identified shared genetic influences through genetic correlations between white matter tracts and 62 other complex traits, including stroke, neuropsychiatric disorders (e.g., ADHD, bipolar disorder, major depressive disorder, schizophrenia), cognition, neuroticism, chronotype, as well as non-brain traits. Common variants associated with white matter microstructure alter the function of regulatory elements in glial cells, particularly oligodendrocytes. White matter associated genes were enriched in pathways involved in brain disease pathogenesis, neurodevelopment process, and repair of white matter damage (P < 1.5 x 10-8). In summary, this large-scale tract-specific study provides a big step forward in understanding the genetic architecture of white matter and its genetic links to a wide spectrum of clinical outcomes.

genetics↗

bioRxiv2020

Single-cell atlas of human developing and azoospermia patients' testicles reveals the roadmap and defects in somatic microenvironment

Non-obstructive azoospermia (NOA) affects 1% of men. However, the unknowns of NOA pathogenesis and even normal spermatogenic microenvironment establishment severely limit the clinical efficacy of NOA treatment. We profiled > 80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. Sertoli cells, which form the scaffold in the testicular microenvironment, exhibited the most obvious damages in NOA patients. We identified the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature but with abnormal immune response, while the cells in idiopathic NOA (iNOA) are basically physiologically immature. Furthermore, inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA.

developmental biology↗

bioRxiv2020

Repurposing low-molecular-weight drugs against the main protease of SARS-CoV-2

The coronavirus disease (COVID-19) pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the global healthcare system. Drug repurposing is a feasible method for emergency treatment. As low-molecular-weight drugs have high potential to completely match interactions with essential SARS-CoV-2 targets, we propose a strategy to identify such drugs using the fragment-based approach. Herein, using ligand- and protein-observed fragment screening approaches, we identified niacin and hit 1 binding to the catalytic pocket of the main protease of the SARS-CoV-2 (Mpro), thereby modestly inhibiting the enzymatic activity of Mpro. Chemical shift perturbations induced by niacin and hit 1 indicate a partial overlap of their binding sites, i.e., the catalytic pocket of Mpro may accommodate derivatives with large molecular sizes. Therefore, we searched for drugs containing niacin or hit 1 pharmacophores and identified carmofur, bendamustine, triclabendazole, and emedastine; these drugs are highly capable of inhibiting protease activity. Our study demonstrates that the fragment-based approach is a feasible strategy for identifying low-molecular-weight drugs against the SARS-CoV-2 and other potential targets lacking specific drugs.

biochemistry↗