Biology subjects

Zhou, Q.

Publications and source records attributed to Zhou, Q..

At least 235 records · Page 13Linked to original sources

bioRxiv2021

SweepCluster: A SNP clustering tool for detecting gene-specific sweeps in prokaryotes

BackgroundThe gene-specific sweep is a selection process where an advantageous mutation along with the nearby neutral sites in a gene region increases the frequency in the population. It has been demonstrated to play important roles in ecological differentiation or phenotypic divergence in microbial populations. Therefore, identifying gene-specific sweeps in microorganisms will not only provide insights into the evolutionary mechanisms, but also unravel potential genetic markers associated with biological phenotypes. However, current methods were mainly developed for detecting selective sweeps in eukaryotic data of sparse genotypes and are not readily applicable to prokaryotic data. Furthermore, some challenges have not been sufficiently addressed by the methods, such as the low spatial resolution of sweep regions and lack of consideration of the spatial distribution of mutations. ResultsWe proposed a novel gene-centric and spatial-aware approach for identifying gene-specific sweeps in prokaryotes and implemented it in a python tool SweepCluster. Our method searches for gene regions with a high level of spatial clustering of pre-selected polymorphisms in genotype datasets assuming a null distribution model of neutral selection. The pre-selection of polymorphisms is based on their genetic signatures, such as elevated population subdivision, excessive linkage disequilibrium, or significant phenotype association. Performance evaluation using simulation data showed that the accuracy and sensitivity of the clustering algorithm in SweepCluster is above 90%. The application of SweepCluster in two real datasets from the bacteria Streptococcus pyogenes and Streptococcus suis showed that the impact of pre-selection was dramatic and significantly reduced the uninformative signals. We validated our method using the genotype data from Vibrio cyclitrophicus, the only available dataset of gene-specific sweeps in bacteria, and obtained a concordance rate of 78%. We noted that the concordance rate could be underestimated due to distinct reference genomes and clustering strategies. The application to the human genotype datasets showed that SweepCluster is also applicable to eukaryotic data and recovered the known sweep regions in a wide dynamic range of pre-selection parameters. ConclusionsSweepCluster is applicable to a broad category of datasets. It will be valuable for detecting gene-specific sweeps in diverse genotypic data and provide novel insights on adaptive evolution.

bioinformatics↗

bioRxiv2021

Butyryl/Caproyl-CoA:Acetate CoA-Transferase: Cloning, Expression and Characterization of the Key Enzyme Involved in Medium-Chain Fatty Acid Biosynthesis

Coenzyme A transferases (CoATs) are important enzymes involved in carbon chain elongation contributing to medium-chain fatty acid (MCFA) biosynthesis. For example, butyryl-CoA:acetate CoA transferase (BCoAT) is responsible for the final step of butyrate synthesis from butyryl-CoA. However, little is known about caproyl-CoA:acetate CoA-transferase (CCoAT), which is responsible for the final step of caproate synthesis from caproyl-CoA. In this study, two CoAT genes from Ruminococcaceae bacterium CPB6 and Clostridium tyrobutyricum BEY8 were identified by gene cloning and expression analysis. The enzyme assays and kinetic studies were carried out using butyryl-CoA or caproyl-CoA as the substrate. CPB6-CoAT can catalyze the conversion of both butyryl-CoA to butyrate and caproyl-CoA to caproate, but its catalytic efficiency with caproyl-CoA as the substrate was 3.8 times higher than that with butyryl-CoA. In contrast, BEY8-CoAT had only BCoAT activity, not CCoAT activity. This demonstrated the existence of a specific CCoAT involved in chain elongation via the reverse {beta}-oxidation pathway. Comparative bioinformatics analysis showed the presence of a highly conserved motif (GGQXDFXXGAXX) in CoATs, which is predicted to be the active center of CoATs. Single point mutations in the conserved motif of CPB6-CoAT (Asp346 and Ala351) led to marked decreases in the activity for butyryl-CoA and caproyl-CoA, indicating that the conserved motif is the active center of CPB6-CoAT, and sites Asp346 and Ala351 were critical residues that affect enzymatic activity. This work provides insight into the function of CCoAT in caproic acid biosynthesis and improves the understanding of the chain elongation pathway for MCFA production.

biochemistry↗

bioRxiv2021

A positive role of task-deactivated default mode network in narrative speech comprehension

During speech comprehension, as listeners need to keep tracking the external audio streams, the default mode network (DMN) is often de-activated and anticorrelated with task-positive networks. Such a pattern has been interpreted as the suppression of the DMN to support externally-oriented cognitive processes. Taking a "two-brain" approach, the current study demonstrated that, despite exhibiting deactivation and anticorrelated with the language network and executive control network, the DMN was not suppressed but played an active role in spoken narrative comprehension. This was evidenced by significant listener-speaker neural couplings in both the posterior and anterior DMN and the positive correlation between the coupling strength and listeners speech comprehension. Moreover, we demonstrated that the functionality of posterior DMN depended on its interaction with the executive control network, rather than its level of activation. Finally, Dynamic Causal Modeling together with the two-brain results indicates the language and executive control networks, the anterior DMN, and the posterior DMN occupied the bottom, intermediate and top layers of a hierarchical system, respectively. These results suggest that the DMN may primarily serve as an internally-oriented system that cooperates with the externally-oriented networks, which may allow the transformation of external acoustic signals into internal mental representations during language comprehension.

neuroscience↗

bioRxiv2021

Evolutionary Analysis of Transcriptional Regulation Mediated by Cdx2 in Rodents

Differences in gene expression, which can arise from divergence in cis-regulatory elements or alterations in transcription factors binding specificity, are one of the most important causes of phenotypic diversity during evolution. By protein sequence analysis, we observed high sequence conservation in the DNA binding domain (DBD) of the transcription factor Cdx2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells (RMES) to study the cis effects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent. Author summaryOur study 1) represented a first systematic analysis of species-specific adaptation in DNA binding pattern of transcription factor. Although the mouse-specific amino acid changes did not manifest functional impact in our system, several explanations may account for it (See Discussion part for the detail); 2) represented a first study of cis-regulation between two reproductively isolated species by using a novel allodiploid system; 3) demonstrated a higher conservation of transcriptional output than that of DNA binding, suggesting the evolvability/plasticity of the latter; 4) finally provided a rich data resource for Cdx2 mediated regulation, including gene expression, chromatin accessibility and DNA binding etc.

evolutionary biology↗

bioRxiv2021

Tracing Human Amygdala across School Age

The developmental pattern of the amygdala throughout childhood and adolescence has been inconsistently reported in previous neuroimaging studies. Given the relatively small size of the amygdala on full brain MRI scans, discrepancies may be partly due to methodological differences in amygdalar segmentation. To investigate the impact of volume extraction methods on amygdala volume, we compared FreeSurfer, FSL and volBrain segmentation measurements with those obtained by manual tracing. The manual tracing method, which we used as the gold standard, exhibited almost perfect intra- and inter-rater reliability. We observed systematic differences in amygdala volumes between automatic (FreeSurfer and volBrain) and manual methods. Specifically, compared with the manual tracing, FreeSurfer estimated larger amygdalae, and volBrain produced smaller amygdalae while FSL demonstrated a mixed pattern. The tracing bias was not uniform, but higher for smaller amygdalae. We further modeled amygdalar growth curves using accelerated longitudinal cohort data from the Chinese Color Nest Project. Trajectory modeling and statistical assessments of the manually traced amygdalae revealed linearly increasing and parallel developmental patterns for both girls and boys, although the amygdalae of boys were larger than those of girls. Compared to these trajectories, the shapes of developmental curves were similar when using the volBrain derived volumes. FreeSurfer derived trajectories had more nonlinearities and appeared flatter. FSL derived trajectories demonstrated an inverted U shape and were significantly different from those derived from manual tracing method. The use of amygdala volumes adjusted for total gray-matter volumes, but not intracranial volumes, resolved the shape discrepancies and led to reproducible growth curves curves between manual tracing and the automatic methods (except FSL). Our findings revealed steady growth of the human amygdala, mirroring its functional development across the school age. Methodological improvements are warranted for current automatic tools to achieve more accurate tracing of the amygdala at school age, calling for next generation tools.

neuroscience↗

bioRxiv2021

Balanced Input from the tRNA Prenyltransferase MiaA Controls the Stress Resistance and Virulence Potential of Extraintestinal Pathogenic Escherichia coli

An ability to adapt to rapidly changing and often hostile environments is key to the success of many bacterial pathogens. In Escherichia coli, the highly conserved enzymes MiaA and MiaB mediate the sequential prenylation and methylthiolation of adenosine-37 within tRNAs that decode UNN codons. Here, we show that MiaA, but not MiaB, is critical to the fitness and virulence of extraintestinal pathogenic E. coli (ExPEC), a major cause of urinary tract and bloodstream infections. Deletion of miaA has pleiotropic effects, rendering ExPEC especially sensitive to stressors like nitrogen and oxygen radicals and osmotic shock. We find that stress can stimulate striking changes in miaA expression, which in turn can increase translational frameshifting and markedly alter the bacterial proteome. Cumulatively, these data indicate that ExPEC, and likely other organisms, can vary MiaA levels as a means to fine-tune translation and the spectrum of expressed proteins in response to changing environmental challenges.

microbiology↗

bioRxiv2021

Molecular basis of ligand recognition and activation of human V2 vasopressin receptor

The V2 vasopressin receptor (V2R) is a class A G protein-coupled receptor (GPCR) and plays a vital role in controlling water homeostasis upon stimulation by the natural peptide arginine vasopressin (AVP). Thus, V2R has attracted intense interest as a drug target for diabetes insipidus, nocturia, and hyponatremia. However, how AVP recognizes and activates V2R remains elusive. Here, we report the 2.6 [A] resolution structure of V2R bound to AVP and the stimulatory G protein Gs, determined by cryo-electron microscopy (cryo-EM). In this complex, AVP presents a unique cyclic conformation formed by an intramolecular disulfide bond and engages the orthosteric binding pocket of V2R in a ligand-specific mode. Comparison of the AVP-V2R-Gs complex to previously reported Gs-coupled class A GPCRs reveals distinct structural features, including a smaller outward movement of TM5 and TM6 and the concomitant shift of Gs protein. Our detailed structural analysis provides a framework for understanding AVP recognition and V2R activation, thereby offering a structural template for drug design targeting V2R.

biophysics↗

bioRxiv2020

A novel and effective Cre/lox-based genetic tool for repeated, targeted and markerless integration in Yarrowia lipolytica

The unconventional yeast Yarrowia lipolytica is extensively applied in bioproduction fields owing to its excellent metabolite and protein production ability. Nonetheless, utilization of this promising host is still restricted by limited availability of precise and effective gene integration tools. In this study, a novel and efficient genetic tool was developed for targeted, repeated, and markerless gene integration based on Cre/lox site-specific recombination system. The developed tool required only a single selection marker and could completely excise all of the unnecessary sequences. A total of three plasmids were created and seven rounds of marker-free gene integration were examined in Y. lipolytica. All the integration efficiencies remained above 90%, and analysis of protein production and growth characteristics of the engineered strains confirmed that genome modification via the novel genetic tool was feasible. Further work also confirmed the genetic tool was effective for integration of other genes, loci, and strains. Thus, this study significantly promotes the application of Cre/lox system and presents a powerful tool for genome engineering in Y. lipolytica. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/424803v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@11b3be9org.highwire.dtl.DTLVardef@fa7e2aorg.highwire.dtl.DTLVardef@170fafaorg.highwire.dtl.DTLVardef@6d4750_HPS_FORMAT_FIGEXP M_FIG C_FIG The novel genetic tool comprised three plasmids, namely, Cre-Y1, Cre-Y2, and Cre-Y3. Cre-Y1 was introduced into the Upleu locus of Po1f, and then recombination between two lox71 sites could remove unnecessary plasmid elements and produce an initial strain harboring a lox71 site. Subsequently, Cre-Y2 was integrated onto the leu2 locus, forming a transitional strain with three lox sites (lox71, lox66, and rclox66). Recombination reactions among these three lox sites could excise unnecessary DNA fragments and retain a lox72 site, an rclox66 site, and a target gene expression cassette in the genome. Similarly, integration of Cre-Y3 produced strains harboring two target gene expression cassettes. Consequently, repeated, targeted, and markerless gene integration could be efficiently realized following iterative integration of Cre-Y2 and Cre-Y3. HighlightsO_LIA powerful genetic tool was developed for targeted and markerless gene integration C_LIO_LIThe genetic tool was effective for various genes, loci, and strains C_LIO_LIOnly a single selection marker was adequate for repeated gene integration C_LIO_LIAll of the useless and redundant sequences would be excised C_LIO_LIAll integration efficiencies could remain above 90% C_LI

synthetic biology↗

bioRxiv2020

Binding strength and hydrogen bond numbers between Covid-19 RBD and HVR of antibody

The global battle against the Covid-19 pandemic relies strongly on the human defence of antibody, which is assumed to bind the antigens Receptor Binding Domain with its Hypervariable Region. Due to the similarity to other viruses such as SARS, however, our understanding of the antibody-virus interaction has been largely limited to the genomic sequencing, which poses serious challenges to the containment, vaccine exploration and rapid serum testing. Based on the physical/chemical nature of the interaction, infrared spectroscopy was employed to reveal the binding disparity, when unusual temperature dependence was discovered from the 1550cm-1 absorption band, attributed to the hydrogen bonds by carboxyl/amino groups, binding the SARS-CoV-2 spike protein and closely resembled SARS-CoV-2 or SARS-CoV-1 antibodies. The infrared absorption intensity, associated with the number of hydrogen bonds, was found to increase sharply between 27{degrees}C and 31{degrees}C, with the relative absorbance matches at 37{degrees}C the hydrogen bonding numbers of the two antibody types (19 vs 12). Meanwhile the ratio of bonds at 27{degrees}C, calculated by thermodynamic exponentials rather than by the laymans guess, produces at least 5% inaccuracy. As a result, the specificity of the SARS-CoV-2 antibody will be more conclusive beyond 31{degrees}C, instead of at the usual room temperature of 20{degrees}C - 25{degrees}C, when the vaccine research and antibody diagnosis would likely be undermined. Beyond genomic sequencing, the temperature dependence, as well as the bond number match at 37{degrees}C between relative absorbance and the hydrogen bonding numbers of the two antibody types, are not only of clinical significance in particular, but also of a sample for the physical/chemical understanding of the vaccine-antibody interactions in general.

microbiology↗

bioRxiv2020

ACE2-Targeting Monoclonal Antibody As A "Pan" Coronavirus Blocker In Vitro and In A Mouse Model

The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1 and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.

immunology↗

bioRxiv2020

A new duck genome reveals conserved and convergently evolved chromosome architectures of birds and mammals

BackgroundDucks have a typical avian karyotype that consists of macro- and microchromosomes, but a pair of much less differentiated ZW sex chromosomes compared to chicken. To elucidate the evolution of chromosome architectures between duck and chicken, and between birds and mammals, we produced a nearly complete chromosomal assembly of a female Pekin duck by combining long-read sequencing and multiplatform scaffolding techniques. ResultsThe major improvement of genome assembly and annotation quality resulted from successful resolution of lineage-specific propagated repeats that fragmented the previous Illumina-based assembly. We found that the duck topologically associated domains (TAD) are demarcated by putative binding sites of the insulator protein CTCF, housekeeping genes, or transitions of active/inactive chromatin compartments, indicating the conserved mechanisms of spatial chromosome folding with mammals. There are extensive overlaps of TAD boundaries between duck and chicken, and also between the TAD boundaries and chromosome inversion breakpoints. This suggests strong natural selection on maintaining regulatory domain integrity, or vulnerability of TAD boundaries to DNA double-strand breaks. The duck W chromosome retains 2.5-fold more genes relative to chicken. Similar to the independently evolved human Y chromosome, the duck W evolved massive dispersed palindromic structures, and a pattern of sequence divergence with the Z chromosome that reflects stepwise suppression of homologous recombination. ConclusionsOur results provide novel insights into the conserved and convergently evolved chromosome features of birds and mammals, and also importantly add to the genomic resources for poultry studies.

genomics↗

bioRxiv2020

Noninvasive Ultrasonic Glymphatic Induction Enhances Intrathecal Drug Delivery

Intrathecal drug delivery is routinely used to bypass the blood-brain barrier in treating varied central nervous system conditions. However, the utility of intrathecal delivery is limited by poor parenchymal uptake of agents from the cerebrospinal fluid. We demonstrate that a simple noninvasive transcranial ultrasound protocol significantly increases the brain parenchymal uptake of intrathecally administered drugs and antibodies. Essentially, we show that our protocol of transcranial ultrasound can accelerate glymphatic fluid transport from the cisternal space into the parenchymal compartment. Specifically, we administered small ([~]1kDa) and large ([~]150 kDa) molecule agents into the cisterna magna of rats and then applied low, diagnostic-intensity focused ultrasound in a scanning protocol throughout the brain. Using both real-time magnetic resonance imaging and ex vivo histologic analyses, we observed significantly increased uptake of each agent into the brain parenchyma from the cisternal cerebrospinal fluid, notably with no brain parenchymal damage. The low intensity of the ultrasound and its noninvasiveness underscores the ready path to clinical translation of this technique for whole-brain delivery of a variety of agents. Furthermore, this technique can be used as a means to probe the causal role of the glymphatic system in the variety of disease and physiologic processes to which it has been correlated. eTOC SummaryA translation-ready ultrasound technique enhances the brain penetration of intrathecally delivered agents via upregulating the glymphatic pathway.

bioengineering↗

bioRxiv2020

Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2 infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab forms bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the "up" conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and their correlation with more potent neutralization and the shedding of S1 subunit.

microbiology↗

bioRxiv2020

UDP-glucose pyrophosphorylase 2, a regulator of glycosylation and glycogen, is essential for pancreatic cancer growth

Pancreatic ductal adenocarcinomas (PDACs) have enhanced nutrient uptake requirements and rapid metabolic processing. The enzyme UDP-glucose pyrophosphorylase 2 (UGP2) rests at the convergence of multiple metabolic pathways, however the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an essential role for UGP2 in the maintenance of PDAC growth in both in vitro and in vivo tumor models. Transcription of UGP2 is directly regulated by the YAP/TEAD complex. Loss of UGP2 leads to decreased intracellular glycogen and defects in N-glycosylation targets important for cell growth including epidermal growth factor receptor (EGFR). In murine xenograft models, knockdown of UGP2 halted tumor growth and repressed expression of EGFR. The critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer new avenues of therapy for otherwise intractable PDACs. Impact StatementConvergent findings reveal that UDP-glucose pyrophosphorylase 2 has a central role in growth and metabolism of pancreatic ductal adenocarcinomas, highlighting novel therapeutic possibilities for this deadly cancer.

cancer biology↗

bioRxiv2020

RNA LEVER Mediates Long-Range Regulation of ε-globin by Keeping PRC2 in Check

Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator required for gene silencing during embryonic development. Previous studies have reported that PRC2 interacts with RNA in a promiscuous manner, but the biological functions of such interaction are unknown. Here we present a seesaw mechanism for the regulation of {varepsilon}-globin through inactivating EZH2 by an upstream non-coding RNA (LEVER). We show that LEVER, a non-coding RNA identified by RNA immunoprecipitation sequencing (RIP-seq) of the PRC2 core subunit EZH2 and Nanopore sequencing, binds PRC2 and thereby prevents the accumulation of H3K27 methylation along the genomic region where LEVER RNA is transcribed. The open chromatin within the LEVER locus in turn competes for the chromatin interaction between the {varepsilon}-globin promoter and the Locus Control Region (LCR), working as a negative regulatory element of {varepsilon}-globin expression. Hence, LEVER RNA negatively regulates {varepsilon}-globin by sequestering PRC2 from repressing the LEVER locus, which is a competitor of the {varepsilon}-globin-LCR interaction.

molecular biology↗

bioRxiv2020

Engineered Trimeric ACE2 Binds and Locks "Three-up" Spike Protein to Potently Inhibit SARS-CoVs and Mutants

SARS-CoV-2 enters cells via ACE-2, which binds the spike protein with moderate affinity. Despite a constant background mutational rate, the virus must retain binding with ACE2 for infectivity, providing a conserved constraint for SARS-CoV-2 inhibitors. To prevent mutational escape of SARS-CoV-2 and to prepare for future related coronavirus outbreaks, we engineered a de novo trimeric ACE2 (T-ACE2) protein scaffold that binds the trimeric spike protein with extremely high affinity (KD < 1 pM), while retaining ACE2 native sequence. T-ACE2 potently inhibits all tested pseudotyped viruses including SARS-CoV-2, SARS-CoV, eight naturally occurring SARS-CoV-2 mutants, two SARSr-CoVs as well as authentic SARS-CoV-2. The cryo-EM structure reveals that T-ACE2 can induce the transit of spike protein to "three-up" RBD conformation upon binding. T-ACE2 thus represents a promising class of broadly neutralizing proteins against SARS-CoVs and mutants.

bioengineering↗

bioRxiv2020

The avian W chromosome is a refugium for endogenous retroviruses with likely effects on female-biased mutational load and genetic incompatibilities

It is a broadly observed pattern that the non-recombining regions of sex-limited chromosomes (Y and W) accumulate more repeats than the rest of the genome, even in species like birds with a low genome-wide repeat content. Here we show that in birds with highly heteromorphic sex chromosomes, the W chromosome has a transposable element (TE) density of >55% compared to the genome-wide density of <10%, and contains over half of all full-length (thus potentially active) endogenous retroviruses (ERVs) of the entire genome. Using RNA-seq and protein mass spectrometry data, we were able to detect signatures of female-specific ERV expression. We hypothesise that the avian W chromosome acts as a refugium for active ERVs, likely leading to female-biased mutational load that may influence female physiology similar to the "toxic-Y" effect in Drosophila. Furthermore, Haldanes rule predicts that the heterogametic sex has reduced fertility in hybrids. We propose that the excess of W-linked active ERVs over the rest of the genome may be an additional explanatory variable for Haldanes rule, with consequences for genetic incompatibilities between species through TE/repressor mismatches in hybrids. Together, our results suggest that the sequence content of female-specific W chromosomes can have effects far beyond sex determination and gene dosage.

evolutionary biology↗

bioRxiv2020

Discovery of A New Class of Integrin Antibodies for Fibrosis

Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of all v integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimabs yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple v integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGF{beta} activation. In IPF patient lung fibroblasts, TGF{beta} treatment induced profound SMA expression in phenotypic imaging assays and Ab-31 demonstrated superior in vitro activity at inhibiting SMA expression, suggesting that the integrin antibody is able to modulate TGF{beta} action though mechanisms beyond the inhibition of latent TGF{beta} activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases. One Sentence Summarytargeting integrin in lung fibrosis

pharmacology and toxicology↗