Biology subjects

Wilson, K.

Publications and source records attributed to Wilson, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Sex-Dependent Microbiome-Metabolome Remodeling Associated with Bacteroides acidifaciens Modulation of Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a severe lung disorder influenced by the interplay between the intestinal microbiome, host metabolism, and immune function. We previously found that Bacteroides acidifaciens (BA) has opposing effects on staphylococcal enterotoxin B (SEB)-induced ARDS, worsening the condition in female mice while alleviating it in males. This study aimed to examine whether these outcomes are linked to sex-dependent changes in the intestinal microbiome and gut-lung metabolome. C3H/HeJ mice of both sexes were orally colonized with Bacteroides acidifaciens before SEB exposure. Stool and bronchoalveolar lavage fluid (BALF) were collected for analysis using 16S rRNA sequencing and untargeted liquid chromatography mass spectrometry metabolomics. Our findings revealed distinct sex-dependent metabolic and microbial responses. In females, disease exacerbation correlated with elevated lipid mediators (leukotriene B4, 13-oxoODE, and 13S-HODE) alongside shifts in bile acid and redox metabolism. The intestinal microbiome showed changes in Bacteroides, Akkermansia, and Lachnospiraceae. Conversely, males showed a protective phenotype characterized by increased butyrate and alterations in sphingolipid, amino acid, redox, and nucleotide pathways. Integrated analyses identified sex-associated microbial communities and metabolomic profiles, highlighting distinct patterns of lipid and redox associations in females versus sphingolipid and short-chain fatty acid patterns in males. These results suggest that host sex influences how a commensal bacterium affects inflammatory lung injury and point to pathways for future research.

microbiology↗

bioRxiv2026

Discovery and Targeting of a Cryptic Human Proteome

First-in-class therapeutics require first-in-class biology. Yet despite decades of genomic and proteomic cataloging, vast regions of the human transcriptome remain dark and their encoded proteins invisible. Here we present RyboCypher, an integrated RNA-sequencing and AI-assisted proteogenomics platform that systematically maps the RyboCypher-derived "dark" transcriptome to unannotated peptides, predicting and empirically identifying cryptic proteins across the uncharted genome. Applied to cancer cell lines, patient tumors, and matched healthy tissues, RyboCypher resolved [~]8.3 million dark RNA isoforms and [~]16 million candidate ORFs. Interrogating these against [~]0.5 billion MS/MS spectra from cellular proteomics, membrane proteomics, and immunopeptidomics datasets (comprising a total of >8,000 raw MS data files ([~]7TB of MS data), derived from 2,229 patient samples), we empirically identified [~]80,000 cryptic peptides ([~]10,000 cancer-associated or cancer-upregulated) at <1% FDR. Altogether, these datasets establish the CypherAtlas, a comprehensive proteogenomic atlas of an unreported proteome comprising thousands of novel proteins, including membrane proteins with targetable extracellular domains, and intracellular proteins accessible through antigen presentation. By linking dark-RNA transcripts, predicted proteins, and patient-level metadata across RyboDyns proprietary experimental data, CypherAtlas further provides the training substrate for multi-modal models such as DarkCypher, which is being developed to prioritize cryptic targets and to forecast their expression in new patient samples. As proof of therapeutic potential, we disclose evidence for a cancer-associated, cryptic protein expressed from the YBX1 locus, (cryptic YBX1; cYBX1) and demonstrate selective in vitro tumor cell killing through a cryptic peptide-MHC (pMHC) complex derived from this protein with a TCR-mimic (TCRm) antibody when formatted as antibody drug conjugates (ADCs). Together, RyboCypher and CypherAtlas establish the dark proteome as a vast and previously inaccessible reservoir of novel targetable biology, laying the foundation for the next generation of first-in-class therapeutics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/743124v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@104c385org.highwire.dtl.DTLVardef@1c065ccorg.highwire.dtl.DTLVardef@5b717forg.highwire.dtl.DTLVardef@1788694_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2026

Long-term small effective population size, inbreeding, and a recessive lethal haplotype drive premature death in the endangered Devils Hole pupfish (Cyprinodon diabolis)

As anthropogenic habitat fragmentation and population decline accelerate globally, growing numbers of species face compounding demographic and genetic threats to long-term survival. Many populations are already forced to persist at chronically small sizes, yet the genomic and fitness consequences of this fate remain poorly understood. Here we leverage the demographic history of the Devils Hole pupfish to investigate how long-term small population size and recent bottlenecks have shaped genetic diversity, genetic load, inbreeding, and fitness through comparative population genomics, historical sequencing, and sampling embryos that died prematurely during development. We find that genetic diversity in Devils Hole pupfish is among the lowest recorded in the wild and that fixed load is high, consistent with thousands of generations of isolation at small population size. Even in the face of this low diversity and high fixed load, we show that inbreeding is still strongly associated with premature embryonic death, which affects up to 25% of offspring in the captive refuge and can be identified in advance based on a characteristic elongated heart tube and reduced heart rate. We discovered a recessive lethal haplotype segregating at [~]20% frequency that accounts for 50% of embryonic deaths and contains mutations in MIB1 and MMP16, genes associated with cardiomyopathy and atrial fibrillation. Our findings link genotype, phenotype, and fitness in an iconic endangered species to provide a rare comprehensive view into the evolutionary dynamics and consequences of long-term small effective population size, demonstrating that endangered species remain vulnerable to inbreeding depression despite extremely low genetic diversity.

evolutionary biology↗

bioRxiv2026

Orally Bioavailable SARS-CoV-2 Protease Inhibitors Bearing a Hydroxymethyl Ketone Warhead

The use of covalent warheads targeting the catalytic cysteine has been a cornerstone in coronavirus main protease (Mpro) inhibitor development, where various electrophilic motifs have been used including aldehydes, nitriles, ketoamides, and hydroxymethyl ketones (HMKs). Recent efforts have been mostly centered around nitrile warheads, given the success of compounds like Nirmatrelvir and Ensitrelvir in the clinic. However, finding and advancing alternative chemotypes with differentiating chemical and pharmacological profiles is essential for future pandemic preparedness. Among such alternatives, HMKs hold special interest because they balance reduced intrinsic electrophilicity with an excellent selectivity profile. Nevertheless, early HMK-based compounds, such as the clinical-stage Mpro inhibitor PF-00835231, suffered from poor oral bioavailability and therefore required intravenous administration, with or without prodrug derivatization of the hydroxyl group. Here, we describe our efforts in advancing the HMK field via the discovery of mCMX110, a lead that has superior potency, increased unbound exposure in vivo, and favorable oral bioavailability in preclinical studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/725542v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@40222aorg.highwire.dtl.DTLVardef@831b88org.highwire.dtl.DTLVardef@184a910org.highwire.dtl.DTLVardef@779095_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC) remains lethal as adaptive resistance to standard-of-care therapy develops, often driven by AR splice variants alongside transcriptional and translational reprogramming. To identify strategies capable of overcoming these mechanisms, we performed an unbiased high-throughput screen of 2,480 mechanistically annotated compounds across advanced prostate cancer models. Exportin-1 (XPO1)-mediated nuclear export emerged as a critical dependency, and matrix-based combination screening uncovered robust synergy between inhibitors of XPO1 and the translation initiation factor EIF4A1. Dual inhibition induced coordinated disruption of oncogenic protein networks, including AR/AR-V7, triggering apoptosis and suppressing cell-cycle and metabolic programs. These effects extended to genetically diverse patient-derived organoids and in vivo xenografts at low doses, approximately 8-fold (Eltanexor) and 12-fold (Zotatifin) below established human single-agent regimens. Together, these findings reveal concurrent control of nuclear export and protein translation as a therapeutic vulnerability in mCRPC, providing a strong rationale for clinical evaluation of XPO1-EIF4A1 co-inhibition to overcome AR-driven resistance. STATEMENT OF SIGNIFICANCEUnbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation.

cancer biology↗

bioRxiv2026

Estimate of the mutation rate in the endangered Devils Hole pupfish provides support for the drift-barrier hypothesis at an outlying extreme

Mutation rates vary by orders of magnitude across eukaryotes. The drift-barrier hypothesis proposes that drift overwhelms selection for lower mutation rates in small populations, leading to higher mutation rates over time due to the gradual accumulation of mutator alleles. Here, we test this hypothesis in one of the smallest long-term isolated populations in the world, the endangered Devils Hole pupfish (Cyprinodon diabolis). We estimated germline mutation rates in adults and embryos that died prematurely using autozygous segments due to recent inbreeding events. Our estimate of 8.09 x 10-9 per base pair per generation was higher than the mean rate for actinopterygian fishes of 5.97 x 10-9 (95% CI: 4.39 x 10-9 - 7.55 x 10-9) but was lower than predicted for such a low effective population size based on a recent meta-analysis of vertebrate mutation rates and similar to species with much larger effective population sizes, contradicting the drift barrier hypothesis. We also found that embryos which died during development had a higher mutation rate than mature adults, potentially reflecting a segregating lethal mutator allele. We analyzed the mutational spectra of germline mutations and found that spectra between embryonic lethal and mature adults were similar and comparable to other fishes, despite environmental differences in temperature, oxygen saturation, and UV exposure. Mutation rates in this endangered species provide new insights into the mechanisms driving mutation rate variation across vertebrates at one extreme of low effective population size in nature.

evolutionary biology↗

bioRxiv2025

Tenotomized Achilles tendons of MRL/MpJ mice show scar-mediated healing, but have superior recovery of biomechanical properties

Tendon healing in Murphy Ross Large (MRL/MpJ) mice was examined using an Achilles tendon tenotomy model, a full transection model, compared to a patella focal injury model in which tendons in MRL/MpJ mice showed regenerative healing. After complete transection, the Achilles tendons of MRL/MpJ mice healed via scar formation, regardless of sex, as did C57BL/6J mice. Tensile testing found that mechanical properties of injured tendons of both MRL/MpJ female and male mice exhibited comparable levels to those of C57BL/6J female and male mice, respectively after 4 weeks of healing, which is during the remodeling phase. After 10 weeks of healing, injured tendons of MRL/MpJ mice possessed smaller heterotopic ossification volumes than those of C57BL/6J mice. Proteomics analysis revealed similar alterations to signaling pathways in injured tendons of MRL/MpJ and C57BL/6J male mice after 4 weeks of healing. However, among the altered pathways, actin cytoskeleton and integrin signaling pathways were two of the top pathways that were more prominently activated in C57BL/6J males than in MRL/MpJ males. These findings indicate that MRL/MpJ mice possess limited capacity to regenerate injured tendons after complete rupture, and that tenotomized Achilles tendons of MRL/MpJ male mice have lesser induction of heterotopic ossification and lower activation of the signaling pathways also induced with injury in C57BL/6J male mice.

pathology↗

bioRxiv2025

Telemetry-validation of dorsal scute microchemistry: complementary tools reconstruct the migratory life-history of an endangered population of Atlantic Sturgeon

An understanding of age-specific habitat requirements and the timing of critical ontogenetic transitions is essential to inform conservation and recovery efforts for Atlantic Sturgeon (Acipenser oxyrinchus). However, these are often difficult to assess due to the species cryptic nature and the consequent lack of temporal and spatial habitat data across life stages. Sampling and microchemistry analysis of dorsal scute apical spines (i.e., dorsal scutes) represents an innovative methodology to reconstruct past life-history events of endangered populations of Atlantic Sturgeon. Here, we establish the broad potential of dorsal scute sampling for wild-caught Atlantic Sturgeon and compare age-estimates and trace-element ratio patterns from dorsal scute with those from pectoral fin spines. We also evaluate microchemistry signatures from both structures to infer past habitat use and age at initial entry into marine waters and, importantly, validate these interpretations using known locations from acoustic telemetry detections. Major ontogenetic shifts in habitat use detected in the microchemistry signatures suggest our methodology was appropriate to identify the timing of initial juvenile migration into marine habitat, while providing additional information regarding the timing of transitions between freshwater and marine habitats that are essential to the management and conservation of this endangered species. As such, the collection of dorsal scute samples is suggested to complement ongoing research efforts for wild-populations and provides additional data points beyond those available from conventional tag-recapture methods alone, allowing researchers and managers to retrospectively identify environmental transitions and habitat use that occur prior to sampling encounters or outside of monitored areas.

ecology↗

bioRxiv2024

What's in Cow Dung Manure? Insights into Its Potential for Supporting Plant Defense System

Solanum lycopersicum, a prominent vegetable crop, suffers major yield losses from early blight disease driven by Alternaria solani. Sustainable alternatives to conventional chemical fungicides are urgently needed to mitigate these losses while minimizing environmental impact. This study investigates the application of the microbial consortium derived from Gir cow dung for enhancing tomato resistance against early blight. Metagenomic analysis of Gir cow dung revealed a rich diversity of beneficial microbes, with Bacillus species being one of the prominent. Three key strains Bacillus subtilis, Bacillus tequilensis, and Bacillus licheniformis were isolated, characterized, and tested for their antagonistic activity against A. solani. The microbial consortium exhibited significant antifungal properties, and the application of the consortium on tomato plants led to a marked reduction in disease progression. Histochemical analyses of treated plants revealed a pronounced increase of hydrogen peroxide, phenolic compounds, and superoxide dismutase, suggesting enhanced activation of plant defense pathways. Comparative gene expression profiling showed the upregulation of key defense-related genes, including PR2b, Chi3, and Pto kinase, in Bo-treated plants, indicating a systemic activation of host defense mechanisms. Untargeted metabolomic analysis using LC-MS/MS further demonstrated significant metabolic reprogramming in microbial consortium-treated plants. Pathway enrichment analysis revealed enhanced accumulation of secondary metabolites, including phenolics and terpenoids, which are known to play vital roles in pathogen defense. Additionally, hierarchical clustering of metabolite profiles highlighted distinct metabolic signatures between Bo-treated and control plants, underscoring the broad biochemical impact of the microbial treatment. Collectively, our findings demonstrate that the microbial consortium derived from Gir cow dung significantly enhances tomato plant resistance to A. solani through multifaceted biochemical, molecular, and metabolic mechanisms. This study provides a sustainable biocontrol strategy that could effectively replace chemical fungicides, contributing to resilient tomato production and advancing the field of agroecological plant disease management.

plant biology↗

bioRxiv2024

Combining in vivo and in vitro approaches to better understand host-pathogen interactions

Nutrition often shapes the outcome of host-parasite interactions, however understanding the mechanisms by which this occurs is confounded by the intimate nature of the association and by the fact that the host and parasite may compete for the same limiting nutrients. One way of disentangling this interaction is to combine in vivo and in vitro approaches. Here, we explore the role of host nutrition in determining the outcome of infections using a model insect-bacterium system: the cotton leafworm Spodoptera littoralis and the blood-borne bacterium Xenorhabdus nematophila. Spodoptera littoralis larvae were reared on one of a series of 20 chemically-defined diets ranging in their protein: carbohydrate (P:C) ratio and caloric density. They were then challenged with either a fixed dose of X. nematophila cells (live or dead) or were sham-injected. Survivorship of larvae challenged with live bacterial cells was strongly dependent on the protein levels of the diet, with mortality being highest on low-protein diets. This trend was reflected in the bacterial growth rate in vivo, which peaked in larvae fed low-protein diets. To determine whether in vivo bacterial growth rates were driven by blood nutrients, rather than an enhanced host immune response, we generated 20 synthetic haemolymphs ( nutribloods) that mimicked the nutritional content of host blood. Bacterial growth rate in the nutribloods was also negatively impacted by their protein content suggesting that nutrient availability and not host immunity was driving the interaction. By comparing standardized bacterial growth rates in vivo and in vitro, we conclude that the outcome of this host-parasite interaction is largely driven by bottom-up effects of nutrients on bacterial growth, rather than by top-down effects of nutrients on host-mediated immune responses. The outcome of host-parasite interactions is typically assumed to be strongly determined by the host immune response. The direct effects of nutrition have been underexplored and may have broad consequences for host-parasite interactions across taxa.

ecology↗

bioRxiv2024

Nutribloods: novel synthetic lepidopteran haemolymphs for understanding insect-microbe interactions in vitro

Understanding the role of nutrients in microbial population dynamics relies on a sound appreciation of their nutritional environment and how this may vary in different habitats. For microbial pathogens and commensals, this can be especially challenging because the microbe may share nutritional resources with its host. Here we design a series of 20 synthetic haemolymphs (nutribloods) that mimic haemolymph nutrient profiles of caterpillars fed on one of 20 chemically-defined diets, that vary in their protein:carbohydrate (P:C) ratio and caloric density. Using these, we are able to simulate the range of nutritional conditions that insect blood pathogens might face, providing a model system for understanding the role of nutrition in microbial growth. We tested this using the entomopathogen, Xenorhabdus nematophila, a gram-positive extracellular bacterium of insect hosts. This revealed that whilst bacterial fitness peaked in nutriblood nutrient space that was high in carbohydrates and low in proteins, levels of amino acids in the nutribloods also appear to be an important driving force for bacterial growth. Using synthetic haemolymphs that had average levels of all nutrients other than carbohydrate, protein or amino acids, we also established that bacterial growth is generally enhanced by carbohydrate and amino acids but reduced by proteins. Here, we have established a tractable model system for examining the role that nutrition plays in the growth of an entomopathogenic bacterium. In future work, this model host-pathogen system can be used to test a range of nutritionally-driven processes, including competition during co-infection and interactions with the host microbiome, as well as comparative studies of other entomopathogens.

physiology↗

bioRxiv2024

Tobacco Smoke Exposure is Characterized by a Distinct Nasal Rhinotype in a Pediatric Population

BackgroundSecondhand tobacco smoke exposure (TSE) increases susceptibility to respiratory diseases, but the mechanisms of action are poorly understood. ObjectiveTo study the effect of TSE in the nasal microbiome of children, and to evaluate whether such effect is dose-dependent with measured levels of cotinine in saliva and urine. MethodsThe study was performed at the Mount Sinai Kravis Childrens Hospital (New York, NY) and the Johns Hopkins Hospital (Baltimore, MD). We enrolled 236 children between 6 months and 10 years of age, both inpatients and outpatients. We collected swabs to characterize the diversity and composition of the nasal microbiome using 16S rRNA gene sequencing and measured cotinine levels in salivary and urinary samples to quantify TSE. We then determined the relationship between these measures and participant respiratory conditions, demographics and lifestyle factors. ResultsInfants with high cotinine levels had lower nasal microbiome alpha diversity and an enrichment in Moraxella, Dolosigranulum and Corynebacterium, which formed a distinct cluster in network analysis. A Dirichlet Multinomial Mixture model identified the existence of two distinct microbial rhinotypes, the first one characterized by significantly higher cotinine levels, lower alpha diversity, and enrichment of these taxa. ConclusionChildren with higher cotinine levels had reduced alpha diversity and a distinct nasal rhinotype. Our results suggest TSE is associated with alterations of the nasal microbiome and identify a rhinotype as a potential biomarker for TSE.

microbiology↗

bioRxiv2024

Polycaprolactone-based shape memory foams as self-fitting vaginal stents

There is an urgent critical need for a patient-forward vaginal stent that can prevent debilitating vaginal stenosis that occurs in up to 75% of patients who undergo pelvic radiation treatments and adolescent patients after vaginal reconstruction. To this end, we developed a self-fitting vaginal stent based on a shape-memory polymer (SMP) foam that can assume a secondary, compressed shape for ease of deployment. Upon insertion, the change in temperature and hydration initiates foam expansion to shape fit to the individual patient and restore the lumen of the stent to allow egress of vaginal secretions. To achieve rapid actuation at physiological temperature, we investigated the effect of architecture of two photocurable, polycaprolactone (PCL) macromers. Star-PCL-tetraacrylate displayed reduced melting temperature in the target range as compared to the linear-PCL-diacrylate. Emulsion-templating was then used to fabricate foams from 75:25 water-in-oil (W/O) emulsions that were subsequently annealed to yield high-porosity SMP foams. Upon axial shape memory testing, both foams displayed excellent shape fixity (90%); however, only the PCL star-foams displayed shape recovery ([~]84%) at 37{degrees}C to its permanent shape. A custom mold and curing system was then used to fabricate PCL star- foams into hollow, cylindrical stents. The stent was crimped to its temporary insertion shape (50% reduction in diameter, OD [~] 11 mm) with a custom radial crimper and displayed excellent shape fixity for deployment (> 95%) and shape recovery ([~] 100%). To screen vaginal stents, we developed a custom benchtop pelvic model that simulated vaginal anatomy, temperatures, and pressures with an associated computational model. A hysteroscope was used to visualize stent expansion and deformation via a scope port near the cervix of the benchtop model. A crimped SMP vaginal stent was deployed in the model and expanded to walls of the canal ([~]70% increase in cross-sectional area) in less than 5 minutes after irrigation with warm water. The vaginal stent demonstrated retention of vaginal caliber with less than 1% decrease in cross-sectional area under physiological pressure. Collectively, this work demonstrates the potential for SMP foams as self-fitting vaginal stents to prevent stenosis. Additionally, this work provides new open-source tools for the iterative design of other gynecological devices. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/577474v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1bc3162org.highwire.dtl.DTLVardef@4e5657org.highwire.dtl.DTLVardef@1069d33org.highwire.dtl.DTLVardef@13aa9da_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender

bioengineering↗

bioRxiv2023

H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs

Polycomb Repressive Complex 2 (PRC2)-mediated histone H3K27 tri-methylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, polycomb-regulated genes are connected through long-range 3D interactions which resolve upon differentiation. Here, we report that polycomb looping is controlled by H3K27me3 spreading and regulates target gene silencing and cell fate specification. Using glioma-derived H3 Lys-27-Met (H3K27M) mutations as tools to restrict H3K27me3 deposition, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened 3D interactions mirroring chromatin architecture of pluripotency, and stringent gene repression that maintains cells in progenitor states to facilitate tumor development. Conversely, H3K27me3 spread in pluripotent stem cells, following neural differentiation or loss of the H3K36 methyltransferase NSD1, dilutes cPRC1 concentration and dissolves polycomb loops. These results identify the regulatory principles and disease implications of polycomb looping and nominate histone modification-guided distribution of reader complexes as an important mechanism for nuclear compartment organization. Highlights{square} The confinement of H3K27me3 at PRC2 nucleation sites without its spreading correlates with increased 3D chromatin interactions. {square}The H3K27M oncohistone concentrates canonical PRC1 that anchors chromatin loop interactions in gliomas, silencing developmental programs. {square}Stem and progenitor cells require factors promoting H3K27me3 confinement, including H3K36me2, to maintain cPRC1 loop architecture. {square}The cPRC1-H3K27me3 interaction is a targetable driver of aberrant self-renewal in tumor cells.

molecular biology↗

bioRxiv2023

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof towards human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = PaxlovidTM), CMX990 has distinctly differentiated potency ([~]5x more potent in primary cells) and human in vitro clearance (>4x better microsomal clearance and >10x better hepatocyte clearance), with good in vitro-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

microbiology↗

bioRxiv2023

Fawn bedsite selection by a large ungulate living in a peri-urban area

Human-wildlife conflict in expanding peri-urban and urban areas is of increasing concern, as a result of growing human populations along with the associated anthropogenic footprint on wildlife habitats. Empirical data from wildlife research carried out within human dominated landscapes are key to understanding the effects of human pressures on wildlife ecology and behaviour, exploring wildlife behavioural flexibility (or phenotypic plasticity), and informing wildlife management decisions. Here, we explored how female fallow deer (Dama dama) responded to human and dog presence during the birthing period in the largest walled urban park in Europe. We collected data on 477 bedsites utilised by 283 neonate fawns across three consecutive fawning seasons, gathered fine-scale data on humans and dogs space use, and built Resource Selection Functions at multiple spatial scales. We found that, when choosing bedsites to give birth and leave fawns unattended, fallow deer mothers significantly avoided hotspots of park visitors on foot (and their dogs) along the hiking trail routes. Bedsites were also unlikely to be in close proximity of paved roads used by vehicle traffic. Additionally, fallow deer mothers were found to select for dense understory vegetation for bedsites, providing low visibility to conceal their offspring. Our results provide detailed insights into bedsite spatial and habitat selection by a large herbivore in response to human activities, and we provide clear indications to wildlife managers to preserve established fawning sites and alleviate human-wildlife conflict during a critical period of the deer annual biological cycle.

animal behavior and cognition↗

bioRxiv2023

Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate

Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone. The chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate. Malnutrition is a leading cause of growth retardation in children; however, after recovery from nutrient deprivation, bone growth is accelerated beyond the normal rate, a phenomenon termed catch-up growth. Though nutritional status is a known regulator of long bone growth, it is largely unknown if and how chondroprogenitor cells respond to deviations in nutrient availability. Here, using fate-mapping analysis in Axin2CreERT2 mice, we showed that dietary restriction increased the number of Axin2+ chondroprogenitors in the resting zone and simultaneously inhibited their differentiation. Once nutrient deficiency was resolved, the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns, contributing to accelerated growth. Furthermore, we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone, and that exogenous IGF-1 canceled this reduction and stimulated differentiation of the pooled chondroprogenitors, decreasing their numbers. Our study of Axin2CreERT2 revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate, and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of the chondroprogenitor cells.

developmental biology↗

bioRxiv2022

Global genomic analysis reveals the genetic origin and secondary invasion of fall armyworm in the Eastern hemisphere

The major plant pest fall armyworm (FAW), Spodoptera frugiperda, is native to the Americas and has colonized African and Asian countries in the Eastern hemisphere since 2016, causing severe damage to multiple agricultural crop species. However, the genetic origin of these invasive populations require more in-depth exploration. We analyzed genetic variation across FAW genomes of 153 newly sequenced individuals from Eastern hemisphere and 127 individuals mostly originating from the Americas. The global genetic structure of FAW shows that the FAW in American has experienced deep differentiation, largely consistent with the Z-chromosomal Tpi haplotypes commonly used to differentiate "corn-strain" and "rice-strain" populations. Results indicate that the invasive Eastern hemisphere populations are different from the American ones and have relatively homogeneous population structure, consistent with the common origin and recent spreading from Africa to Asia. Our analyses suggest that north-and central American "corn-strain" FAW are the most likely sources of the invasion into the Eastern hemisphere. Furthermore, evidence based on genomic, transcriptomic and mitochondrial haplotype network analysis suggest that there has been an earlier independent introduction of FAW into Africa that introgressed into the recent invasive population.

molecular biology↗