Biology subjects

Martin, D.

Publications and source records attributed to Martin, D..

At least 19 recordsLinked to original sources

bioRxiv2026

ZBTB7B is a Master Regulator of Salivary Acinar Cell Function

Salivary glands exhibit transcriptional programs that distinguish them from other tissues, yet the upstream regulatory logic underlying these programs is not well defined. To identify transcription factors (TFs) that structure salivary identity, we generated RNA-seq and ATAC-seq from human major and minor salivary glands and inferred TF[->]TF regulatory edges from high-confidence chromatin footprints. ZBTB7B emerged as the most connected regulator across salivary samples. To locate regulatory regions associated with salivary-specific transcription, we trained hidden Markov models (HMMs) on chromatin accessibility across 4 Mbp windows surrounding salivary-specific and non-salivary-specific transcription start sites. The resulting chromatin states distinguished promoter-proximal openness from distal enhancer activity and identified salivary-specific enhancers enriched for ZBTB7B motifs. These enhancer states correlated strongly with expression of salivary genes, including AQP5, indicating that distal regulation contributes substantially to salivary transcriptional specificity. To assess the consequences of losing Zbtb7b, we performed single-cell RNA-seq and spatial transcriptomics on submandibular and parotid glands from Zbtb7b knockout mice. Knockout mice exhibited reduced salivary flow, shifts in acinar cell proportions, and the emergence of a neonate-like acinar population characterized by loss of canonical secreted proteins and increased expression of MHC class I genes. These transcriptional and cellular changes occurred despite preserved gland architecture, suggesting that Zbtb7b stabilizes adult acinar identity rather than supporting structural maintenance. Together, these data identify ZBTB7B as a master regulator of salivary transcriptional networks, acting through both promoter-proximal and enhancer-level mechanisms, and demonstrate that loss of Zbtb7b disrupts acinar identity and impairs salivary function.

genomics↗

bioRxiv2026

LifeSciBench: Evaluating Language Models on Realistic, Expert-Level Tasks in the Life Sciences

We introduce LifeSciBench, a benchmark of 750 expert-authored tasks designed to evaluate whether language models can handle realistic life science research work. The majority of existing life sciences benchmarks have a narrow scope or are purely knowledge-based, and therefore fail to capture the complexity of real-world research, which often involves ambiguities and requires the accurate execution of multiple dependent judgment calls. Additionally, almost all existing benchmarks span at best a small collection of subdomains within the life sciences; there is at present no existing life sciences benchmark with both the requisite breadth and depth required to convincingly measure proficiency in real-world professional research settings. LifeSciBench addresses this gap by spanning seven representative scientific workflows and seven life science domains, with each constituent task paired with a human expert-written rubric. Across five frontier and domain-specialized models, GPT-Rosalind performs best, with a task-weighted mean normalized rubric score of 0.576 and a task-weighted response pass rate of 36.1% (response-level values are first averaged within each task, and the resulting task-level values are then averaged with equal weight). LifeSciBench remains unsaturated, with 171 tasks (22.8%) having no observed passing response from any evaluated model and 261 tasks (34.8%) having a best-model pass rate below 20%. LifeSciBench therefore serves as a high-resolution evaluation of practical scientific reasoning and operational decision-making in the life sciences.

bioinformatics↗

bioRxiv2026

A genetic screen unveils the polymerization cycle of the bacterial actin-like MreB

MreB, a bacterial actin homolog and polymerizing ATPase, is central to cell-shape maintenance and cell-wall integrity. Its functions rely on its ability to assemble into dynamic, membrane-associated polymers. However, how nucleotide binding and hydrolysis, MreB-MreB contacts, and membrane association are coordinated to enable polymer assembly and disassembly remains unclear. Here, we combined genetics and live-cell microscopy with biochemical approaches to dissect these processes. Using a highly sensitive reporter of MreB activity, we identified, through a genetic screen, residues critical for MreB function in Bacillus subtilis. Subsequent extensive characterization of corresponding stable variants of the homologous Geobacillus stearothermophilus MreB revealed that ATP binding, but not ATP hydrolysis, is required for polymerization. Productive longitudinal intraprotofilament contacts are required for efficient ATP hydrolysis and enhance membrane association. Perturbations predicted to weaken lateral interprotofilament contacts altered membrane association and modulated ATPase activity. Together, these effects provide experimental evidence consistent with long-range functional coupling among the longitudinal and lateral protofilament interfaces, the distant nucleotide-binding site, and membrane association dynamics. Moreover, impaired ATP hydrolysis delays disassembly of lipid-associated polymers, indicating that hydrolysis promotes polymer turnover. These results establish key mechanistic steps coordinating ATP-driven MreB polymerization and turnover and provide a basis for a complete MreB assembly-disassembly cycle and for further elucidating how MreB dynamics contribute to cell-wall organization.

microbiology↗

bioRxiv2026

Coevolving Mutations in Chronic SARS-CoV-2 Infections

The SARS-CoV-2 pandemic has been marked by two outstanding features that have had major impacts on global public health: the repeated emergence and growth of highly divergent saltation variants with no known close relatives and the development of adverse health effects extending beyond the period of acute infection, called long Covid, in a proportion of the population. Chronic infections in immunocompromised hosts are the most likely explanation for the emergence of saltation variants, and some evidence indicates that viral persistence contributes to long Covid. Knowledge of intrahost evolution during prolonged SARS-CoV-2 infection is therefore vital for understanding the global evolution of SARS-CoV-2 and for deciphering the nature of long Covid and promising avenues for treatment. We assembled a collection of over 3000 independent, full-length SARS-CoV-2 sequences deriving from posited or confirmed chronic infections. We describe 14 distinct mutation patterns (MPs) that repeatedly appear in these sequences--each involving mutations in multiple genomic regions--including four CD8 T cell-escape MPs and two MPs that represent adaptation to tissue compartments outside the upper-respiratory tract. The existence of these MPs promises new insights into the life cycle and evolution of SARS-CoV-2 and the nature of persistent SARS-CoV-2 infection.

evolutionary biology↗

bioRxiv2026

Reconciling fast Hepatitis B evolutionary rates with ancient co-divergence

Estimating evolutionary rates and divergence times for hepatitis B virus (HBV) has long been complicated by conflicting calibration approaches and extensive rate variation. To unlock the full potential of ancient and modern HBV genomic data, we develop a Bayesian mixed-effects molecular clock model that accounts for various sources of rate variation including time-dependent rate decay. Our analyses reveal a pronounced decline in evolutionary rates over time, reconciling HBV divergence estimates with human migration events across both deep and more recent timescales. We show that HBV spread into Europe through both Neolithic farming expansions and later steppe migrations, paralleling patterns proposed for Indo-European language origins. Phylogeographic reconstructions suggest that the Neolithic-associated lineage dispersed at approximately 1 km/year, consistent with archaeological estimates, while genotype D expanded during the Bronze Age at an almost threefold higher rate, plausibly driven by technological innovations underlying steppe expansions. Historical overlap between these lineages facilitated recombination, giving rise to genotype E, which has become a dominant HBV genotype in Africa. These findings demonstrate that ancient viral genomes, when analyzed with models capturing complex rate dynamics, provide a powerful lens on human prehistory and the processes shaping pathogen diversity.

evolutionary biology↗

bioRxiv2026

Rare plants can make an important contribution to sustain local biodiversity through biological interactions

Plants, as structural elements of habitats, contribute greatly to the maintenance of local biodiversity through their biological interactions. In this study we explore whether their rarity, according to Rabinowitzs (1981) three criteria, is related to the richness and diversity of arthropods and other plants they are associated to, in a gypsum-rich steppe. We first analysed whether the geographic abundance and ecological specialisation of 32 characteristic and dominant plant species are related to the diversity (richness and phylogenetic diversity (MPD)) and degree of local specialisation of arthropods associated with them (1,694 taxa). Then, we focused on a non endemic and non specialized plant in the study area (Krascheninnikovia ceratoides) to explore the effect of population size on two types of interactions: aerial arthropods and plant facilitation. Results indicate that: 1) plant species abundance (geographical range) is not related to the richness or MPD of communities of associated arthropods, 2) plant species ecological specialization (edaphic endemisms or gypsophiles) do not contribute differentially to the maintenance of singular arthropod communities, and 3) the community of aerial arthropods and plants interacting with K. ceratoides in a small population are not necessarily less diverse than those in patches of similar size in a large population. Results also revealed that the two plant species with fewer interactions (one rare, one widespread) do show the highest singularity in their interactions with arthropods. Our study illustrates the important contribution of rare plants to the conservation of local biodiversity.

ecology↗

bioRxiv2026

NeuroFLAME: A Scalable, Privacy-Preserving Federated Framework for Secure, Reproducible, and Multi-Site Neuroimaging Analysis

Federated analysis offers a scalable approach to multi-site neuroimaging research by enabling distributed statistical modeling, machine learning, decomposition, harmonization, and validation without exchanging sensitive individual-level data. However, a significant implementation gap exists, as the majority of federated clinical neuroimaging studies remain technical proofs of concept, struggling to fully navigate the rigorous data-sharing regulations and security constraints of real-world clinical and research environments. Compounding this, existing federated analysis frameworks are typically exposed as command-line tools and configuration files, imposing a considerable setup burden that demands specialized technical expertise from neuroscience researchers. To address these barriers, we present NeuroFLAME, an enterprise-grade, open-source federated neuroimaging platform built upon the NVIDIA FLARE (NVFlare) framework. NeuroFLAME couples a client-outbound-only communication framework with a graphical user interface specifically tailored for neuroscientists. Using certificate-based trust and containerized execution, the platform ensures reproducible analyses with baseline privacy guarantees through data localization and mTLS encryption; advanced protections such as differential privacy and homomorphic encryption are available as optional configurations. By ensuring that clients only need outbound communication and that raw data never leaves each site, NeuroFLAME is designed to support institutional data governance requirements and regulatory frameworks such as HIPAA and GDPR. We demonstrate the platform's utility through three federated analysis workflows, each implemented as a NeuroFLAME computation: multi-site federated closed form voxel-wise regression, decentralized constrained joint independent component analysis (dcjICA) and federated label-based dimensional prediction. Empirical validation of both workflows shows that NeuroFLAME achieves high consistency with established centralized approaches, effectively bridging the gap between experimental federated learning prototypes and production-ready collaborative tools for privacy-preserving, large-scale federated neuroimaging analysis.

neuroscience↗

bioRxiv2026

Evolutionary landscapes of zygotic genome activation across animals

During early animal embryogenesis, gene expression control shifts from maternally deposited products to newly transcribed RNA through zygotic genome activation (ZGA). Although essential and universal, ZGA remains poorly understood outside a few model species. Here, we generated a transcriptomic atlas of early embryogenesis across 61 animal species from 13 phyla and used a unified computational framework to infer ZGA timing systematically. We find extensive variation in ZGA onset across animals, but show that the ratio between genome size and egg cytoplasmic volume, a proxy for the nuclear-to-cytoplasmic ratio, robustly predicts when genome activation begins. We also reveal that zygotic genes also differ from maternal transcripts in genomic architecture, function and evolutionary conservation, suggesting that ZGA follows a conserved molecular logic despite flexible transcriptomic outputs.

evolutionary biology↗

bioRxiv2026

Non-fibrillar prion protein oligomers transmit structural information during early assembly

The prion paradigm is founded on the transmission of structural information from aggregated assemblies to soluble protein substrates, a process classically attributed to fibril-end-mediated templating. Whether non-fibrillar assemblies or transient oligomeric states can also participate in folding information transfer remains unclear. Here, using recombinant prion protein (PrP), rational mutagenesis, hetero-oligomerization assays, arrested reaction conditions, and single-particle atomic force microscopy coupled to infrared nano-spectroscopy (AFM-IR), we examine the earliest stages of PrP assembly from the perspective of folding information transmission. We show that polymerization-defective PrP variants can be incorporated into oligomeric assemblies through structural complementation, in which folding information supplied by wild-type PrP restores their assembly competence. Under arrested reaction conditions, transient polymerization-competent conformers further contribute to folding information transfer at subcritical concentrations. Domain-resolved analyses reveal a modular oligomeric architecture in which a {beta}-sheet-rich B domain constitutes the primary scaffold for folding information transfer. Preformed O1 oligomers then act as autonomous conformational templates that promote mutant incorporation and undergo hierarchical condensation through accretion of a structurally distinct E domain. Together, these findings demonstrate that non-fibrillar PrP oligomers and transient assembly intermediates can store and transmit folding information and may function as oligomer-based secondary nucleation platforms, expanding the conceptual framework of prion assembly beyond fibril-end elongation alone.

biochemistry↗

bioRxiv2026

Characterizing Physicochemical Selection in Protein Evolution with Property-Informed Models (PRIME)

AbstractStandard probabilistic models of coding sequence evolution effectively identify where and when selection acts but remain agnostic to the mechanistic realization of these forces. We introduce PRIME (PRoperty Informed Models of Evolution), a framework of codon-level maximum likelihood methods--including global (G-PRIME), episodic (E-PRIME), and site-specific (S-PRIME) implementations--that explicitly model amino acid exchange-ability as a function of physicochemical properties. By parameterizing attributes such as molecular volume, hydropathy, and secondary structure propensities, PRIME resolves the biophysical basis of selective constraint across both the sequence and the phylogeny. At the site level, S-PRIME leverages an explicit biophysical taxon-omy to precisely categorize residues as conserved, neutral, or changing for specific properties, resolving selective signals that remain invisible to traditional rate-based metrics. Our analysis of a benchmark of 24 diverse datasets and a genome-wide screen of 18,944 mammalian genes demonstrates that biophysical realism yields substantial improvements in model fit, acting synergistically with rate variation to explain complex evolutionary patterns. We find that power to detect physicochemical constraints at individual sites is fundamentally governed by simple informational redundancy (substitutions per unique amino acid; AUC = 0.91), with sensitivity exceeding 90% in data-rich alignments. E-PRIME reveals a distinct biophysical hierarchy: while core packing and beta-sheet scaffolds are rigidly conserved, alpha-helix propensity and surface electrostatics serve as the primary substrates for adaptive tuning. Furthermore, PRIME importance weights align with aspects of the primary semantic axes of deep learning representations (ESM-2) and capture key features of experimental fitness landscapes. By trans-forming abstract evolutionary rates into interpretable biophysical rules, PRIME provides a useful framework for characterizing the mechanistic drivers of protein diversity.

evolutionary biology↗

bioRxiv2026

Ulacamten: A Novel, RLC-Targeting Cardiac Myosin Inhibitor for Potential Treatment of Cardiac Hypercontractility, Including HFpEF

BackgroundCardiac myosin inhibitors (CMIs) demonstrate advantages over other guideline-directed therapy for patients with obstructive hypertrophic cardiomyopathy (oHCM). By reducing hypercontractility, CMIs abrogate excessive systolic function and improve diastolic function; diminish hypertrophy of the left ventricle (LV); and improve exercise capacity, functional class, and symptoms. Whether CMIs are therapeutic in heart failure with preserved ejection fraction (HFpEF) is of interest because a significant subset of these patients demonstrate supranormal ejection fractions and abnormal LV structure, characteristics in common with HCM, where CMIs have proved effective. ObjectivesOur goal was to characterize the mechanism of myosin inhibition for ulacamten and determine its efficacy in a rodent model of HFpEF. MethodsUlacamten was characterized using biophysical and biochemical approaches, cardiomyocytes from humans and the ZSF1 obese rat model of HFpEF, hypercontractile human-engineered heart tissues, and echocardiography in the ZSF1 rat model. ResultsUnlike the other CMIs, aficamten and mavacamten, ulacamten binds outside the S1 domain of myosin and requires the regulatory light chain domain to bind and inhibit the activity of 2-headed myosin. Ulacamten only partially inhibits the myosin ATPase activity in both myofibrillar and protein systems, but inhibition of contractility was nearly complete in cardiomyocytes. Improvement in relaxation was demonstrated in hypercontractile-engineered heart tissues, and chronic treatment of ZSF1 obese rats showed benefits in both cardiac structure and function. ConclusionsUlacamten inhibits myosin in a manner distinct from aficamten and mavacamten, potentially broadening the mechanistic properties of CMIs available for treatment of hypercontractile cardiac dysfunction. CONDENSED ABSTRACTCardiac myosin inhibitors (CMIs) abrogate excessive systolic function and improve diastolic function, diminish cardiac hypertrophy, and improve exercise capacity in humans with obstructive hypertrophic cardiomyopathy (oHCM). Supranormal ejection fraction underlies heart failure with preserved ejection fraction (HFpEF) in some patients. We describe a new CMI, ulacamten, with binding and inhibitory properties distinct from two other FDA-approved CMIs, aficamten and mavacamten. Specifically, ulacamten requires 2-headed myosin to inhibit activity, whereas aficamten and mavacamten inhibit single-headed myosin. Ulacamten inhibits contractility in primary myocytes isolated from control human and hypercontractile ZSF1 obese rat hearts, as well as engineered heart tissues created with induced pluripotent stem cell cardiomyocytes bearing an HCM mutation. Chronic treatment of ZSF1 obese rats as a preclinical model of HFpEF improves diastolic function and reduces hypertrophy and fibrosis, broadening the potential mechanistic landscape of CMIs. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/701387v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@11f9cecorg.highwire.dtl.DTLVardef@776847org.highwire.dtl.DTLVardef@15f19ddorg.highwire.dtl.DTLVardef@9b20c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Indistinct changes in the mammal fauna between 1986-2017 at Judbarra-Gregory National Park, Northern Territory

The mammal fauna in many parts of northern Australia has undergone dramatic changes in the past 20-30 years, though longitudinal data that spans this period are limited and largely from coastal and high rainfall regions. We examined data from Judbarra-Gregory National Park that has been collected in a systematic manner (once in 1986 and then 2005-2017), including two years where camera trapping was included (2015 and 2017). We standardised this data in a simple manner (i.e., species by relative abundance and site frequency) to examine if there were any stark changes over this time span. We also undertook some simple modelling of mammal pattern with respect to fire and fractional green and bare cover metrics. Though we recognise some limitations in our comparisons (i.e., spatial variation in sites and methods), the data indicated that the mammal fauna had generally not changed substantially in composition, relative abundance or frequency across sites. There were meaningful models correlating mammal pattern to fire frequency, time since fire, fraction green and bare parameters. However, some species symptomatic of small mammal decline elsewhere (i.e., Rattus tunneyi) may have become less common, whereas other species were recorded for the first time in more recent years (2010-2017), particularly by camera traps (i.e., Trichosurus vulpecula, Isoodon macrourus, Melomys burtoni). We postulate that change in the mammal fauna on the semi-arid fringe of tropical savannas may have occurred prior to the 1980s, with a long history of cattle grazing a possible contributing factor. The mammal fauna there, is also perhaps naturally sparse and heterogeneous in spatial and temporal distribution.

ecology↗

bioRxiv2025

Exhausted-like effector CD8 T cells mediate immune-stromal interactions at mucosal Chronic Graft-versus-Host Disease onset

Chronic graft-versus-host disease (cGVHD) frequently follows allogeneic hematopoietic stem cell transplantation and impacts the mucosa. This atlas study highlights the role of exhausted-like effector CD8+ T cells (TEXEF) in oral mucosal cGVHD pathogenesis. Biopsies from the oral mucosa were collected at oral cGVHD onset or at six months post-transplant and analyzed using single-cell RNA sequencing and other modalities. At cGVHD onset, in addition to changes in the myeloid compartment, two distinct populations of CD8+T cells with a TEXEF phenotype were prevalent: an inflammatory CD8T cell cluster (CD8T_4) expressing CCL4, CD69, and TNFSF9, and an exhausted CD8T cell cluster (CD8T_5) characterized by the expression of CXCL13, HIF1A, and HLA-DRA, both correlated with clinical disease severity. Pseudo-time analysis suggests a transition from the inflammatory pre-exhausted CD8T_4 cluster to the cytolytic, terminally exhausted CD8T_5 cluster. The CXCL9-CXCR3 interactions among CD8+ T cells, fibroblasts and myeloid cells are implicated in tissue damage. Onset of cGVHD despite frequent oral mucosal FOXP3 regulatory CD4T cells suggests potential impaired Treg function or CD8+T cell dysfunction. These findings highlight TEXEF cells as key contributors to oral cGVHD pathology and potential therapeutic targets for mitigating sustained tissue injury in cGVHD.

immunology↗

bioRxiv2025

Human ectodermal organoids reveal the cellular origin of DiGeorge Syndrome

Neurocristopathies account for half of all birth defects and several cancers highlighting the need to understand early neural crest (NC) development, for which suitable human models dont exist. Here, we present a pluripotent-stem-cell-based 3D ectodermal organoid model that faithfully recapitulates early ectodermal patterning of future central nervous system, epidermis and cranial and trunk NC, as well as a diverse selection of NC derivatives --offering a comprehensive platform to study neurocristopathies from early induction of pluripotent-like stem cells at the neural plate border to differentiated cells. DiGeorge syndrome (DGS) is caused by a hemizygous microdeletion of [~]fifty genes, many of which play broad roles during embryogenesis. While DGS is traditionally considered to originate from all germ layers, its clinical manifestations--including craniofacial anomalies, cardiac outflow tract defects, thymic hypoplasia and thyroid dysfunction--are consistent with tissues requiring NC contributions. This raises the question why DGS mainly manifest in organs of NC origin? Using patient-derived iPSCs, we show that DGS organoids display reduced pluripotency gene expression and impaired maintenance of ectodermal stem cells, leading to defective NC specification, posteriorization of cranial NC, and failure to form cartilage. We identify a small subset of genes within the DGS deletion as potential drivers of these early NC defects. Consequently, impaired NC cells are further affected during cranial and vagal mesenchyme maturation, likely worsened by hemizygosity of additional DGS genes that individually, without the initial NC defect, are insufficient to cause the disease. We hypothesize that DGS is primarily, or possibly entirely, a neurocristopathy.

developmental biology↗

bioRxiv2025

An allelic resolution gene atlas for tetraploid potato provides insights into tuberization and stress resilience

Tubers are modified underground stems that enable asexual, clonal reproduction and serve as a mechanism for overwintering and avoidance of herbivory. Tubers are wide-spread across angiosperms with some species such as Solanum tuberosum L. (potato) serving as a vital crop for human consumption. Genes responsible for tuber initiation and disease resistance have been characterized in potato including StSP6A, a homolog of Flowering Time, that functions as tuberigen, the equivalent of florigen. To elucidate additional molecular and genetic mechanisms underlying potato biology including tuber initiation, tuber development, and stress responses, we generated a developmental and abiotic/biotic-stress gene expression atlas from 34 tissues and treatments of Atlantic, a tetraploid cultivar. Using the haplotype-phased tetraploid Atlantic genome assembly and expression abundances of 129,218 genes, we constructed gene coexpression modules that represent networks associated with distinct developmental stages as well as stress responses. Functional annotations were given to modules and used to identify genes involved in tuberization and stress resilience. Structural variation from a pan-genomic analysis across four cultivated potato genome assemblies as well as domestication and wild introgression data allowed for deeper insights into the modules to identify key genes involved in tuberization and stress responses. This study underscores the importance of transcriptional regulation in tuberization and provides a comprehensive framework for future research on potato development and improvement.

plant biology↗

bioRxiv2025

High resolution diel transcriptomes of autotetraploid potato reveal expression and sequence conservation among rhythmic genes

Photoperiodic changes in diel cycles of gene expression are pervasive in plants. Timing of circadian regulators together with light signals regulate multiple photoperiod dependent responses such as growth, flowering or tuber formation. However, for most genes the importance of cyclic mRNA levels is less clear. We analyzed the diel transcriptome of modern cultivated potato, a highly heterozygous autotetraploid. Clonal propagation and limited meiosis have led to the accumulation of deleterious alleles and therefore tetraploid potato is an ideal model system to investigate the conservation of cyclic expression and cyclic genes during the artificial selection process. We observed that cyclic alleles were more highly expressed than non-cyclic ones and were highly co-expressed not only under diel cycles but also across tissues, developmental stages and stress conditions. Moreover, the smaller ratio of non-synonymous to synonymous differences within cyclic as compared to non-cyclic allelic groups indicates that cyclic genes, in general, have more conserved core functions than those of non-cyclic ones. In accordance with this observation, fully rhythmic allelic groups were highly enriched in photosynthesis and ribosome biogenesis genes, which play core functions in plants. Furthermore, we investigated differences in cyclic expression patterns between photoperiods. We identified transcription factors potentially regulating the strong differences in phase between photoperiods observed in ribosome biogenesis and pathogen response genes. Finally, analyses of genes involved in tuber formation suggests that the regulation of CO gene transcription is not the only factor enabling tuberization under long days in modern cultivated potato. This study not only provides high quality diel transcriptomic datasets of cultivated potato but also important insight on the role of allelic diversity in rhythmic expression in plants.

plant biology↗

bioRxiv2025

From Randomness to Recognition: Modeling the Evolution of DNA Sequence Information During SELEX

Systematic Evolution of Ligands through Exponential Enrichment (SELEX) was used as a model system to explore the evolution of DNA sequence information and function during enrichment of molecular recognition to a series of related target molecules. Using a Natural Language Processing (NLP) based approach, a model was trained on an unlabeled mixture of oligonucleotide sequences sampled from both unenriched libraries and from six libraries that had been enriched for binding to either peptide or protein targets. This general model (pre-trained model) was then used to generate latent space representations of sequences that contained embedded binding information. Unsupervised clustering was used to create two dimensional maps that allowed comparison of the overlap between the latent space representations of sequences from different unenriched and enriched libraries. Replicate, independent enrichments to the same targets starting from completely unique random libraries gave rise to essentially indistinguishable latent space representations. However, similar representations between unenriched and enriched sequences, or between enriched sequences from different targets, resulted in distinct clustering patterns. The extent of overlap between the patterns from unenriched and enriched libraries was correlated with overall target binding by the enriched library. Further, the pre-trained model was fine-tuned to classify which target library each sequence belonged to, and the accuracy of classification between unenriched and enriched sequences was also correlated with the overall binding of the enriched library to its target. Finally, it was possible to distinguish libraries enriched for binding to two different targets differing by as few as 1 in 30 amino acids. Thus, using NLP-based approaches, it is possible to relate the DNA sequences present in an enriched library with the ability of the library to specifically bind its intended target, providing a tool for both guiding the enrichment process and more deeply understanding the structure-binding relationships that evolve.

biochemistry↗

bioRxiv2025

Combined ADAMTS10 and ADAMTS17 inactivation exacerbates bone shortening and skin phenotypes

Weill-Marchesani syndrome (WMS) is characterized by severe short stature, short hands and feet (brachydactyly), joint contractures, tight skin, and heart valve, eye, and skin anomalies. Whereas recessive WMS is caused by mutations in ADAMTS10, ADAMTS17, or LTBP2, dominant WMS is caused by mutations in FBN1 (encoding fibrillin-1). Since bone growth is driven by chondrocyte proliferation and hypertrophy in the growth plates, the genetics of WMS suggests that the affected ECM proteins act within the same pathway to regulate chondrocyte and growth plate function. Here, we investigated the role of the secreted ADAMTS proteases ADAMTS10 and ADAMTS17 in growth plate function and ECM formation. We generated Adamts10;Adamts17 double knockout (DKO) mice, which showed significant postnatal lethality compared to single Adamts10 or Adamts17 KO mice. Importantly, we observed severe bone shortening DKO mice, which correlated with a narrower hypertrophic zone in their growth plates. ADAMTS17 substrates identified by N-terminomics and yeast two-hybrid screening identified the ECM proteins fibronectin and collagen VI (COL6). However, validation experiments did not reveal direct proteolysis of either fibronectin or COL6 by ADAMTS17. We then investigated ECM formation in primary ADAMTS10- and ADAMTS17-deficient skin fibroblasts and observed compromised fibronectin deposition concomitant with aberrant intracellular accumulation of fibrillin-1. These findings support a role for ADAMTS17 in ECM protein secretion and assembly. Collectively, our data suggest that ADAMTS10 and ADAMTS17 regulate bone growth by regulating chondrocyte hypertrophy or hypertrophic chondrocyte turnover. Mechanistically, ADAMTS17 appears to be a critical regulator of ECM protein secretion or pericellular matrix assembly, whereas ADAMTS10 likely modulates ECM formation at later stages, possibly regulating the spatio-temporal deposition of fibrillin isoforms.

cell biology↗