Biology subjects

Joshi, J.

Publications and source records attributed to Joshi, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Mechanistic prediction of fecal microbiota transplant engraftment and Clostridioides difficile colonization resistance with μODE

Shotgun metagenomics routinely resolves microbial community composition down to the strain level via metagenome-assembled genomes (MAGs), but translating these static catalogs into mechanistic, time-resolved understandings of ecosystem dynamics remains a critical computational bottleneck. Here, we present muODE, a fully automated framework that converts MAGs into dynamical simulations of community metabolism equipped with a composable, literature-grounded ecology layer, fundamentally designed to serve as a mechanistic hypothesis-testing engine. It employs dynamic flux balance analysis (dFBA) coupled to a shared extracellular pool and integrates a composable ecology layer capturing pH inhibition, time-varying antibiotic pharmacokinetics, bile-acid transformations, and spore dormancy. To evaluate the core engine, we cross-validated the dFBA machinery to machine precision against an independent reference implementation. We provide native export to the established COMETS engine for third-party verification. Benchmarking against two independent experimentally validated datasets confirmed that while monoculture growth is robustly captured, overflow secretion and directed community composition remain strictly bounded by the flux-routing limitations of max-biomass FBA. However, when applied to rate-modifying ecological feedback, muODE mechanistically and quantitatively reproduces bile-acid-mediated colonization resistance against Clostridioides difficile. With a single rate parameter calibrated so that baseline deoxycholate matched its measured physiological concentration, the framework reproduced the uncalibrated antibiotic-induced collapse of deoxycholate, with the calibrated inhibitor concentration coinciding with the independently set inhibitory threshold of the pathogen and driving a ~44x shift in the simulated pathogen-susceptibility ratio; bile-acid transformation is represented in the composable ecology layer rather than in the genome-scale stoichiometry. Finally, applying muODE end-to-end to a real longitudinal fecal microbiota transplant (FMT) yielding 139 de novo genome-scale metabolic models, the framework successfully recovered the clinical direction of treatment. By transparently diagnosing the structural competitive-exclusion bias that limits precise compositional prediction, muODE motivates the necessity of community-objective extensions while transitioning microbiome modeling from descriptive taxonomy toward testable, quantitatively-validated dynamic hypothesis testing, laying the essential mechanistic groundwork for the predictive engineering of safe, targeted ecological therapeutics. muODE is freely available at https://github.com/cumbof/muODE.

microbiology↗

bioRxiv2026

A Saturated Aminotriester Lipid Enhances Amonafide Activity in Human Colorectal Cancer Cells

The delivery of small-molecule therapeutics across cellular membranes remains a fundamental challenge in drug development, particularly for compounds whose physicochemical properties limit intracellular bioavailability. Inspired by the low toxicity, biodegradability, and synthetic accessibility of triethanolamine-derived lipids, we investigated a series of C18 aminotriester lipids as excipients for the codelivery of anticancer therapeutics. Four structurally related triester lipids bearing saturated, cis-monounsaturated, trans-monounsaturated, and di-unsaturated C18 tails were synthesized through straightforward esterification reactions with triethanolamine. These lipids were evaluated for their ability to enhance the antiproliferative activity of several anticancer agents, including paclitaxel, doxorubicin, amonafide, homoharringtonine, camptothecin, and SN-38. Across multiple drug classes, the aminotriester lipids exhibited minimal intrinsic cytotoxicity and generally produced limited enhancement of drug potency. However, the fully saturated tris-stearate aminotriester lipid selectively enhanced the antiproliferative activity of amonafide in HCT-116 colorectal cancer cells, particularly at lower concentrations. In contrast, unsaturated lipid analogues displayed negligible enhancement effects, and the activity of the tris-stearate lipid was substantially attenuated in A549 lung adenocarcinoma cells, weakly observed in HT-29 colorectal cancer cells, and absent in CT26 murine colorectal cancer cells. Lactate dehydrogenase release assays indicated that these effects were not associated with membrane lysis or nonspecific cytotoxicity. Further, fluorescence microscopy time course experiments suggest improved membrane trafficking of amonafide when codelivered stoichiometrically with fully saturated C18 aminotriester lipids. Collectively, these findings demonstrate that saturated triethanolamine-based aminotriester lipids may function as selective and biocompatible codelivery excipients for certain small-molecule therapeutics. The observed dependence on both lipid saturation state and cellular context suggests that membrane organization and lipid packing may play important roles in mediating these effects. These results establish a foundation for further mechanistic investigations into aminotriester lipid-assisted small-molecule delivery systems.

cancer biology↗

bioRxiv2026

Biogeography and cryptic diversity of the ancient centipede genus Digitipes (Scolopendromorpha) in South and Southeast Asia

Understanding the relative roles of vicariance and dispersal in shaping diversity and distribution patterns is central to historical biogeography. In this study, we investigate the historical biogeography of the ancient centipede genus Digitipes Attems, 1930 from South and Southeast Asia. First, we determined the phylogenetic position of the genus Digitipes within the Order Scolopendromorpha (n=414) by assembling primary and published sequences (n=30) for two mtDNA markers (COI, 16S) and one nuclear marker (28S) using Maximum Likelihood and Bayesian inference. We further used single-locus and multi-locus coalescent-based species delimitation methods to identify putative species within the genus Digitipes. We then used three fossil calibrations to estimate divergence times in a Bayesian framework, and used the resulting time-calibrated phylogeny for biogeographic analysis in a likelihood framework (BioGeoBEARS). The genus Digitipes was monophyletic with strong support, with SEA lineages nested within the Indian clade and sister to the D. barnabasi species complex from the Western Ghats. D. pruthii, the Eastern Ghats species, was nested with the Western Ghats species clade. A single-locus mPTP-based species-delimitation method suggested the presence of 24 putative species, far exceeding the number of morphologically described species, indicating an underestimation of species diversity. Divergence time estimates suggest that Digitipes began diversifying around 126 mya (100-159 mya), affirming its Gondwanan origin. Time-stratified ancestral area reconstruction suggested that early vicariance, followed by jump dispersal and range expansion, shaped the distribution of the genus Digitipes in South and Southeast Asia. There was one dispersal event from India to Southeast Asia, following a transient land connection between them, around 50 mya, supporting the Out-of-India hypothesis. Additionally, three jump dispersal events and five range expansions explained diversification within peninsular India. Particularly, D. pruthii originated from a jump dispersal event from the Central Western Ghats to the Eastern Ghats around 37 mya. Our results highlight the importance of an integrative taxonomic framework to delineate hidden diversity and to obtain robust species hypotheses for testing biogeographic hypotheses.

evolutionary biology↗

bioRxiv2026

Dengue serotype-1 virus like particles induce antibody responses following HeLa cell expression

Dengue disease remains a significant global health threat, with current vaccines exhibiting variable efficacy and safety concerns. Virus-like particles (VLPs) offer a promising alternative by mimicking native virus structures without infectious genomes. We engineered a mammalian expression plasmid encoding Dengue-1 prM and E proteins, optimized for secretion using Japanese Encephalitis virus signal sequences, and transiently expressed it in HeLa cells. Purified VLPs exhibited spherical morphology ([~]39 nm diameter) consistent with native virions, as confirmed by transmission electron microscopy. Immunization of mice with these VLPs elicited robust Dengue-1 specific IgG antibody responses. Our study demonstrates production of immunogenic Dengue-1 VLPs in HeLa cells, highlighting their potential as a vaccine candidate and a tool for serodiagnosis. Further characterization of VLP epitopes and protective efficacy is warranted to advance vaccine development. ImportanceDengue remains a significant global health challenge, with serotype 1 being one of the dominant strains causing recurrent outbreaks in Nepal. Existing vaccines demonstrate limited efficacy and pose significant safety concerns, particularly in seronegative populations. To address these limitations, this study explores virus-like particles (VLPs) as a safer alternative vaccine platform. VLPs elicit robust immunogenicity by mimicking the structure of native virus while completely lacking genetic components. This study combines DENV1 structural proteins with optimized expression systems to enhance immunogenicity. This work is particularly significant as the first dengue vaccine research conducted in Nepal, directly addressing antigenic mismatches between existing commercial vaccines and locally circulating viral strains. Furthermore, the study provides scalable platform for developing region-specific dengue vaccines for other serotypes and flaviviruses.

immunology↗

bioRxiv2026

Divergent venoms among two closely related co-distributed centipede species, Scolopendra morsitans and S. hardwickei in tropical Asia

Venom is an important functional trait that helps predatory animals capture prey. Centipede predatory venoms are complex cocktails of multiple proteins, such as neurotoxins (scoloptoxins), cytotoxins, {beta}-pore-forming toxins, and enzymes. We examined venom phenotypes in two closely related and co-occurring centipede species, Scolopendra morsitans (n=28) and S. hardwickei (n=11), in peninsular India to determine whether their venoms are similar or dissimilar. An integrated proteo-transcriptomic approach was used to characterise the venom phenotypes of the two species across multiple individuals in peninsular India. We used species occurrence records and species distribution models to assess the distributional overlap among these species within the peninsular Indian region. The species showed significant overlap in their current and projected geographical ranges, corresponding with their co-occurrence. We characterised the venom profiles of both species and found that the venoms were cocktails of enzymes, {beta}-pore-forming toxins, and neurotoxins comprising 110 and 84 proteins in S. morsitans and S. hardwickei, respectively. However, the venom composition of both species differed significantly in toxin abundance and species-specific protein repertoires. This indicates trait divergence in venom phenotypes, suggesting that distinct venom compositions may facilitate coexistence among ecologically similar predatory centipedes. The observed variation in venom phenotypes among co-distributed species opens up important avenues for future research into their ecological roles and functional significance. In this study, we provided a detailed account of venom composition across multiple individuals from the species geographic range and highlighted the importance of investigating the role of venom as a trait that could influence species interactions and shape communities in these diverse tropical forests.

ecology↗

bioRxiv2026

Structural Basis of M1 Muscarinic and H3 Histamine Receptor Inhibition in OPC Differentiation

Muscarinic and histamine receptors are neurotransmitter-binding proteins within the large family of G protein-coupled receptors (GPCRs) and are relevant to human health and disease, including multiple sclerosis (MS), a chronic immune-mediated inflammatory demyelinating disease of the central nervous system (CNS) with neurodegenerative components. MS affects approximately 1 in 333 people, and women are affected at roughly threefold higher rates than men. A major pathological feature of MS is demyelination with incomplete remyelination of axons in the CNS. Because oligodendrocyte progenitor cells (OPCs) can differentiate into mature oligodendrocytes that restore myelin, small molecules that promote OPC differentiation represent a potential therapeutic strategy. High-throughput screening identified 18 hit compounds with EC50 values below 0.2 M, including the lead compound CN045, which showed an EC50 of 40 nM in vitro. Cheminformatic and experimental target-identification studies implicated the M1 muscarinic receptor and the H3 histamine receptor as candidate targets. To interpret these findings, we performed docking, molecular dynamics simulations, and binding free-energy analyses on complexes involving CN045 and clemastine, a known antihistamine with antimuscarinic activity. The simulations support weaker and less stable binding of CN045 to H3 than to M1 and identify residue-level interactions that contribute to stability within the M1 binding pocket. Comparisons between CN045 and clemastine at M1 further suggest that the two ligands sample different local conformational ensembles, including differences in conserved microswitch behavior associated with active-like versus inactive-like receptor states. Together, these results provide a structural framework for understanding ligand-specific M1 engagement and may help guide future optimization of remyelination-promoting compounds.

biophysics↗

bioRxiv2026

Frugivore species richness influences dietary specialisation and network properties in Asian wet tropical forests

AimTo examine how variation in frugivore species richness influences dietary specialisation and the organisation of plant-frugivore interaction networks in tropical forests. LocationSix undisturbed lowland wet tropical forest sites across four biodiversity hotspots in south and south-east Asia. Time period2016-2024. Major taxa studiedAvian frugivores and fleshy-fruited woody plants. MethodsWe recorded plant-avian frugivore interactions across six undisturbed evergreen forest sites spanning a seven-fold gradient in frugivore species richness, while holding forest type and phylogenetic composition broadly comparable. Using over 4,200 hours of focal observations on 551 fruiting plants, we recorded more than 34,000 feeding visits by 138 frugivore species on 133 plant species. We used a) Joint species distribution models to determine the relative influence of fruit and seed traits, and b) network analyses to evaluate how dietary breadth and network properties varied with frugivore species richness. ResultsAcross sites, frugivore visitation was primarily explained by fruit and seed morphology, with seed size accounting for an average of 39.7% of explained variation, followed by fruit width (24.4%), fruit crop size (21.9%), and pulp lipid content (14.1%). Frugivores in species-rich communities exhibited narrower dietary breadth (Pearsons r = -0.87 between normalised degree and species richness). Correspondingly, plant-frugivore networks became less connected and nested, and more modular, with increasing frugivore richness (Pearsons r = -0.9, -0.98, and 0.84, respectively). Main conclusionsIncreasing frugivore species richness intensifies dietary specialisation, which in turn drives changes in plant-frugivore network structure. These findings highlight how local species richness shapes interaction networks through changes in consumer niche breadth, with implications for the organisation of tropical forest mutualistic communities.

ecology↗

bioRxiv2025

Comparing the genetic diversity of two threatened Rhyticeros hornbill species with contrasting geographic range sizes

Island endemics exhibit low genetic diversity due to founder effects and geographical isolation, increasing their vulnerability to inbreeding depression. The Narcondam Hornbill (Rhyticeros narcondami), restricted to the 6.8 km2 Narcondam island in the Andaman archipelago, has the smallest range size among hornbills, a globally threatened group of birds. We compared the genetic diversity of the Narcondam Hornbill with the Wreathed Hornbill (Rhyticeros undulatus) distributed from the Eastern Himalaya to Bali. We generated DNA sequences for four mitochondrial markers ; Cytochrome B (Cytb), cytochrome c oxidase subunit I (COI), NADH dehydrogenase subunit 2 (ND2) and displacement loop (D-loop) regions) from 14 Narcondam Hornbill faecal samples and for three markers (Cytb, COI and ND2) from 19 Wreathed Hornbill tissue samples from north-east India. Our results suggest markedly lower genetic diversity in the island endemic Narcondam Hornbill compared to the Wreathed Hornbill. Specifically, Cytb and COI showed no genetic variation in the island endemic, compared to three to five haplotypes in the Wreathed Hornbills. In the ND2 region, Narcondam Hornbills showed seven haplotypes among 13 samples compared to the Wreathed Hornbills six haplotypes among eight samples. The observed genetic diversity in the D-loop in the Narcondam Hornbill was lower than other island-endemic hornbill species in the Philippines. The extremely low genetic diversity in the Narcondam Hornbill likely stems from a small founder population and/or past hunting pressures that reduced its numbers to approximately 30% of its current population of 1000 birds, rendering the Narcondam Hornbill susceptible to environmental and human-driven changes.

genetics↗

bioRxiv2025

Predicting the toxicity of chemical compounds via Hyperdimensional Computing

Accurately and efficiently assessing the potential toxicity of chemical compounds is critical given their wide application across pharmaceutical, industrial, and environmental domains. Traditional toxicological evaluations, which predominantly rely on intensive in vitro and in vivo assays, are frequently slow and expensive processes. Here, we introduce a novel application of Hyperdimensional Computing (HDC), an emerging computational paradigm inspired by the way the human brain works in encoding information, for the efficient classification of chemical compounds as either toxic or non-toxic. Our methodology employs Simplified Molecular Input Line Entry System (SMILES) representations of compounds, drawing data from the comprehensive Tox21 dataset. We delineate a pipeline wherein these chemical structures are encoded into high-dimensional binary vectors, which subsequently serve as the foundation for training and classification within the HDC framework. This approach leverages HDCs inherent advantages, including its resilience to noise, parallel processing capabilities, and efficacy in identifying intricate patterns. This work demonstrates the viability of HDC as a promising alternative for large-scale toxicity prediction, offering a computationally efficient and scalable solution. This research significantly contributes to the field of cheminformatics by validating HDCs potential in chemical property prediction, thereby facilitating accelerated identification of hazardous substances and mitigating the reliance on intensive laboratory experimentations.

bioinformatics↗

bioRxiv2025

A novel Vector-Symbolic Architecture for graph encoding and its application to viral pangenome-based species classification

Viral species classification is crucial for understanding viral evolution, epidemiology, and developing effective diagnostics and treatments. Traditional methods often rely on sequence similarity, which can be challenging for rapidly evolving viruses. Pangenomes, offering a comprehensive representation of species genomic diversity, provide a richer perspective, but their analysis often requires advanced computational methods. We investigate the use of Hyperdimensional Computing (HDC), also known as Vector-Symbolic Architecture (VSA), an emerging computing paradigm that relies on vectors in high-dimensional spaces to encode a multi-species viral pangenome. We develop a new method for encoding graph-structured viral pangenomes using high-dimensional vectors. Pangenomes are represented as weighted de Bruijn graphs constructed using sequences of consecutive k-mers from the genomes, while information about the genome species (their class) is encoded as specific weights on the edges of the graph. The weighted de Bruijn graph representation is encoded into a single high-dimensional vector. We tested three classification strategies: a flat model at the species level, a flat model at the genus level, and a two-step hierarchical model. We applied our method to a pangenome comprising 542 viral species from NCBI GenBank. Our results reveal a complex relationship between model architecture and classification accuracy. The flat species-level model achieved the highest accuracy, correctly classifying 87.08% of test genomes. Counter-intuitively, simplifying the problem to the genus level or using a hierarchical approach degraded performance, with accuracies dropping to 60.51% and 33.57% respectively. These outcomes highlight critical challenges in alignment-free classification, such as signal dilution in overly broad taxonomic groups and error propagation in multi-step models. The models reconstruction rate proved to be a reliable measure of confidence, rather than a direct predictor of correctness. This novel approach offers a promising new direction for viral classification, not only for its predictive power but its ability to reveal underlying challenges in genomic taxonomy.

bioinformatics↗

bioRxiv2025

Establishing Vibrio natriegens as a high-performance host for acetate-based poly-3-hydroxybutyrate production

Acetate can be a sustainable and renewable carbon source which holds significant promise for biotechnological production but is underutilized industrially due to limited microbial efficiency. Vibrio natriegens, recognized for exceptionally fast growth rates, represents a compelling host for developing efficient acetate-based bioprocesses. In this study, adaptive laboratory evolution significantly enhanced V. natriegens ability to grow on acetate as the sole carbon source, achieving an 89% increase in growth rate. Genetic and transcriptomic analyses revealed key adaptations improving acetate uptake and metabolism via increased salt tolerance, boosted Pta/AckA pathway activity, and rewired quorum sensing. Further metabolic engineering and bioprocess optimization enabled the evolved strain to reach high cell densities and efficiently convert acetate into the bioplastic poly-3-hydroxybutyrate (PHB), with productivities up to 0.27 g/L/h and PHB accumulation reaching 45.66% of cell biomass. These advances position V. natriegens as a highly promising microbial platform for sustainable, scalable, and cost-effective biomanufacturing using acetate as green feedstock. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/661028v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@ebd5b0org.highwire.dtl.DTLVardef@11a28bforg.highwire.dtl.DTLVardef@6950aforg.highwire.dtl.DTLVardef@303d7b_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2025

In-situ diversification and regional attributes shape asymmetric diversity of Miliusa (Annonaceae) in tropical Asia.

AimWe examine biogeography and speciation patterns in Miliusa Lesch. ex A. DC. ([~]65 species) distributed in tropical Asia to understand the uneven distribution of its extant diversity. LocationTropical Asia TaxonMiliusa (Annonaceae) MethodsPhylogenetic reconstruction was performed using six plastid markers across 52 species using both ML and BI approaches. Divergence times were estimated using two fossil calibrations and an optimised relaxed clock, and ancestral areas were inferred with BioGeoBEARS. Speciation rates were examined using ClaDS and the DR statistic, and community structure was assessed using phylogenetic diversity metrics. ResultsMiliusa likely originated in the mid-Miocene, with Indo-Burma and peninsular India (PI) as its ancestral range. Its extant diversity is primarily attributed to in-situ speciation, with dispersal or vicariance playing limited but important roles in PI, and Wallacea and Sahul. Lineages in Indo-Burma began accumulating in the mid-Miocene, preceding those in PI ([~]10 Myr) and Wallacea and Sahul ([~]5 Myr). PI showed signs of lineage saturation and had lower speciation rates compared to Wallacea and Sahul and Indo-Burma, both of which had similar rates. All regions exhibited phylogenetic clustering, but Indo-Burma and PI differed in their sensitivity to phylogenetic depths. Main conclusionsThe uneven diversity of Miliusa is shaped by time for speciation, age, and dispersal, although their relative influence varies across regions. In Indo-Burma, long-term geo-climatic stability and greater niche availability likely facilitated the persistence of lineages, rapid speciation, and dispersal, making it an evolutionary hotspot for Miliusa. In contrast, PI exhibited lower richness and speciation rates despite being old, likely due to the contraction of wet habitats in the Miocene that limited available niches for speciation. Lineages in Wallacea and Sahul show typical island-like radiations, with speciation rates comparable to the larger and more geo-climatically stable Indo-Burma, despite their more recent origin. Overall, our results highlight the role of Miocene-driven climatic vicariance and Pliocene-Pleistocene climatic fluctuations in shaping the diversification dynamics and regional diversity patterns across tropical Asia.

evolutionary biology↗

bioRxiv2025

De novo genome assemblies of threatened Asian hornbills (Bucerotidae) reveal declining population trajectories during the late Pleistocene

2.Asian hornbills are flagship species of the wet tropics that face significant threats from hunting, habitat loss, and fragmentation. Despite being conservation flagships, whole genome information is available for only two of the 32 Asian hornbill species. In this study, we provide the first de novo genome assemblies for four hornbill species (Bucerotidae) in Asia. We present hybrid genome assemblies for Buceros bicornis and Rhyticeros undulatus, and short-read genomes for Anthracoceros coronatus, and Aceros nipalensis. The genome sizes of these hornbills range from 1.1 Gb to 1.3 Gb with over 93% completeness and gene prediction BUSCO. We also provide annotated mitogenomes for each of these species. Furthermore, we estimated Pleistocene population trajectories for these four species, which vary in their habitat preferences. Our results indicate that Pleistocene climatic fluctuations have led to dramatic population declines in all four species. We believe that this study provides robust genomic resources to support future conservation genomics efforts for hornbills.

genomics↗

bioRxiv2025

Spatial patterns of diversity in forest birds of peninsular India

Biodiversity is structured via complex interactions among ecological, geological, and climatic processes. Regions with high heterogeneity in climate and topography are known to harbor fine scale patterns in diversity which are often overlooked in global scale analyses. Here, we investigate spatial phylogenetic patterns of forest bird diversity across peninsular India, a region with high topographic and climatic heterogeneity. Using a comprehensive global bird phylogeny, we employ metrics such as Phylogenetic Diversity (PD), Phylogenetic Endemism (PE), and their relative forms (RPD, RPE) to quantify evolutionary history and endemism of forest birds in peninsular India. We examine the roles of contemporary climate, historic climatic stability, and topography in shaping these patterns. Our results reveal a strong gradient in diversity, with the southern Western Ghats acting as a major hotspot for both taxonomic and phylogenetic diversity and endemism. We detect distinct ecological and phylogenetic community structures across the peninsula, likely shaped by regional species pools and biogeographic barriers. Areas with greater topographic complexity, higher precipitation, and greater historic climatic stability were found to support high diversity. Our study provides critical insights for biogeography in this understudied yet highly biodiverse region for forest birds.

ecology↗

bioRxiv2025

Effects of frugivore species pool and seed size on the diversity and functional composition of frugivores visiting fruiting trees

The relationship between biodiversity and ecosystem functioning in seed dispersal remains understudied despite its critical role in maintaining plant diversity in the tropics. Field studies on this relationship are often confounded by environmental and phylogenetic variations across species richness gradients. We examined how overall avian frugivore species richness at a site influenced the frugivore richness, visitation rates and functional composition of two key effect traitsbeak width and hand-wing indexon fruiting trees. Across six sites in tropical Asia, spanning a sevenfold gradient in frugivore species richness but with similar forest types and phylogenetically nested frugivore communities, we recorded 34,014 interactions between 134 avian frugivores and 131 plant species. Our results provide some support for the biodiversity-ecosystem functioning relationship, as higher overall frugivore species richness increased the number of frugivore species visiting individual fruiting trees but not the functional composition of frugivores. Seed size had a stronger influence on the frugivore species richness, visitation rates, and the beak size of visiting frugivores, highlighting the dominant role of morphological trait matching in influencing plant-frugivore interactions. Our findings suggest functional redundancy in certain aspects of seed dispersal effectiveness due to density compensation and the presence of key seed disperser lineages in species-poor sites.

ecology↗

bioRxiv2025

Sequencing of a dairy isolate unlocks Kluyveromyces marxianus as a host for lactose valorization

The use of genetically modified non-conventional yeast provides significant potential for the bioeconomy by diversifying the tools available for the development of sustainable and novel products. In this study, we sequenced and annotated the genome of Kluyveromyces marxianus Y-1190 to establish it as a platform for lactose valorization. The strain was chosen for rapid growth on lactose-rich dairy permeate, high transformation efficiency, and ease of culturing in bioreactors. Genomic sequencing revealed that K. marxianus Y-1190 possesses single nucleotide polymorphisms associated with efficient lactose metabolism. The strain is diploid with notable genomic heterogeneity, which appears to be critical for its robust growth and acid tolerance. To further exploit this platform strain, we developed protocols for gene and chromosome manipulation using CRISPR editing, constructed and validated a series of promoters compatible with MoClo vectors, and designed synthetically inducible promoters for K. marxianus. These tools enable precise control over gene expression, allowing for the tailored optimization of metabolic pathways and production processes. The synthetic promoters provide flexibility for dynamic expression tuning, while the CRISPR-based editing protocols facilitate targeted genetic modifications with high efficiency. Together, these advancements significantly enhance the genetic toolbox for K. marxianus, positioning it as a versatile platform for industrial biotechnology. These tools open new opportunities for the sustainable production of bio-based chemicals, fuels, and high-value products, leveraging lactose-rich feedstocks to contribute to a circular economy.

synthetic biology↗

bioRxiv2024

Insights from Molecular Docking and Dynamics Simulations of P2RX7-????Syn Complex

Alpha-synucleinopathies, characterized by extracellular alpha-synuclein (Syn) accumulation and aggregation, have been linked to neurological disorders including Parkinsons disease (PD) and multiple system atrophy (MSA). Syn interacts with membrane proteins, phospholipids, and cholesterol, leading to membrane damage and inflammation. This interaction heightens the likelihood of Syn engaging with P2RX7, a non-selective cationic transmembrane receptor that is primarily overexpressed in immune and neural cells. Activation of P2RX7 by Syn is implicated in neuronal degeneration, potentially causing pore dilation and increased inflammation. However, the precise molecular mechanisms and binding sites for this interaction, as well as the conformational dynamics of P2RX7 in response to Syn, remain unclear. We attempted to elucidate the molecular mechanisms and binding sites for P2RX7-Syn interaction, by integrating the data curation, molecular docking, and molecular dynamics (MD) simulations coupled with structural analyses. We elucidated interactions between P2RX7 and the N-terminal domain (NTD) of Syn using cryo-EM structures of P2RX7 in both ATP-bound and unbound states and assessed how Syn influences P2RX7structural and functional dynamics. Initially, the analyses revealed that Syn interactomes are mainly involved in regulating mitochondrial homeostasis, while P2RX7 interactors are linked to receptor internalization and calcium transport. Molecular docking with six tools identified that Syn-NTD fragments preferentially bind to the proximal region of P2RX7 transmembrane domain. Microsecond all atom MD simulations in a POPS lipid bilayer showed significant atomic fluctuations, particularly in the head region, lower body, and large loop of P2RX7 cytoplasmic domain. Secondary structure analysis indicated unfolding in regions related to pore dilation and receptor desensitization. Further by contact-based and solvent accessibility analyses, along with protein structure network (PSN) studies, we identified crucial residues involved in Syn-P2RX7 interactions. This insight deepens our understanding of how Syn and P2RX7 interact, offering a detailed atomic view of the structural and functional changes that occur during these interactions. This understanding could advance our grasp of neurodegenerative diseases and be vital for devising future preventive and therapeutic strategies. Author summaryNeural homeostasis is crucial for neuron survival and function, with protein-protein interactions, particularly between Syn and P2RX7, playing a vital role. Accumulation of Syn can worsen neuronal damage through its interaction with P2RX7. Traditional biological experiments struggle with time-scale limitations, but advances in computational methods--like molecular dynamics (MD) simulations and protein structure network (PSN) analysis--allow detailed atomic-level study of these interactions. This study used these computational tools to explore the dynamics between Syn and P2RX7, aiming to uncover structural and functional changes relevant to protein interactions and neural damage. The findings contribute to understanding the dynamics of P2RX7-Syn interactions.

bioinformatics↗

bioRxiv2024

A passage through India: the biotic ferry model supports the build-up of Indo-Australian biodiversity of an ancient soil arthropod clade

AimScutigeromorpha is a globally distributed, ancient group of centipedes with at least 400 million years of evolutionary history. We assess the biogeographic history of the order, with a particular focus on the Peninsular Indian Plate (PIP), a Gondwanan fragment. We hypothesize that continental vicariance explains the disjunct distribution of extant scutigeromorphs, that PIP scutigeromorphs are of ancient Gondwanan origins, and that East Gondwana vicariance explains the diversification of the subfamily Thereuoneminae into its Asian and Australian clades. LocationGlobal TaxaCentipedes, Scutigeromorpha MethodsWe use a novel molecular dataset sampled across the PIP and a global sequence database representing the geographic distribution of all families and subfamilies. We employ molecular phylogenetic analyses on two mitochondrial and three nuclear markers, molecular species delimitation and ancestral range estimation to reconstruct biogeographic history. ResultsAncestral scutigeromorphs were likely widely distributed across Gondwana and diverged prior to any continental vicariance. Scutigeromorph biogeography is shaped by continental vicariance, long-distance dispersal and jump dispersal, indicating an ability to colonize areas far from their ancestral range. The PIP emerged as the ancestral range of Thereuoneminae, which started diversifying during the Cretaceous Period. Subsequent in-situ diversification within the PIP and dispersals into Asia, Australia, and the Pacific Islands best explained the extant distribution of Thereuoneminae, more so than East Gondwana vicariance. Main conclusionsThe in-situ diversification of PIP species and their ancient divergence suggest they represent Gondwanan relicts in a landmass whose biota is primarily dispersal-driven. A single dispersal event from the PIP generated most of the extant diversity in Australia, another Gondwanan fragment. Furthermore, the discovery of 11 putative species from the PIP and the Andaman Islands, five times more than was known, highlights the Wallacean and Linnean shortfalls in tropical Asia.

evolutionary biology↗