Biology subjects

Mathur, V.

Publications and source records attributed to Mathur, V..

13 recordsLinked to original sources

bioRxiv2026

Benchmarking DNA Foundation Models: Biological Blind Spots inEvo2 Variant-Effect Prediction

DNA foundation models such as Evo and DNABERT-2 have generated considerable interest for clinically relevant genomics applications, particularly variant-effect prediction (VEP). However, rigorous benchmarks tailored to assessing their understanding of known biological constraints remain limited. Here, we develop controlled evaluation metrics based on well-characterized nuclear and mitochondrial sequence features and curated variant sets. Applying these benchmarks to Evo2, we identify systematic blind spots in short-range biological signals (e.g. codon usage bias) and observe sensitivity to contextual features that should be biologically neutral. These findings challenge current claims of zero-shot pathogenicity prediction and raise concerns regarding the clinical readiness of such models. The bench-marking framework introduced here provides a foundation for improving training strategies and for standardized evaluation of future genomic foundation models.

genomics↗

bioRxiv2025

Phagocytosis repurposed: infection strategies in a globalmarine diatom-parasite interaction

Microbial host-parasite interactions shape global biogeochemical cycles, yet their cellular and evolutionary mechanisms remain poorly understood. Here, we developed a novel model pathosystem to explore the interaction between the globally distributed eukaryotic microparasite, Pirsonia, and its host, the bloom-forming diatom, Coscinodiscus. Culture conditions recapitulated Pirsonias rapid life cycle in vitro and live-cell imaging enabled quantitative assessments of infection dynamics and host mortality. To investigate the genetic basis of this interaction, we assembled the Pirsonia genome and identified unique genetic innovations relative to their oomycete relatives. Time-resolved dual RNA-Seq enabled tracking of parasite gene expression through the infection cycle and revealed an upregulation of an expanded multi-gene family of integrin-like proteins in Pirsonia zoospores, analogous to the variable surface proteins in other parasitic lineages. Genes upregulated during infection were associated with cytoskeletal dynamics and drug inhibition assays confirmed that actin is required for host infection, consistent with the presence of parasitic pseudopodia on infected hosts. The dependence on both actin-based phagocytic mechanisms and parasitic-like surface proteins highlights Pirsonias intermediate state between predator and parasite, providing new insights into the evolution of parasite strategies and the complex cellular interactions controlling parasitic shunts in marine trophic networks.

evolutionary biology↗

bioRxiv2025

Identifying a next-generation antimalarial trioxolane in a landscape of artemisinin partial resistance

For over two decades, artemisinin-based combination therapy (ACT) has been the standard of care for the treatment of uncomplicated falciparum malaria. However, artemisinin partial resistance (ART-R) is now prevalent in Southeast Asia and has emerged in eastern Africa, threatening ACT efficacy. Mechanistically, ART-R results from an endocytosis defect that limits concentrations of host-derived free heme in the parasite digestive vacuole, allowing early ring-stage parasites to survive exposure to the artemisinin component of ACT. The artemisinin-inspired 1,2,4-trioxolane artefenomel exhibits an extended pharmacokinetic exposure profile that predicts efficacy against ART-R parasites. Unfortunately, the development of artefenomel was halted recently after almost a decade of clinical trials. Herein, we describe the discovery of RLA-4735 and its single-enantiomer form RLA-5764, next-generation antimalarial trioxolanes that exhibit excellent in vitro potency against Plasmodium falciparum and single-exposure efficacy in a murine P. berghei model, thus retaining many of the favorable pharmacokinetic and pharmacodynamic properties of artefenomel while markedly improving solubility and development potential. In P. falciparum samples collected from patients in Uganda in 2019 and 2023, ex vivo ring-stage survival assays revealed the emergence of the ART-R phenotype over this timeframe, and furthermore demonstrated markedly superior activity of artefenomel and RLA-4735 as compared to dihydroartemisinin (the active metabolite of artemisinin components of ACTs) against ART-R parasites. Overall, our findings suggest a role for next-generation trioxolanes in addressing ART-R, and present a potent new, artefenomel-adjacent chemotype with good potential to deliver new development candidates. Summary SentenceKlope et. al. described the discovery and in vivo characterization of antimalarial endoperoxides effective against artemisinin-resistant parasites as potential development candidates for uncomplicated, blood-stage malaria.

pharmacology and toxicology↗

bioRxiv2024

Cross-species interactome analysis uncovers a conserved selective autophagy mechanism for protein quality control in plants

Selective autophagy is a fundamental protein quality control pathway that safeguards proteostasis by degrading damaged or surplus cellular components, particularly under stress. This process is orchestrated by selective autophagy receptors (SARs) that direct specific cargo for degradation. While significant strides have been made in understanding the molecular framework of selective autophagy, the diversity of SAR repertoires across species remain largely unexplored. Through a comparative interactome analysis across five model organisms, we identified a suite of conserved and lineage-specific SAR candidates. Among these, we validated CESAR as a conserved SAR critical for proteostasis under heat stress. CESAR specifically facilitates the degradation of hydrophobic, ubiquitinated protein aggregates and is indispensable for heat stress tolerance. Our study offers a rich resource for SAR discovery and positions CESAR as a pivotal regulator of proteostasis, with broad implications for improving stress resilience in plants.

plant biology↗

bioRxiv2024

Biological activities and metabolic profile of endophytic Bacillus haynesii from Momordica charantia

Endophytes share a complex intimate relationship due to which they are capable of synthesizing metabolites that are either similar or derivative of host bioactive compounds. Such endophytes especially from medicinal plants can be prospected for commercial-scale production of the therapeutic compound. Thus, the study evaluates the antioxidant and anti-inflammatory potential of Momordica charantia fruit endophyte Bacillus haynesii R2MCFF61, and determines its metabolite profile through LC-Q-TOF-MS for the bioactive compounds produced. B. haynesii R2MCFF61 showed significant antioxidant and anti-inflammatory potential with increased DPPH scavenging activity in the standard compound and inhibition of protein denaturation respectively. The metabolic profile of this endophyte showed 23 compounds, mostly consisting of metabolites from lipid, phenylpropanoid and triterpenoid pathways. B. haynesii R2MCFF61 showed production of cucurbitane-triterpenoids namely Momordicoside K, 19-dimethoxycucurbita-5(10),6,22(E),24-tetraen-3{beta}-ol and 23(E)-7{beta}-methoxycucurbita-5,23,25-trien-3{beta}-ol. These compounds are mainly produced by M. charantia fruit and their production by its endophyte is reported for the first time. Thus, these results indicate the promising therapeutic potential of B. haynesii R2MCFF61 which can be utilized as a low-cost sustainable source of these bioactive compounds.

microbiology↗

bioRxiv2022

SARS-CoV-2 impacts the transcriptome and epigenome at the maternal-fetal interface in pregnancy

During pregnancy, the maternal-fetal interface plays vital roles in fetal development. Its disruption is frequently found in pregnancy complications. Recent works show increased incidences of adverse pregnancy outcomes in COVID-19 patients; however, the mechanism remains unclear. Here, we analyzed the molecular impacts of SARS-CoV-2 infection on the maternal-fetal interface. Generating bulk and single-nucleus transcriptomic and epigenomic profiles from COVID-19 patients and control samples, we discovered aberrant immune activation and angiogenesis patterns in patients. Surprisingly, retrotransposons were dysregulated in specific cell types. Notably, reduced enhancer activities of LTR8B elements were functionally linked to the downregulation of Pregnancy-Specific Glycoprotein genes in syncytiotrophoblasts. Our findings revealed that SARS-CoV-2 infection induced significant changes to the epigenome and transcriptome at the maternal-fetal interface, which may be associated with pregnancy complications. One-Sentence SummaryPregnant COVID-19 patients show placental epigenetic and transcriptional changes, associated with adverse pregnancy outcomes.

genomics↗

bioRxiv2021

Picozoa are archaeplastids without plastid

The endosymbiotic origin of plastids from cyanobacteria gave eukaryotes photosynthetic capabilities and launched the diversification of countless forms of algae. These primary plastids are found in members of the eukaryotic supergroup Archaeplastida. All known archaeplastids still retain some form of primary plastids, which are widely assumed to have a single origin. Here, we used single-cell genomics from natural samples combined with phylogenomics to infer the evolutionary origin of the phylum Picozoa, a globally distributed but seemingly rare group of marine microbial heterotrophic eukaryotes. Strikingly, the analysis of 43 single-cell genomes shows that Picozoa belong to Archaeplastida, specifically related to red algae and the phagotrophic rhodelphids. These picozoan genomes support the hypothesis that Picozoa lack a plastid, and further reveal no evidence of an early cryptic endosymbiosis with cyanobacteria. These findings change our understanding of plastid evolution as they either represent the first complete plastid loss in a free-living taxon, or indicate that red algae and rhodelphids obtained their plastids independently of other archaeplastids.

evolutionary biology↗

bioRxiv2020

Taxonomy of the apicomplexan symbionts of coral, including Corallicolida ord. nov., reassignment of the genus Gemmocystis, and description of new species Corallicola aquarius gen. nov. sp. nov. and Anthozoaphila gnarlus gen. nov. sp. nov.

Corals (Metazoa; Cnidaria; Anthozoa) have recently been shown to play host to a widespread and diverse group of intracellular symbionts of the phylum Apicomplexa. These symbionts, colloquially called corallicolids, are mostly known through molecular analyses, and no formal taxonomy has been proposed. Another apicomplexan, Gemmocystis cylindrus (described from the coral Dendrogyra cylindrus), may be related to corallicolids, but lacks molecular data. Here, we isolate and describe motile trophozoite (feeding) corallicolids cells using microscopic (light, SEM, and TEM) and molecular phylogenetic analysis to provide the basis for a formal description. Phylogenetic analyses using nuclear and plastid rRNA operons, and three mitochondrial protein sequences derived from single cell transcriptomes, all confirm that these organisms fall into a discrete deep-branching clade within the Apicomplexa not closely related to any known species or major subgroup. As a result, we assign this clade to a new order, Corallicolida ord. nov., and family, Corallicolidae fam. nov. We describe a type species, Corallicola aquarius gen. nov. sp. nov. from its Rhodactis sp. host, and also describe a second species, Anthozoaphila gnarlus gen. nov. sp. nov., from the coral host Madracis mirabilis. Finally, we propose reassigning the incertae sedis taxon G. cylindrus from the order Agamococcidiorida to the Corallicolida, based on similarities in morphology and host localization to that of the corallicolids.

microbiology↗

bioRxiv2020

Complement factor C1q mediates chronic neuron loss and inflammation post-brain injury

While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of cortical injury that does not directly damage subcortical structures, we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with altered cortical rhythms. Blocking C1q counteracted most of these outcomes, suggesting that C1q is a disease modifier in TBI. Since the corticothalamic circuit is important for sensory processing, attention, cognition, and sleep, all of which can be impaired by TBI, this circuit could be a new target for treating TBI-related disabilities.

neuroscience↗

bioRxiv2019

Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete pro-inflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to age-related and genetic forms of neurodegeneration.

neuroscience↗

bioRxiv2019

Multiple independent origins of apicomplexan-like parasites

Apicomplexans are a diverse group of globally important parasites, that include pathogens like Plasmodium, the causative agent of malaria. Despite their current obligate parasitic nature, apicomplexans evolved from photosynthetic algae and retain a remnant plastid (chloroplast). Such a complex evolutionary transition was unexpected, but here we show that it occurred at least three times independently. Using single-cell genomics and transcriptomics from diverse uncultivated parasites, we find that two genera previously classified within the Apicomplexa, Piridium and Platyproteum, form separately branching lineages in phylogenomic analyses. Both retain cryptic plastids with genomic and metabolic features convergent with apicomplexans. These findings suggest a predilection in this lineage for both the loss of photosynthesis and the transition to a morphologically similar parasitic lifestyle, resulting in multiple lineages of highly convergent animal parasites.

evolutionary biology↗

bioRxiv2018

A widespread coral-infecting apicomplexan contains a plastid encoding chlorophyll biosynthesis

The Apicomplexa are an important group of obligate intracellular parasites that include the causative agents of human diseases like malaria and toxoplasmosis. They evolved from free-living, phototrophic ancestors, and how this transition to parasitism occurred remains an outstanding question. One potential clue lies in coral reefs, where environmental DNA surveys have uncovered several lineages of uncharacterized, basally-branching apicomplexans. Reef-building corals form a well-studied symbiotic relationship with the photosynthetic dinoflagellate Symbiodinium, but identification of other key microbial symbionts of corals has proven elusive. Here, we used community surveys, genomics, and microscopy to identify an apicomplexan lineage, which we name corallicola, that was found in high prevalence (>80%) across all major groups of corals. In-situ fluorescence and electron microscopy confirmed that corallicola lives intracellularly within the tissues of the coral gastric cavity, and possesses clear apicomplexan ultrastructural features. We sequenced the plastid genome, which lacked all genes for photosystem proteins, indicating that corallicola harbours a non-photosynthetic plastid (an apicoplast). However, the corallicola plastid differed from all other known apicoplasts because it retains all four genes involved in chlorophyll biosynthesis. Hence, corallicola shares characteristics with both its parasitic and free-living relatives, implicating it as an evolutionary intermediate, and suggesting that a unique ancestral biochemistry likely operated during the transition from phototrophy to parasitism.

microbiology↗

bioRxiv2018

Aged blood inhibits hippocampal neurogenesis and activates microglia through VCAM1 at the blood-brain barrier

An aged circulatory environment can promote brain dysfunction and we hypothesized that the blood-brain barrier (BBB) mediates at least some of these effects. We observe brain endothelial cells (BECs) in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of Vascular Cell Adhesion Molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, the shed, soluble form of VCAM1 is prominently increased in the aged circulation of humans and mice, and aged plasma is sufficient to increase VCAM1 expression in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic ablation of VCAM1 in BECs counteracts the detrimental effects of aged plasma on young brains and reverses aging aspects in old mouse brains. Thus, VCAM1 is a negative regulator of adult neurogenesis and inducer of microglial reactivity, establishing VCAM1 and the luminal side of the BBB as possible targets to treat age-related neurodegeneration.

neuroscience↗