Biology subjects

Ahmed, S.

Publications and source records attributed to Ahmed, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Biodiversity Dimensions in Mangroves: Uncovering Interactions and Spatial Drivers in the Sundarbans

Mangroves play a crucial role in supporting global biodiversity and ecosystem functioning, yet how their multidimensional diversity interact and respond under diverse stress conditions remains underexplored. To address this gap, using species, environmental, functional trait and forest structural data collected from the permanent sample plot (PSP) network (110 PSPs) of the worlds largest mangrove ecosystem, the Sundarbans, we answer three key questions: (Q1) How are structural, functional, taxonomic, and phylogenetic diversities interconnected? We hypothesized that these diversity components are positively correlated (H1). (Q2) What are the key environmental stressors and how the diversity components are influenced by multiple stressors? We hypothesized that these stressors negatively affect all diversity components (H2). (Q3) What spatial patterns emerge in the distributions of these diversity components? Here we hypothesized that these diversity components vary across space under changing environmental conditions (H3). Our results show that taxonomic, functional, structural, and phylogenetic diversity have varying degrees of interconnection. While taxonomic and structural diversity are strongly correlated, functional and phylogenetic diversity exhibit more independent patterns, suggesting distinct ecological processes shape each dimension. Salinity, elevation, silt, community structure and downstream-upstream gradient (i.e., upriver position) have strong influences on all the diversity components although the magnitude of the influence varies. GAM results reveal that salinity and siltation act as the primary negative drivers for most dimensions; however, functional richness and divergence show a unique positive response to salinity. Furthermore, we found that community structure and upriver position significantly influence diversity patterns, often in a non-linear fashion. Though taxonomic, structural, and phylogenetic diversity show higher values mainly in the moderate and low saline areas, functional richness shows higher values in high saline areas. Overall, our results provide strong support for all the hypotheses. Our findings highlight the importance of holistic approach integrating taxonomic, structural, functional, and phylogenetic dimensions for maintaining biodiversity and ecosystem functions in dynamic mangrove ecosystems and emphasize the need for conservation efforts that target moderate-stress zones to preserve both ecological and evolutionary diversity. HighlightsO_LIExplored the interconnection between four dimensions of biodiversity (taxonomic, structural, functional, and phylogenetic) and how they respond to multiple stressors in the worlds largest mangrove forest. C_LIO_LIHigh salinity and siltation act as the primary environmental stressors that negatively affect overall biodiversity. C_LIO_LIStructural diversity is strongly related to species richness, serving as a key indicator of ecosystem health. C_LIO_LIFunctional and phylogenetic diversity follow independent spatial patterns, promoting the need for multi-dimensional monitoring. C_LI

ecology↗

bioRxiv2026

Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses

Mitochondrial Ca2+ uptake governs metabolism and cell fate, yet how signals from other organelles shape this remains incompletely defined. Although lysosomes are relatively small Ca2+ stores, their strategic positioning at organelle contact sites suggests they may amplify Ca2+ transfer within nanodomains. Here, we show that activation of the lysosomal Two-pore channel 2 (TPC2) initiates rapid mitochondrial Ca2+ uptake through an endoplasmic reticulum-dependent relay requiring IP receptors and the mitochondrial calcium uniporter channel. The extent of mitochondrial Ca2+ accumulation scales with TPC2 activity without affecting global Ca2+ responses, identifying TPC2 as a specific amplifier of lysosome-mitochondria Ca2+ exchange. Moderate TPC2 activation transiently enhances oxidative phosphorylation, whereas sustained enhancement increases susceptibility to Ca2+-induced mitochondrial permeability transition. In stroke models, hyperactivation of TPC2 exacerbates injury, while acute pharmacological inhibition at reperfusion confers neuroprotection, including in human iPSC-derived neurons. Thus, lysosomal Ca2+ release acts as an upstream regulator of mitochondrial energetic resilience under stress.

cell biology↗

bioRxiv2026

AI-Guided CRISPR Screen Accelerates Discovery of New Drug Targets

Psoriasis affects over 125 million people worldwide, yet the mechanistic understanding of keratinocyte-driven inflammation remains incomplete, limiting therapeutic innovation beyond costly systemic biologics that are prone to side effects. Here, we performed the first genome-wide CRISPR knockout screen in primary human adult epidermal keratinocytes to systematically identify regulators of IL-17 receptor A (IL17RA), a central node in psoriatic inflammation. To prioritize therapeutically tractable targets from over 19,000 screened genes, we integrated a large language model - VirtualCRISPR - trained on functional genomics data, identifying arachidonate 5-lipoxygenase (ALOX5) and oxytocin receptor (OXTR) as high-confidence novel hits with minimal prior association with psoriasis. Multi-omics validation revealed that ALOX5 and OXTR regulate IL17RA expression through distinct signaling pathways - ALOX5 through lipid mediators that stabilize the receptor at the cell surface, and OXTR through calcium signaling that reprograms cellular metabolism. Topical delivery of their inhibitors Zileuton (ALOX5) and Cligosiban (OXTR) exhibited therapeutic efficacy comparable to systemic anti-IL17RA antibody in the imiquimod-induced psoriasis model, suppressing pathogenic Th17/Tc17 responses, polarizing macrophages toward anti-inflammatory phenotypes, and normalizing epidermal hyperproliferation. Proteomic profiling in human 3D organotypic skin and murine models confirmed on-target pharmacology and revealed convergent suppression of neutrophil-keratinocyte inflammatory circuits. The use of VirtualCRISPR significantly shortened the timescale from screen to the identification of druggable hits with robust validation, and this work establishes a blueprint for integrating AI-driven target prioritization with functional genomics to accelerate therapeutic discovery.

genomics↗

bioRxiv2026

Distinct cochlear cell types associated with genetic susceptibility to sensory and metabolic hearing loss in older adults from the CLSA

Hearing loss is a heterogeneous condition that can be classified into different subtypes with diverse genetic and cellular components. To investigate the cochlear cell types underlying the genetic basis of sensory and metabolic components of age-related hearing loss (ARHL), we integrated human genome-wide association study data with mouse cochlear single-cell RNA sequencing data using the single-cell disease relevance score tool. These analyses revealed that genes associated with the sensory component of ARHL in older humans were most highly expressed in the hair cells, while genes associated with metabolic component of ARHL in older humans were most highly expressed in spiral ganglion neurons. To assess whether age-related transcriptional changes might influence these patterns, we performed age-stratified analyses. In younger mice, sensory hearing loss-associated genes revealed significant heterogeneity in expression in supporting cells within the sensory epithelium. In contrast, the greatest heterogeneity in the expression of metabolic hearing loss-associated genes was observed in intermediate cells of the stria vascularis in older mice. These findings provide evidence for the role of distinct genetic and cellular risk profiles for different ARHL subtypes, suggesting that prevention and therapeutic strategies may require targeting specific cell populations at different life stages.

genomics↗

bioRxiv2026

A Comprehensive epidemiological and molecular study of gastrointestinal helminths of Companion Animals in Northeastern Bangladesh: A neglected zoonotic threat

BackgroundGastrointestinal helminths of companion animals are neglected sources of zoonotic infection in low and middle-income countries. In Bangladesh, close humananimal contact and large free-roaming dog and cat populations may facilitate parasite transmission, yet region-specific data remain limited. This study assessed the prevalence, species diversity, and zoonotic potential of gastrointestinal helminths in companion animals in northeastern Bangladesh. MethodsA cross-sectional study was conducted between January and December 2025 across urban and rural areas of the Sylhet Division. Fecal samples from 900 animals (600 dogs and 300 cats; owned and stray) were examined using standard coproscopic techniques. Molecular confirmation of selected positive samples was performed using PCR targeting ITS-2, 18S rRNA, and mitochondrial cox1 genes, followed by sequencing. Risk factors associated with infection were evaluated using multivariable logistic regression. ResultsOverall, 45.9% (95% CI: 42.6-49.2) of animals were infected with at least one gastrointestinal helminth, with mixed infections detected in 18.4%. Prevalence was similar in dogs (45.7%) and cats (46.3%) but significantly higher in stray animals (65.7%) than in owned animals (36.6%). Predominant zoonotic helminths included Ancylostoma spp., Toxocara canis, Toxocara cati, Dipylidium caninum, and Taenia/Echinococcus spp. Molecular analysis confirmed 93% of morphologically identified infections and revealed high genetic similarity to zoonotic reference strains. Stray status, lack of deworming, young age, and outdoor roaming were significant risk factors for infection (p < 0.05). ConclusionsCompanion dogs and cats in northeastern Bangladesh harbor a high burden of zoonotic gastrointestinal helminths and represent important reservoirs for human exposure. Strengthening One Health-based surveillance, routine deworming, and stray animal management is essential to reduce zoonotic transmission.

microbiology↗

bioRxiv2026

Cortical astrocytes control stress resilience

BackgroundChronic stress exposure is a risk factor for several psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depression (MDD), with the prefrontal cortex (PFC) playing a key role in mediating this stress susceptibility. However, most individuals who are exposed to chronic stress are resilient and do not develop psychopathology. Recent evidence suggests that glial cells, especially astrocytes, play an important role in controlling stress-induced anxiety- and depression-like behavior, yet their role in contributing to stress resilience is not understood. MethodsUsing fiber photometry, chemogenetics, and RNA-sequencing in male mice, we establish a role for PFC astrocytes in stress resilience. ResultsWe demonstrate that stress-induced increases in astrocytic calcium activity are both necessary and sufficient for resilience. Bioinformatic analysis reveals robust transcriptional responses in PFC astrocytes that differ between susceptible vs. resilient mice and are unique when compared to astrocytic transcriptional changes in other limbic regions. Comparison with human RNA-sequencing data indicates that molecular changes observed in PFC astrocytes from susceptible mice converge with gene expression changes observed in MDD patients. ConclusionsTogether, these data support targeting astrocytes as a potential therapy for negative behavioral consequences following stress exposure and reveal potential molecular mechanisms within PFC astrocytes that could contribute to depressive-like behaviors.

neuroscience↗

bioRxiv2026

Structure and mechanism of human sphingosine-1-phosphate transporter MFSD2B

Sphingosine-1-phosphate (S1P) is an essential signaling lipid that maintains vascular integrity and regulates immune cell trafficking. The major facilitator superfamily domain-containing protein 2B (MFSD2B) serves as the main S1P exporter in red blood cells and platelets; however, its structure and transport mechanism are unclear. Here, we report the 3.0 [A] cryo-EM structure of human MFSD2B bound to S1P. S1P is captured in a distinctive binding state, deeply buried within the C-domain, with its sphingoid tail accommodated by a hydrophobic pocket and its phosphate group coordinated by a cluster of polar residues within the transporters cavity. Mutagenesis and molecular dynamics simulations identify the TM2/TM11 lateral opening as the primary pathway for S1P translocation, with key charged residues acting as sequential anchors during transport. Furthermore, we demonstrate that MFSD2B functions as a uniporter, and that subtle rewiring of local charge networks can alter its coupling mechanism. Our work provides a molecular framework for understanding S1P transport mediated by MFSD2B in hematopoietic cells.

biochemistry↗

bioRxiv2026

ACCURATE PREDICTION OF ASPARAGINE DEAMIDATION IN BIOLOGICS USING ADVANCED MACHINE LEARNING MODELS

The spontaneous deamidation of asparagine residues remains a major obstacle to the stability and efficacy of protein therapeutics. Currently available models in the literature for predicting deamidation liabilities can suffer from limited generalizability, likely due to biases such as sequence similarity within datasets. In this study, we built machine learning models using protein language models (e.g., ESM2) and graph neural networks (GNNs), trained on a comprehensive dataset of 591 asparagine sites from over 105 protein molecules. To address the critical issue of data leakage, we implemented a peptide grouping strategy yielding more accurate estimates of model performance for novel deamidation sites. Our analysis shows that, when sequence similarity bias is controlled, protein language models match traditional feature-based models that use amino acid composition, k-mers, PSSMs, and predicted secondary structure/solvent accessibility, while offering substantial computational advantages. Additionally, our GNN-based pipeline further increases prediction accuracy by up to 8% compared to language model-only tools and delivers a 15-25% improvement over motif-based approaches. This methodological framework enables more reliable and rapid in-silico prediction of deamidation liabilities, potentially reducing costly late-stage interventions in protein therapeutic development and is generalizable to the modeling of additional protein post-translational modifications.

bioengineering↗

bioRxiv2025

Organoid Pharmacotyping of Pancreatic Cancer Enables Functional Precision Oncology and Drug Repurposing

PurposePancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited benefit from current cytotoxic regimens and poor predictive value of genomics alone. Patient-derived organoids (PDOs) represent a promising platform for functional precision oncology, yet systematic pharmacotyping of genomically annotated PDAC PDOs remains sparse. Experimental DesignWe established a clinically annotated panel of ten treatment-naive PDAC PDOs spanning well-, moderately-, and poorly differentiated tumors. PDOs were evaluated for morphologic and genomic fidelity and screened against 1,813 clinically relevant small molecules in a high-throughput 384-well format. Drug sensitivities were quantified at the compound and drug-family levels and integrated with histologic grade, pathway-level mutational profiles, and available clinical treatment information. ResultsPDOs preserved hallmark tumor features, including glandular organization and subclonal mutational architecture. Pharmacotyping revealed both shared and subtype-specific vulnerabilities. Classical (well/moderately differentiated) PDOs showed enriched mutations in DNA repair, mitotic spindle, and chromatin-regulatory pathways and were preferentially sensitive to topoisomerase inhibitors, microtubule poisons, and HDAC inhibitors. In contrast, basal (poorly differentiated) PDOs displayed coordinated defects in mitochondrial function, vesicle trafficking, and ubiquitin-mediated proteostasis, at the pathway level, that conferred a previously unrecognized vulnerability to cardiac glycosides. Sensitivities to standard PDAC agents were heterogeneous across models, underscoring the limited predictive value of genotype alone and the need for functional drug testing. ConclusionsThis integrated genomic and pharmacologic analysis demonstrates that PDO pharmacotyping identifies biologically grounded, actionable vulnerabilities in PDAC, including novel therapeutic opportunities in basal, chemo-resistant tumors. These findings support PDO-guided functional profiling as a clinically relevant platform for refining drug selection and expanding treatment options for patients with PDAC. SignificancePDAC is dominated by chemoresistance and lacks reliable genomic predictors of therapy response. By integrating high-throughput drug screening with mutation-informed pathway analysis in patient-derived organoids, we identify differentiation-linked therapeutic liabilities, including a previously unrecognized vulnerability to cardiac glycosides in basal PDAC. These results highlight PDO pharmacotyping as a powerful functional complement to genomics for guiding treatment selection in pancreatic cancer.

cancer biology↗

bioRxiv2025

Recombinant Lactococcus lactis-based multivalent vaccine targeting Campylobacter jejuni colonisation and modulating cecal microbiota in poultry

BackgroundDiarrhoeal diseases remain the second leading cause of preventable death globally, particularly among children under the age of five in developing countries, accounting for an estimated 2-3 million deaths annually. Among the bacterial pathogens causing diarrheal illness, Campylobacter jejuni (C. jejuni) remains one of the major contributors, particularly in LMICs. As a common gut pathogen, C. jejuni expresses several secretory or surface-expressed colonisation proteins, namely Hcp, VgrG, CadF, FlpA, and JlpA. Most of these proteins play pivotal roles in bacterial self-survival, host-cell adhesion, and invasion in avian and non-avian hosts. MethodsTo minimise the C. jejuni adhesion and subsequent colonisation in the avian gut, we explored the potential of a multivalent mucosal vaccine composition using these putative subunits of C. jejuni. For this purpose, we bioengineered a food-grade Lactic Acid-producing Bacterium, Lactococcus lactis (L. lactis), to express three key immunogenic subunits, Hcp, CadF and JlpA. Utilising this live vector-based multi-component mucosal vaccine platform, we investigated the immunoprotective potential of these antigens in chickens. Since the particular strain of L. lactis is non-colonising, we used chitosan as a natural mucoadhesive, biodegradable polymer to microencapsulate the engineered bacteria to increase their gut retention time for optimal interaction with local immune cells. ResultsOur in vivo immunisation study demonstrated that oral administration of this multivalent vaccine formulation elicited a strong local antibody response (sIgA) and upregulated key pro-inflammatory cytokines, leading to robust mucosal immune protection against the cecal colonisation of C. jejuni. Moreover, gut metagenomic analysis of vaccinated birds revealed a marked reduction in the phylum Campylobacterota, accompanied by an increased abundance of the phyla Bacillota and Bacteroidota, as part of a beneficial microbial community. ConclusionsTogether, this study underscores the potential of a live vector-based, multivalent mucosal vaccine as a promising, cost-effective strategy to reduce the risk of foodborne transmission of C. jejuni, particularly in poultry production systems.

immunology↗

bioRxiv2025

The Microglial TREM2 Receptor Programs Hippocampal Development in a Mouse Model of Childhood Deprivation

Childhood neglect and deprivation are the most common forms of adversity, yet their biological impact on cognitive development--and how enrichment mitigates these effects--remains unclear. Using limited bedding (LB) as a mouse model of deprivation, we previously showed that abnormal microglial-mediated synaptic pruning during the second and third postnatal weeks leads to impaired synaptic connectivity and hippocampal dysfunction, particularly in males. Here, we demonstrate that LB reduces expression of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in different mouse strains and that TREM2 deficiency contributes to, but does not fully explain, impaired microglial pruning. Overexpressing TREM2 restored microglial phagocytic function and rescued deficits in hippocampal connectivity and fear learning. Brief postnatal enrichment (P14-P17) also normalized synaptic pruning in a TREM2-dependent manner. Together, our findings identify TREM2 as a key molecular mediator of experience-dependent plasticity, revealing its central role in linking early-life deprivation and enrichment to cognitive outcomes later in life.

neuroscience↗

bioRxiv2025

Unveiling the Diversity and Demography of Sharks and Rays at key landing sites in Bangladesh

In Bangladeshs marine waters in the Bay of Bengal, sharks and rays face grave threats from unsustainable fishing practices and habitat degradation. Findings from our taxonomic assessment of elasmobranchs landed at the two most important marine fish landing stations in Bangladesh bring new information and insights about the nature of the Threatened elasmobranch bycatch. This study presents findings from a taxonomic assessment at Coxs Bazar and Chattogram, two crucial landing stations in Bangladesh where most shark bycatch landings happen. Over two years, 525 fish were sampled; 206 samples were of sharks, 91 of rays, and 64 of rhino rays, representing over 29 species across 12 families. Among them are 4 families of sharks, 5 rays, and 3 rhino rays. The predominant families observed were Carcharhinidae, Glaucostegidae, and Rhinopteridae. The most frequently landed species were Sphyrna lewini, Glaucostegus younholeei, Carcharhinus leucas, Gymnura poecilura, and Mobula mobular. Out of the 525 samples, 65% (n=340) were female, 35% (n=183) were male, and the rest (n=2) were unidentified. Finding one sample of Pristis pristis indicates the severity of the decline. Additionally, for Glaucostegus granulatus, 12 among the 13 studied specimens were adult females. A significant proportion of the sampled specimens, 45%, were juveniles, while only 24% were adults. This is likely because these fishing boats bringing the catch operate in inshore water and nearshore seas, which are potential nursery grounds. The overlapping of fishing grounds and these critical habitats poses a significant challenge in elasmobranch conservation and hinders population recovery. The high number of juveniles and female adults in the catch reminds us of the necessity of integrating threatened bycatch reduction measures into the countrys fisheries management.

zoology↗

bioRxiv2025

Maternal exercise rescues fetal akinesia-impaired joint and bone development

Fetal movements exert mechanical forces that shape the developing skeleton. Conditions that impair fetal movements can cause skeletal defects, but interventions are limited. Here, we show that maternal wheel running exercise regulates fetal skeletal development in mice. In wild-type fetuses, maternal exercise stimulated joint and bone morphogenesis. We reasoned that these effects occurred through either indirect maternofetal communication or direct mechanical stimulation of the fetus. Maternal exercise did not alter placental measures of nutrient transport. However, in the Splotch-delayed (Spd) mouse model of fetal akinesia, which features intact maternofetal communication but lacks fetal movements, maternal exercise substantially rescued fetal akinesia-impaired joint and bone development and prevented disuse-induced resorption of the deltoid tuberosity. Further, direct mechanical stimulation of Spd limbs explanted from systemic factors similarly stimulated joint morphogenesis. Together, these findings identify maternal exercise as a regulator of fetal skeletal development, providing a platform for studying skeletal developmental mechanobiology and suggesting potential therapeutic applications for fetuses with impaired movement.

developmental biology↗

bioRxiv2025

Erratic Maternal Care Induces Avoidant-Like Attachment Deficits in a Mouse Model of Early Life Adversity

Attachment theory offers an important clinical framework for understanding and treating negative effects of early life adversity. Attachment styles emerge during critical periods of development in response to caregivers ability to consistently meet their offsprings needs. Attachment styles are classified as secure or insecure (anxious, avoidant, or disorganized), with rates of insecure attachment rising in high-risk populations and correlating with a plethora of negative health outcomes throughout life. Despite its importance, little is known about the neural basis of attachment. Work in rats has demonstrated that limited bedding and nesting (LB) impairs maternal care and produces abnormal maternal attachment linked to increased pup corticosterone. However, the effects of LB on attachment-like behavior have not been investigated in mice where additional genetic and molecular tools are available. Furthermore, no group has utilized home-cage monitoring to link abnormal maternal care with deficits in attachment-like behavior. Using home-cage monitoring, we confirmed a robust increase in maternal fragmentation among LB dams. Abnormal maternal care was correlated with elevated corticosterone levels on post-natal day seven (P7) and a stunted growth trajectory that persisted later in life. LB did not alter maternal buffering at P8 or maternal preference at P18, indicating that certain attachment-like behaviors remain unaffected despite exposure to high levels of erratic maternal care. However, LB pups vocalized less in response to maternal separation at P8, did not readily approach their dam at P13, and exhibited higher anxiety-like behavior at P18, suggesting that LB induces avoidant-like attachment deficits in mice. Significance StatementThe impoverished conditions of limited bedding and nesting (LB) cause erratic maternal care and elevated corticosterone levels in rat and mouse pups. The increase in corticosterone levels causes attachment-like deficits in rat pups; however, it remains unclear whether similar deficits are observed in mice, where additional genomic and molecular tools are available. Using continuous home-cage monitoring, we confirmed a substantial increase in erratic maternal care and elevated corticosterone levels in 7-day-old mouse pups. LB mouse pups exhibited attachment-like deficits in some, but not all, tests, underscoring the robustness of this evolutionarily conserved bond. Despite some similarities, the attachment abnormalities observed in mice differed from previous reports in rats, paving the way for in-depth mechanistic studies in mice.

neuroscience↗

bioRxiv2025

Macrophage migration inhibitory factor is a potential therapeutic target for cisplatin induced peripheral neuropathy in breast cancer

BackgroundCisplatin (CP) is an effective chemotherapy drug for several cancers. However, the use of CP is associated with peripheral neuropathy, a painful nerve disorder. Unfortunately, no therapies are available for CP-induced peripheral neuropathy (CisIPN). This study explored the role of a cytokine, the macrophage migration inhibitory factor (MIF), as a potential therapeutic target for CisIPN. MethodsThe role of neuroinflammation and MIF in CisIPN was evaluated in mice models of CisIPN, with and without breast cancer, after treatment with the anti-inflammatory drug Dexamethasone (Dex). Circulating MIF levels in animals were examined using ELISA. Pharmacological inhibition of MIF was achieved using the small molecule inhibitors, CPSI-1306 and ISO-1. Mechanical and thermal sensitivities of animals were assessed using von frey filament and cold acetone assays. Macrophage infiltration in peripheral nerve tissues was examined using CD68 and Iba-1 staining. ResultsOur results showed that Dex suppressed mechanical hyperalgesia in CisIPN animals, which was accompanied by downregulation of MIF. We also found that circulating MIF levels were increased in CisIPN animals. Furthermore, direct inhibition of MIF using CPSI-1306 and ISO-1 led to suppression of mechanical hyperalgesia, without compromising the anti-tumor efficacy of CP, in CisIPN animals. We did not find any significant change in macrophage infiltration in the peripheral nerve tissues of CisIPN animals. Immunostaining results indicated that sensory neurons in the DRGs and Schwann Cells in the sciatic nerves are potential sources for increased MIF in CisIPN. InterpretationOverall, our results strongly suggest that MIF is a promising therapeutic target for CisIPN.

neuroscience↗

bioRxiv2025

Immunogenicity and Structural Features of a Stabilized Clade-C HIV-1 Env Derived from a Pediatric Elite-neutralizer

The envelope (Env) glycoprotein derived from circulating viruses in elite-neutralizers (who naturally develop broadly neutralizing antibodies (bNAbs)), serves as potential template for HIV-1 vaccine design. Herein, we report the structure and immunogenicity of soluble clade-C HIV-1 Env trimer (330) derived from a pediatric elite-neutralizer (AIIMS_330). Using SOSIP, NFL and ferritin-nanoparticle (NP) platforms, we engineered immunogens that preserved native-like Env conformation, exhibited high thermostability and nanomolar affinity for diverse bNAbs, with minimal reactivity to non-neutralizing antibodies. Cryo-EM structure solved at 5 [A] resolution of 330-SOSIP trimer-autologous bNAb 44m complex revealed interactions at GDIR motif, N332 supersite along with additional contacts at E293, K337, K446 and glycans N326, N442, N448, as compared to our previously reported BG505-44m structure. Rabbit immunizations with soluble and NP-displayed formats elicited autologous, and heterologous neutralization of tier-1 clade-C viruses. Herein we define a structurally resolved HIV-1 clade C Env that supports multivalent vaccine strategies and provides mechanistic insights toward rational HIV-1 immunogen design.

immunology↗

bioRxiv2025

Modeling human phenotypes in the nematode C. elegans during an undergraduate developmental biology course

Caenorhabditis elegans is a widely used model organism in biomedical research due to its genetic tractability, short life cycle, and conservation of many developmental processes with humans. In this study, undergraduate students conducted nine independent experiments during a Developmental Biology course to model human phenotypes using C. elegans. Each group selected a human phenotype of interest, identified a gene associated with the phenotype, and then determined the orthologous or homologous gene in C. elegans. By obtaining mutants and designing phenotypic assays, students investigated the extent to which the worm models could recapitulate aspects of the human condition. This collective work highlights both the potential and limitations of C. elegans as a model for human phenotypic variation and disease and demonstrates the value of undergraduate inquiry as a catalyst for scientific engagement and research-based learning.

scientific communication and education↗

bioRxiv2025

MYBL2 maintains stemness and promotes theta-mediated end joining in triple negative breast cancer

Triple negative breast cancer (TNBC) has a poor prognosis due to limited treatment options and high metastasis risk. Breast cancer (BC) stem/progenitor cells, also known as tumour initiating cells, are a small, difficult to target population within the tumour responsible for metastasis and therapy resistance. MYBL2 overexpression is commonly linked to poor prognosis and metastasis but its role in BC stem/progenitor cells remains elusive. To determine the role of MYBL2 in BC stem/progenitor cells we generated TNBC cell lines with inducible MYBL2 downregulation. Our findings reveal that elevated MYBL2 is essential for self-renewal, DNA repair, and replication stress response in these cells and lowering MYBL2 impairs stemness and self-renewal both in vitro and in vivo. Accordingly, our functional and mechanistic analyses indicate that high-MYBL2 stem/progenitor cells exhibit increased sensitivity to Pol{theta} inhibitors which is lost upon MYBL2 downregulation due to transcriptional suppression. Combining Pol{theta} inhibitors with ATR inhibitors further enhances this sensitivity, in vitro and ex vivo. This study thus identifies Pol{theta}/ATR inhibition as a synthetic lethality strategy to eradicate BC stem/progenitor cells and underscores MYBL2 expression as a biomarker for patient stratification in this treatment.

cancer biology↗