Biology subjects

Kaur, P.

Publications and source records attributed to Kaur, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Long-read sequencing quantifies synthetic mRNA abundance, integrity and host response in vivo

Synthetic mRNA can be used to reprogram biological systems and is increasingly used in vaccines, gene therapies and other advanced therapeutics. However, measuring mRNA abundance, molecular integrity and biological effects in complex samples remains challenging. Existing assays typically quantify short transcript regions or infer delivery from lipid or protein readouts. Here we present a long-read nanopore sequencing method that directly quantifies synthetic mRNA in complex cell and tissue samples. The approach enables absolute quantification of full-length synthetic mRNA, maps degradation at nucleotide resolution and simultaneously profiles associated host transcriptional responses. Applied to lipid nanoparticle (LNP) delivered mRNA in mice, the method revealed tissue-specific delivery and degradation patterns and uncovered a critical disconnect between mRNA accumulation and protein expression across organs. This approach enables integrated measurement of mRNA fate, integrity and biological responses, and will enable mechanistic studies of RNA delivery, stability, translation and innate immune recognition.

pharmacology and toxicology↗

bioRxiv2026

Targeting cellular senescence alleviates bone marrow aging

Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.

cell biology↗

bioRxiv2026

Dietary fiber intake associates with improved survival and microbiomecomposition in allogeneic hematopoietic cell transplantation

Diet is linked to changes in gut microbiota and metabolite production with clinical relevance in several disease settings, although these effects remain poorly defined. We performed prospective, real-time diet monitoring (37,929 food items, 3,837 patient days) and longitudinal microbiome and metabolite profiling (1,230 fecal samples) in a clinical cohort of 173 patients undergoing allogeneic hematopoietic cell transplantation. Patients with pre-transplant fiber intake above the cohort average had significantly improved overall survival (p=0.014) and reduced incidence of grades 2-4 acute graft-versus-host disease (GVHD) (p=0.032) post-transplant. Those consuming insoluble fiber had increased microbial diversity, enriched butyrate-producing taxa, and depleted Enterococcus. Those who developed lower gastrointestinal GVHD had reduced fecal butyrate levels. In a GVHD preclinical model, we confirmed that a fiber-enriched diet increased survival, cecal butyrate, and regulatory-to-conventional T cell ratio. Thus, we demonstrated that dietary fiber has clinical significance as a modifiable factor with microbiome-mediated effects.

cancer biology↗

bioRxiv2026

Collagen targeting IL-12 combined with Doxorubicin enhances the anti-tumor effect against osteosarcoma

Osteosarcoma (OS) is the most prevalent primary bone malignancy in children and adolescents; however, therapeutic outcomes remain suboptimal due to tumor heterogeneity, chemoresistance, and inadequate immune activation. Doxorubicin (Dox), the standard therapy that induces immunogenic cell death, has its efficacy compromised by the immunosuppressive tumor microenvironment (TME). While interleukin-12 (IL-12) can activate and recruit various immune cells, making it an attractive combination partner, its systemic delivery is severely limited by dose-limiting toxicity. We have previously reported that intravenous injection of A3 collagen binding domain (CBD) of von Willebrand Factor preferentially accumulates into the TME of various tumor models enriched in collagen I and III. Furthermore, CBD-fused IL-12 (CBD-IL-12) demonstrated superior therapeutic effects against various cancer models compared to unmodified IL-12 due to its collagen-targeted delivery and the resulting tumor-localized inflammation. Given that the OS TME also exhibits higher collagen I and III expression compared to normal bone, we hypothesized that a CBD-IL-12 fusion protein could showcase potent anti-tumor efficacy in OS via tumor-specific accumulation. Here, we demonstrated that CBD-IL-12 exhibited 4-fold enhanced tumor accumulation compared to unmodified IL-12 and increased cytotoxic T cell infiltration by 2.2-fold within the immune-cold microenvironment in a mouse model of OS. The combination of CBD-IL-12 with Dox significantly prolonged median survival in two independent murine OS models. This coordinated approach utilizing Dox coupled with precision-targeted IL-12 immunotherapy represents a clinically translatable strategy that overcomes the inherent limitations of single-agent treatments for OS. HighlightO_LICollagen-targeted IL-12 increases tumor accumulation in osteosarcoma. C_LIO_LIThe collagen-targeted IL-12 synergizes with doxorubicin in osteosarcoma models. C_LIO_LICombination therapy enhances T cell differentiation and activates innate immunity. C_LI

bioengineering↗

bioRxiv2026

Junctional β-Catenin Stabilization Links Wnt Signaling and Force Generation

{beta}-catenin plays two fundamental roles in animal tissues: it acts as a transcriptional effector of canonical Wnt signaling and as a core structural component of adherens junctions that mediate cell-cell adhesion. In canonical Wnt signaling, the post-transcriptional regulation of {beta}-catenin abundance, primarily through regulated phosphorylation, ubiquitination, and proteasomal degradation, determines whether the pathway is "off" or "on." Despite the central importance of {beta}-catenin stabilization, in vivo measurements of {beta}-catenin protein lifetime and stabilization dynamics during development remain limited. Here, we measure the stability of endogenous {beta}-catenin in vivo using tandem fluorescent protein timers (tFPs; "Timers") inserted as minimally disruptive cassettes within the endogenous locus. Timers allow simultaneous visualization of a newly synthesized, rapidly accumulating pool (fast-maturing GFP) and a long-lived, stabilized pool (slow-maturing RFP). Surprisingly, the strongest stabilization does not occur in canonical Wnt patterning stripes; instead, we observe marked stabilization of junctional {beta}-catenin at the leading edge during dorsal closure, a force-generating morphogenetic process. This stabilization is not explained by canonical Wnt ligand input and seems to reflect a stability program linked to {beta}-catenins adhesive function in adherens junctions. We suggest that a stable junctional pool of {beta}-catenin is vital for dorsal closure mechanics and provide evidence that this stabilization is regulated by Dishevelled and JNK, thus connecting Wnt pathway components to mechanotransduction.

developmental biology↗

bioRxiv2026

Targeting IL-6-STAT3/STAT4 Signaling Restores FOXP3 Expression in Pulmonary Arterial Endothelium and Reveals Novel Biomarkers for PAH

BackgroundInterleukin-6 (IL-6) is a central driver of pulmonary vascular remodeling in idiopathic, heritable, and connective tissue disease-associated pulmonary arterial hypertension (PAH). Elevated IL-6 correlates with right ventricular (RV) dysfunction and poor survival. However, the specific downstream mechanisms by which IL-6 drives pathogenesis remain poorly defined. We investigated the therapeutic impact of direct IL-6 neutralization and its regulation of a novel epigenetic signaling axis in PAH. Materials and MethodsWe evaluated species-specific IL-6-neutralizing antibodies in murine Sugen/hypoxia and rat monocrotaline models of PAH. RV structure and function were assessed using cardiac MRI and invasive hemodynamics. Lung transcriptomic profiling was performed by RNA sequencing mouse lung tissue. Key findings were validated in explanted human PAH lungs, serum, and peripheral blood mononuclear cells (PBMCs), and further interrogated through mechanistic in vitro studies in human pulmonary artery endothelial cells (PAECs). ResultsIL-6 neutralization significantly improved RV function, reduced pulmonary arterial pressures, and attenuated pulmonary vascular remodeling in both experimental models. Transcriptomic analysis identified a dysregulated FOXP3 signaling axis. Mechanistically, IL-6 induced cooperative binding of phosphorylated STAT3 and STAT4 to the FOXP3 promoter, facilitating DNMT1-mediated DNA methylation and stable gene silencing. IL-6 blockade restored downstream FOXP3 expression, rescued downstream BMPR2 signaling, and re-established endothelial homeostasis. In clinical PAH cohorts, FOXP3 expression was markedly reduced and inversely correlated with circulating IL-6 levels and indices of disease severity. ConclusionIL-6 drives pulmonary hypertension through STAT3/STAT4- and DNMT1-dependent epigenetic repression of FOXP3, linking chronic inflammation to BMPR2 dysfunction and pulmonary vascular remodeling. IL-6 neutralization reverses this pathogenic program in experimental PAH. FOXP3 emerges as a mechanistic biomarker of disease severity and a potential tool for precision stratification of patients likely to benefit from IL-6-targeted therapies. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LISynergistic Gene Repression: The study demonstrates that phosphorylated STAT3 functional transcriptional complex that binds directly to the FOXP3 promoter. Acting as a molecular scaffold, this complex actively represses FOXP3 expression within the pulmonary endothelium. C_LIO_LIEpigenetic Silencing Mechanism: IL-6 does not merely induce a transient suppression of FOXP3. Instead, IL-6/STAT3 signaling recruits DNMT1 to the FOXP3 promoter, leading to site-specific DNA methylation and long-term epigenetic silencing. This mechanism provides a direct molecular link between chronic systemic inflammation and sustained pulmonary vascular injury. C_LIO_LIThe FOXP3-BMPR2 Connection: The findings identify FOXP3 as a critical positive regulator of BMPR2 expression. Neutralization of IL-6 disrupts this pathological inhibitory loop, permitting restoration of BMPR2 signaling, the central gatekeeper of pulmonary vascular integrity and homeostasis. C_LIO_LITranslational Biomarkers: Importantly, the molecular changes within the lung are reflected systemically. Suppressed FOXP3 expression is readily detectable in PBMCs and serum, offering a non-invasive biomarker that correlates with pulmonary hemodynamic status and vascular health. C_LI Clinical ImplicationsO_LIPrecision Patient Stratification: FOXP3 expression in PBMCs and serum functions as a surrogate marker of pulmonary vascular epigenetic health. This could identify a specific inflammatory endotype of PAH patients most likely to respond to IL-6-targeted therapies. C_LIO_LIPrognostic Biomarker: Because FOXP3 levels integrate both systemic inflammatory burden and dysfunction of the RV-pulmonary vascular axis, they may provide a more sensitive tool for monitoring therapeutic response and predicting clinical worsening than current standard-of-care markers. C_LI

molecular biology↗

bioRxiv2026

Disruption of PI3K/OxPhos Coupling by Trehalose Drives a BCAA to Lipid Metabolic Switch in Hormone Receptor Positive Breast Cancer

Cancer cells sustain proliferation through dynamic coordination between mitochondrial oxidative phosphorylation (OxPhos) and anabolic carbon metabolism. How this metabolic coupling can be selectively destabilized in subtype-specific contexts remains poorly defined. Here we identify trehalose, a disaccharide previously linked to autophagy modulation, as a regulator of mitochondrial-anabolic integration in breast cancer. Using high-resolution respirometry, untargeted metabolomics, and signalling analyses across estrogen/progesterone receptor-positive (ER) and triple-negative models, we show that trehalose preferentially impairs mitochondrial bioenergetics in OxPhos-dependent ER cells. Trehalose reduced electron transport system capacity, NADH-linked respiration, mitochondrial membrane potential, and coupling efficiency, while suppressing mitochondrial biogenesis markers. These bioenergetic effects coincided with attenuation of PI3K/Akt signalling and induction of p21-associated growth arrest. Metabolomic profiling revealed a coordinated redistribution of carbon flux characterized by depletion of branched-chain amino acids (BCAAs) and glycolytic intermediates alongside accumulation of long-chain fatty acids and cholesterol. Correlation network analysis uncovered a strong inverse relationship between BCAA-linked metabolism and lipid abundance, indicating a regulated metabolic trade-off rather than nonspecific stress. Functionally, trehalose enhanced the efficacy of mitochondrial-interfering agents such as tamoxifen and colchicine, while exerting minimal effects in metabolically flexible triple-negative cells. Together, these findings define trehalose as a metabolic modulator that constrains mitochondrial plasticity and enforces a lipid-buffered, growth-restrictive state in ER breast cancer, revealing a therapeutic vulnerability linked to mitochondrial dependency.

cancer biology↗

bioRxiv2025

Role of zinc in growth, stress response and virulence gene expression of pathogenic Mucorale Rhizopus arrhizus

During COVID-19 pandemic, the cases of mucormycosis increased substantially, with rhino-orbito-cerebral form linked to uncontrolled diabetes being the predominant manifestation. Some clinical and epidemiological studies associated the usage of zinc supplements with the occurrence of COVID-19 associated mucormycosis, but experimental evidence remains limited. This study aimed to elucidate the impact of zinc enrichment on Rhizopus arrhizus, the predominant causative agent of mucormycosis. The effect of zinc supplementation (5 to 150 {micro}M) on fungal growth, metabolic activity, antifungal susceptibility and biofilm formation, along with cell-wall (Congo red), oxidative (hydrogen peroxide) and osmotic (sodium chloride) stress was evaluated in RPMI-1640. Morphological changes were visualized by scanning electron microscopy. Gene expression was monitored by RNA sequencing. Zinc supplementation promoted R. arrhizus growth in a concentration-dependent manner, with the effect being particularly pronounced under less-favorable conditions, such as alkaline conditions resembling the nasal pH of diabetics. Exposure to zinc enhanced the metabolic activity, and partly alleviated the cell-wall and oxidative stress. Susceptibility to amphotericin B and posaconazole was unchanged. Zinc-supplemented cultures over-expressed multiple genes, notably those associated with respiratory electron transport chain, ergosterol biosynthesis, chitosan production, oxidative stress response, mucoricin, high-affinity iron permease, iron transport multi-copper oxidase and ferric-reductase-like protein. Zinc also augmented the growth/metabolism of several other Mucorales but not Aspergillus fumigatus and Candida albicans. The findings suggest that zinc supplementation supports mucoralean growth and enhances the expression of key virulence factors, implying that excessive intake of zinc supplements during COVID-19 pandemic likely contributed to the emergence of mucormycosis. IMPORTANCEMucormycosis remains a highly devastating fungal infection that presented additional challenges during the COVID-19 pandemic. Several risk factors were implicated in the emergence of COVID-19 associated mucormycosis (CAM), including inappropriate corticosteroid usage and COVID-19 associated glycemic imbalance. The excessive intake of nutritional supplements, especially that of zinc, owing to self-medication and over-prescription, was also proposed as a plausible factor in the rise of CAM in many clinical/epidemiological studies. This study experimentally evaluated the potential impact of zinc enrichment on pathogenic Mucorales. The work demonstrates that zinc supplementation supports Rhizopus arrhizus growth, metabolism and stress response, and enhances the expression of key virulence factors, including mucoricin and iron transporters. Notably, the augmentation was specifically observed in pathogenic Mucorales but not Aspergillus fumigatus and Candida albicans. The work provides experimental evidence for the potential association of zinc over-availability with the occurrence of CAM, and strengthens evidence-based therapeutic practices in clinical settings.

microbiology↗

bioRxiv2025

Continuous DNA Methylation Deconvolution-Based Surrogate for B-Cell Differentiation State in CLL

Chronic Lymphocytic Leukemia (CLL) is clinically divided into IGHV mutated (M-CLL) and IGHV unmutated (U-CLL) subtypes, which are thought to arise from distinct cells of origin along the B-cell differentiation pathway. We measured genome-scale DNA methylation in purified CLL samples (n = 89) and utilized reference-based cell deconvolution techniques to develop a continuous metric of epigenetic similarity across a B-naive-like to B-memory-like scale (B-Index). B-Index accurately classifies CLL into clinical subtypes (98.8%), has a stronger epigenetic signal than IGHV gene percent identity, and demonstrates additional epigenetic signal within the M-CLL subgroup. We demonstrate that U-CLL is epigenetically more similar to B-memory than B-naive cells and reconcile previous reports of a B-naive-like epigenetic signal. The B-memory-like program of U-CLL is enriched for binding sites of transcription factors related to the germinal center activation pathway. Our findings provide epigenetic evidence for discerning CLL mechanisms of initiation and cell of origin. We also identified an epigenetic signal associated with tumor burden, which may have some relation to viral infections such as Epstein-Barr-Virus. Our cell-type deconvolution-based approach to developing a continuous metric for CLL epigenetic differentiation state can be applied to other tumors with multiple subtypes across differentiation stages.

cancer biology↗

bioRxiv2025

Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development

Clonal hematopoiesis (CH) is associated with an increased risk of non-hematologic chronic diseases including metabolic disorders, yet the causality remains poorly defined. DNMT3A is the most frequently altered gene in CH, commonly through monoallelic loss-of-function (LOF) and Arg882His (RH) hotspot mutations. Here we demonstrate in a mouse model that CH driven by Dnmt3a RH and especially LOF promotes obesity, diabetes, and chronic liver disease, further exacerbated by high-fat diet (HFD).

pathology↗

bioRxiv2025

A new genome assembly of the pea cultivar Cameor provides resources for functional genomics and genetics

Significant improvements in sequencing technologies have allowed the development of more contiguous genome assemblies in many plant species. The pea genome is characterized by its richness in repeated elements and its long and complex centromeres. This makes its assembly challenging. In this paper, we present an improved version of the genome sequence of the French cultivar Cameor. This sequence was obtained by combining Nanopore and PacBio long-read sequencing, Hi-C contact maps and Bionano maps. The assembly of centromeres was refined using a combination of FISH and ultra-long Nanopore read analyses. Overall, Cameor_v2 genome assembly is a highly continuous pea genome assembly with small total gap size and a large contig N50. In this version, the orientation of chromosomes was revised according to internationally accepted karyotype rules. Gene annotation statistics indicated a high completeness of gene sequences, with most gene sequences with 3 and 5 UTR. This genome assembly with its associated data constitute a useful resource for pea genetics, comparative mapping and functional genomics.

genomics↗

bioRxiv2025

Collagen-binding IL-12 expressing STEAP1 CAR-T cells reduce toxicity and eradicate mouse prostate cancer in combination with checkpoint inhibitors

Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose significant challenges for chimeric antigen receptor (CAR)-T cell therapies to tackle solid tumors. CAR-T cells were armed with immunostimulatory payloads, such as interleukin-12 (IL-12), to overcome this issue, but faced intolerable toxicity during clinical development. Here, we show that collagen-binding domain-fused IL-12 (CBD-IL-12) was retained within syngeneic murine prostate tumors, after secretion from CAR-T cells targeting human six transmembrane epithelial antigen of the prostate 1 (STEAP1). This led to equivalently high intratumoral interferon-{gamma} levels without hepatotoxicity and infiltration of T cells into non-target organs, compared with unmodified IL-12. Both innate and adaptive immune compartments were dramatically activated and recognized diverse tumor antigens after CBD-IL-12 CAR-T cell treatment. Combination immunotherapy of CBD-IL-12 CAR-T cells and immune checkpoint inhibitors eradicated large tumors in an established prostate cancer model, without pre-conditioning chemotherapy. The therapy generated anti-tumor immunological memory. CBD-fusion to potent yet toxic payloads of CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumors.

bioengineering↗

bioRxiv2025

A cell atlas of human and mouse synovium from early and advanced stages of knee osteoarthritis: BHLHE40 regulates fibroblast activation

Osteoarthritis (OA) is a destructive joint disease affecting multiple tissues, including synovium. Previous studies have identified some distinct fibroblast subtypes within synovium; however, the characterization of fibroblast subsets during distinct stages of knee (K)OA disease, and their contributions to the endogenous mechanisms that drive synovial fibrosis during KOA, are not well characterized. Here we profile synovium from early- (KL I) and advanced- (KL III/IV) stages of radiographic KOA. First, bulk-RNA sequencing of early- and advanced-staged KOA synovial tissue revealed transcriptomic differences between the two disease stages. Using single-nuclei RNA sequencing (snRNA-seq) and flow cytometry, we identified distinct fibroblast subsets and uncovered an endotypic shift in fibroblast subsets during KOA pathogenesis, transitioning from DPP4+ in early-stage to ITGB8+ in advanced-stages. SnRNA-seq of synovium from mice with experimental KOA revealed analogous populations of Dpp4+ and Itgb8+ fibroblasts in tissue from early and advanced model stages. Human advanced-stage KOA synovial tissue had stronger expression of matrisome-annotated genes compared to early-stage tissue. BHLHE40, a crucial transcriptional regulator of ECM related genes, was identified as upregulated in ITGB8+ fibroblasts compared to DPP4+ fibroblasts. Using primary human OA fibroblasts in vitro, and conditional knock out mice in vivo, we found that fibroblast-intrinsic loss of BHLHE40 increased fibrosis-related gene expression, enhanced fibroblast activation and induced severe synovial fibrosis in vivo. In contrast, overexpression of BHLHE40 in vitro was able to suppress TGF-{beta}-induced fibroblast activation. Overall, this study provides a comprehensive cellular atlas of KOA synovium and has identified BHLHE40 as a crucial regulator of fibroblast-mediated synovial fibrosis.

molecular biology↗

bioRxiv2024

Identification of Ephrin type-B receptor 4 as a critical mediator of tissue fibrosis

Pulmonary fibrosis (PF) is a pathology associated with interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF). Fibrosis promotes continual secretion of extracellular matrix (ECM), producing non-functional scar tissue and causing organ failure. This study investigated the tyrosine kinase receptor Ephrin type-B receptor 4 (EphB4) as a mediator of PF. To this end, we generated mice with conditional Col1a2-driven deletion of Ephb4 and used a preclinical mouse model of PF, total and single nuclei RNA (snRNA) sequencing, NanoString, previously published single cell data, computational analysis, and functional assays of mouse and human healthy control and IPF lung fibroblasts. Col1a2-CreERT-driven Ephb4 deletion, or EphB4 inhibition via NVP-BHG712, markedly protected against bleomycin-induced PF. Total RNA-sequencing of fibroblasts isolated from Ephb4-deficient fibrotic mouse lungs exhibited reduced expression of ECM, ER Cargo, and protein trafficking-related genes. NVP-BHG712 reduced expression of these identified genes in mouse lung fibroblasts under fibrotic conditions in vitro. SnRNA sequencing of mouse lungs treated with NVP-BHG712 identified transcriptomic changes of ECM genes in specific fibroblast subpopulations. RNA sequencing, computational, and functional assays using mouse and human IPF fibroblasts identified elastin as a key mediator involved in EphB4 signaling. Combined, our data show that EphB4 is a crucial mediator of PF.

pathology↗

bioRxiv2024

Random subsamples of animal populations can reveal intrinsic differences in sociality with key implications in ecology, conservation and disease transmission

Animal populations are under mounting stress from the dual threats of climate change and rapid global human population growth, raising significant concerns about declining wildlife and the rising risk of zoonotic diseases. In many species, social interactions can be a highly plastic suite of behaviours that are responsive to these disturbances and are consequential to other processes like disease transmission and population dynamics. Studying social interactions can be challenging in that researchers often rely on wildlife population subsamples due to practical constraints and costs, which can introduce biases in the reliability of social network metrics. We investigated the extent to which subsamples can depict intrinsic characteristics of wildlife populations using data from three distinct species: peri-urban fallow deer, Alpine ibex and Angolan giraffe. We showed that random subsamples of these populations could still reveal differences in their social behaviour, indicating that, as long as researchers have a reliable estimate of population size, subsampling animal populations can be an effective and precise method to infer their sociality and offer valuable empirical data for management, conservation and zoonotic disease ecology. Furthermore, we demonstrate that non-random sampling, influenced for instance by animal personality and related trappability, can introduce significant biases in social network estimates. These findings underscore the importance of accounting for sampling biases in social network analysis and offer a robust framework for using partial networks in ecological studies and conservation management.

ecology↗

bioRxiv2024

Codon Usage Bias Analysis of Human Papillomavirus 18s L1 Protein and its Host Adaptability

Human Papillomavirus 18 (HPV 18) is known as a high-risk variant associated with cervical and anogenital malignancies. High-risk types HPV 18 and HPV 16 (human papillomavirus 16) play a major part in about 70 percent of cervical cancer worldwide (Ramakrishnan et al., 2015). The L1 protein of HPV 18 (HPV 18s L1 protein), also known as major capsid L1 protein is targeted in the vaccine development against HPV 18 due to its non-oncogenic and non-infectious properties with self-assembly ability into virus-like particles. In the present analysis, an extensive codon usage bias analysis of HPV 18s L1 protein and adaptation to its host human was conducted. The Effective number (Nc) Grand Average of Hydropathy (GRAVY), Index of Aromaticity (AROMO), and Codon Bias Index (CBI) values revealed no biases in codon usage of HPV 18s L1 protein. The data of the Codon Adaptation Index (CAI), and Relative Codon Deoptimization Index (RCDI) indicate adaptation of HPV 18s L1 protein according to its host human. The domination of selection pressure on codon usage of HPV 18s L1 protein was demonstrated based on GC12 vs GC3, Nc vs GC3, and frequency of optimal codons (FOP). The Parity plot revealed that the genome of HPV 18s L1 protein has a preference for purine over pyrimidine, that is G nucleotides over C, and no preference for A over T but A/T richness was observed in the genome of HPV 18s L1 protein. In the Nucleotide composition, GC1 richness ultimately represents evolutionary aspects of codon usage. Furthermore, these findings can be used in currently ongoing vaccine development and gene therapy to design viral vectors.

bioinformatics↗

bioRxiv2024

A conjugative plasmid exploits flagella rotation as a cue to facilitate its transfer

Conjugation-mediated DNA delivery is the primary mode for antibiotic resistance spread; yet, molecular mechanisms regulating the process remain largely unexplored. While conjugative plasmids typically rely on solid surfaces to facilitate donor-to-recipient proximity, the pLS20 conjugative plasmid, prevalent among Gram-positive Bacillus spp., uniquely requires fluid environments to motivate its transfer. Here we unveiled that pLS20, carried by B. subtilis, induces adhesin-promoted multicellular clustering, which can accommodate various species, offering a stable platform for DNA delivery in liquid milieu. We further discovered that induction of pLS20 promoters, governing crucial conjugative genes, hinges on the presence of donor cell flagella, the major bacterial motility organelle. Moreover, pLS20 regulatory circuit is strategically integrated into a mechanosensing signal transduction pathway responsive to flagella rotation, harnessing propelled flagella to activate conjugation genes exclusively during the host motile phase. This flagella-conjugation coupling strategy, provides the plasmid with the benefit of disseminating into remote destinations, infiltrating new niches.

microbiology↗

bioRxiv2024

Using an agent based model to inform sampling design for animal social network analysis

Producing accurate and reliable inference from animal social network analysis depends on the sampling strategy during data collection. An increasing number of studies now use large-scale deployment of GPS tags to collect data on social behaviour. However, these can rarely capture whole populations or sample at very high frequencies. To date, little guidance exists when making prior decisions about how to maximise sampling effort to ensure that the data collected can be used to construct reliable social networks. We use a simulation-based approach to generate a functional understanding of how the accuracy of various network metrics is affected by decisions along three fundamental axes of sampling effort: coverage, frequency and duration. Researchers often face trade-offs between these three sampling axes, for example due to resource limitations, and thus we identify which axes need to be prioritised as well as the effectiveness of different deployment and analytical strategies. We found that the sampling level across the three axes has different consequences depending on the social network metrics that are estimated. For example, global metrics are more sensitive than local metrics to the proportion of the population tracked, and that among local metrics some are more sensitive to sampling duration than others. Our research demonstrates the importance of establishing an optimal sampling configuration for drawing relevant and robust inferences, and presents a range of practical advice for designing GPS based sampling strategies in accordance with the research objectives.

ecology↗