Biology subjects

Joshi, A.

Publications and source records attributed to Joshi, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Structure-Based Design of Small-Molecule Inhibitors of Human Interleukin-6

Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6R followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. A critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies are in clinical use that either target IL-6R or hIL-6 to inhibit signaling. Here, we perform high throughput structure-based computational screening using ensemble docking for small molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scored ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with second-highest calculated binding affinity showed experimentally [~]84% inhibitory effect on IL6-induced STAT3 reporter activity at 10-5 molar concentration. This finding may pave the way for designing small molecule inhibitors of hIL-6 of therapeutic significance.

bioinformatics↗

bioRxiv2024

Selection of Bone-Targeting Peptides for Therapeutic Intervention: An In Vivo Evaluation and Comparison Study

Hydroxyapatite (HA)-binding peptides are emerging as promising candidates for bone-targeted therapies due to their strong affinity for mineralized tissues and biocompatibility. However, most studies to date have focused on in vitro characterization, providing limited insight into their in vivo performance. This study bridges that gap by evaluating the in vivo behavior of HA-binding peptides D8, E8, YD8, and YE8 using fluorescence imaging to assess their biodistribution in healthy and pathological bone environments. In healthy animal models, D8 demonstrated the strongest binding across mineralized tissues, including the skull, femur, and tibia, while YD8 showed moderate binding. In contrast, E8 and YE8 exhibited limited localization influenced by peptide dosage and binding kinetics. Pathological models, including defective tibia and osteogenesis imperfecta (OIM) mice, revealed preferential accumulation of D8 and YD8 in structurally compromised regions, underscoring their potential for targeting diseased bone microenvironments. Fluorescence imaging, enhanced by spectral unmixing algorithms, proved effective for assessing peptide localization and distribution. These findings highlight the utility of HA-binding peptides for bone-targeted therapies and emphasize the importance of in vivo studies in advancing their therapeutic and diagnostic applications. This work provides a foundation for optimizing peptide designs to improve specificity and efficacy in bone repair and regeneration.

bioengineering↗

bioRxiv2024

Identification of genetic variation in genes linked to buparvaquone resistance in Theileria sp infecting dairy cattle in India.

Buparvaquone (BQO) is used for treatment of bovine theileriosis, a tickborne disease caused by parasites of the Theileria genus. Studies on T. annulata have linked the mechanism of BQO resistance predominantly to genetic variations in the parasite cytochrome b (cytb) gene. In addition, cryptic mechanisms of resistance involving the parasite peptidyl-prolyl isomerase (pin1) and dihydroorotate dehydrogenase (dhodh) genes require assessment. In India, where bovine theileriosis is endemic, and BQO is widely used for treatment, monitoring and establishing the link between genetic variations in cytb, dhodh and pin1 genes and BQO resistance is essential. In this study, multiplexed PCR amplification and nanopore sequencing approaches were used for genotyping the complete gene loci of the target genes. Analysis of 420 T. annulata field samples collected from seven different states of India revealed the presence of previously reported variations S129G, A146T and P253S in cytb and A53P in pin1, which are linked to BQO resistance. The role of A146T, a highly prevalent variation which mostly co-occurred with I203V, in BQO resistance needs to be evaluated. From 60 samples having T. orientalis infection, the genetic variations identified from the three genes were found to be mostly natural variations based on the reference genotypes and were distinct from T. annulata variations. This study has revealed the presence of BQO resistance-linked cytb gene mutations in T. annulata infecting dairy cattle in India and establishes a nanopore sequencing method for molecular surveillance of genetic variation in field samples. Author SummaryBuparvaquone (BQO) is the most effective drug that is available for the treatment of cattle theileriosis caused by parasites of the Theileria genus. However, treatment failure due to drug resistance is reported, and gene mutations linked to BQO resistance have been reported in African and Middle Eastern countries. These mutations occur in the cytochrome b (cytb) and peptidyl-prolyl isomerase (pin1) genes in the parasite. In this study, genetic variations occurring in these two genes and the parasite dihydroorotate dehydrogenase (dhodh) gene have been mapped using PCR amplification and Nanopore sequencing from field samples collected from seven different states of India. At least three previously reported mutations linked to BQO resistance were found in the T. annulata cytb gene sequence obtained from field samples. While one of these mutations (A146T) was highly prevalent, the other two were found to occur in only a few samples. Similarly, the BQO resistance linked to A53P mutation in the T. annulata pin1 gene was present in only a few samples. Despite their low frequency, the presence of these mutations reveals the existence of BQO resistance due to genetic variations in the parasite population present in India. This is the first comprehensive report of BQO resistance-conferring mutations occurring in Theileria parasites affecting dairy cattle in India and establishes a scalable method for large-scale molecular surveillance studies.

genomics↗

bioRxiv2024

Generating Biomedical Knowledge Graphs from Knowledge Bases, Registries, and Multiomic Data

As large clinical and multiomics datasets and knowledge resources accumulate, they need to be transformed into computable and actionable information to support automated reasoning. These datasets range from laboratory experiment results to electronic health records (EHRs). Barriers to accessibility and sharing of such datasets include diversity of content, size and privacy. Effective transformation of data into information requires harmonization of stakeholder goals, implementation, enforcement of standards regarding quality and completeness, and availability of resources for maintenance and updates. Systems such as the Biomedical Data Translator leverage knowledge graphs (KGs), structured and machine learning readable knowledge representation, to encode knowledge extracted through inference. We focus here on the transformation of data from multiomics datasets and EHRs into compact knowledge, represented in a KG data structure. We demonstrate this data transformation in the context of the Translator ecosystem, including clinical trials, drug approvals, cancer, wellness, and EHR data. These transformations preserve individual privacy. We provide access to the five resulting KGs through the Translator framework. We show examples of biomedical research questions supported by our KGs, and discuss issues arising from extracting biomedical knowledge from multiomics data.

bioinformatics↗

bioRxiv2024

Prostate-specific membrane receptor PPAP facilitates E. coli invasion of luminal prostate cells via FimH binding

Bacterial prostatitis caused by uropathogenic Escherichia coli (UPEC) strains is a highly prevalent and recurrent infection responsible for significant morbidity in men. However, the molecular pathogenesis of prostatitis remains poorly understood, partly due to the lack of comprehensive in-vitro models. In this study, we introduce a murine prostate organoid model that replicates the cellular heterogeneity of the prostate epithelium with a cell composition and transcriptional signature comparable to the native prostate tissue. Using this model, we uncovered that UPEC preferentially attaches to, invades, and replicates within luminal prostate cells. This selective interaction is mediated by the binding of the bacterial adhesin FimH to the prostate- specific membrane protein PAPP, which is exclusively expressed on luminal prostate cells. Altogether, we identified a new mechanism by which UPEC infects the prostate epithelium, highlighting FimHs adaptability in engaging host receptors and its potential for targeted therapeutic strategies.

molecular biology↗

bioRxiv2024

Assembly of branched chain amino acid (BCAA) to toxic fibrils may be related to pathogenesis of Maple syrup urine disease (MSUD)

Inborn errors of metabolism (IEMs) are a group of diseases caused by mutations in single genes, leading to the buildup of metabolites that are typically toxic or disrupt normal cellular function. The etiological relation of metabolic disorders has been uncovered through the study of metabolite amyloids. Various metabolites that accumulate in IEMs have been reported to self-assemble into organized structures. These structures exhibit similar physicochemical properties as proteinaceous amyloid fibrils. In this context, our study illustrated the aggregation properties of Branched chain amino acid (BCAA) i.e. Isoleucine, Leucine and Valine that accumulate in Maple syrup urine disease (MSUD) to investigate their propensities to assemble into amyloid-like fibrils. The structural morphologies of BCAA were studied via. microscopic techniques like Scanning electron microscopy (SEM), optical microscopy and phase contrast microscopy. Further, characterization techniques were employed to understand the physicochemical properties of the self-assemblies and its underlying mechanism. The amyloid-like nature of these aggregates was confirmed using Thioflavin T (ThT) and Congo Red (CR) assays, indicating a possible cytotoxic effect. The MTT assay reveals BCAAs were cytotoxic and significantly decrease cell viability. Our study plays a key role in understanding the physicochemical properties of MSUD in association to amyloid disease, possibly paving the way for the development of therapeutic solutions in the future. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/616096v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@13f26daorg.highwire.dtl.DTLVardef@10fdef5org.highwire.dtl.DTLVardef@f6e1d7org.highwire.dtl.DTLVardef@64f608_HPS_FORMAT_FIGEXP M_FIG C_FIG The self-assembly of BCAA-Ile, Leu, Val was investigated and the findings indicate that their aggregation may follow an amyloidogenic pathway.

bioengineering↗

bioRxiv2024

Hippocampal representations of alternative possibilities are flexibly generated to meet cognitive demands

The cognitive ability to go beyond the present to consider alternative possibilities, including potential futures and counterfactual pasts, can support adaptive decision making. Complex and changing real-world environments, however, have many possible alternatives. Whether and how the brain can select among them to represent alternatives that meet current cognitive needs remains unknown. We therefore examined neural representations of alternative spatial locations in the rat hippocampus during navigation in a complex patch foraging environment with changing reward probabilities. We found representations of multiple alternatives along paths ahead and behind the animal, including in distant alternative patches. Critically, these representations were modulated in distinct patterns across successive trials: alternative paths were represented proportionate to their evolving relative value and predicted subsequent decisions, whereas distant alternatives were prevalent during value updating. These results demonstrate that the brain modulates the generation of alternative possibilities in patterns that meet changing cognitive needs for adaptive behavior.

neuroscience↗

bioRxiv2024

AyurPhenoClusters define common molecular roots for rare diseases and uncover ciliary dysfunctions in syndromic conditions

The heterogeneity of underlying causes and the variability of symptoms across Multiple organs in rare diseases present significant challenges when approached from an organ-centric perspective. Ayurveda, however, takes a multisystem perspective, assessing diseases through kinetic (Vata:V ), metabolic (Pitta:P ), and structural (Kapha:K ) dimensions, each with distinct phenotypic and molecular correlates. This study explores rare diseases from a systems perspective by integrating Ayurveda and unifying terminologies from both disciplines using Human Phenotype Ontology (HPO). Experts categorized 10,610 HPO terms into Ayurvedic phenotypic groups (V/P/K ) and applied the Expectation Maximization (EM) algorithm to cluster 12,678 diseases. This yielded six distinct clusters, termed AyurPhenoClusters, with 2,814 diseases uniquely classified and enriched for V/P/K phenotypes. Functional annotation of these, highlighted key biological processes: (i) embryogenesis and skeletal morphogenesis, (ii) endocrine and ciliary functions, (iii) DNA damage response and cell cycle regulation, (iv) inflammation and immune response, (v) immune function, hemopoiesis, and telomere aging, and (vi) small molecule metabolism and transport. Notably, the K predominant cluster had the highest ciliary gene enrichment (43%), followed by the V predominant cluster (16%), suggesting potential ciliopathies in V cluster. This systems-based approach enhances the understanding of rare diseases by bridging Ayurveda with modern medicine, for improved diagnostics and therapeutics

genetics↗

bioRxiv2024

Molecular basis of pathogenicity of the recently emerged FCoV-23 coronavirus

The ability of coronaviruses to recombine and cross species barriers affects human and animal health globally and is a pandemic threat. FCoV-23 is a recently emerged, highly pathogenic recombinant coronavirus responsible for a widespread outbreak of feline infectious peritonitis (FIP) likely linked to in-host viral evolution. Here, we report cryoEM structures of two FCoV-23 spike (S) isoforms explaining that the in-host loss of domain 0 observed in clinical samples enhances entry into cells and fusogenicity by facilitating protease access, leading to biotype switching and lethality. We show that FCoV-23 can use several aminopeptidase N (APN) orthologs as receptors and reveal the molecular determinants of receptor species tropism, including a glycan modulating human receptor utilization. We define antigenic relationships among alphacoronaviruses infecting humans and other mammalian species and identify a cross-reactive alphacoronavirus monoclonal antibody inhibiting FCoV-23 pseudovirus entry, paving the way for vaccine and therapeutic development targeting this highly pathogenic virus.

biochemistry↗

bioRxiv2024

Chaperone-mediated heterotypic phase separation regulates liquid-to-solid phase transitions into amyloid fibrils

Biomolecular condensates formed via the phase separation of proteins and nucleic acids are thought to regulate a myriad of cellular processes with exquisite spatiotemporal precision. However, such highly dynamic, viscoelastic, mesoscopic, intracellular membraneless bodies can undergo aberrant liquid-to-solid transitions into a range of amyloid-like species. The formation of such pathological assemblies necessitates their clearance by the cellular protein quality control machinery comprising molecular chaperones. Nonetheless, the mechanism underlying the chaperone-mediated regulation of protein homeostasis within biomolecular condensates remains elusive. Here, we present a unique case demonstrating that a heat shock protein 40 (Hsp40), Ydj1, promotes the heterotypic phase separation of intrinsically disordered tau via intermolecular electrostatic and hydrophobic interactions. Through a diverse array of tools involving high-resolution fluorescence imaging, single-droplet steady-state and picosecond time-resolved fluorescence anisotropy, and single-molecule FRET (Forster resonance energy transfer), we elucidate the diverse structural conformations of tau present within phase-separated heterotypic condensates that are otherwise predisposed to aggregation. Our vibrational Raman spectroscopy and electron microscopy data show that the presence of Ydj1 in tau-Ydj1 condensates abolishes the formation of amyloid fibrils, unlike tau-only droplets. By sequentially deleting segments, we identify amyloidogenic hexapeptide motifs located in the hydrophobic microtubule-binding region of tau that foster contacts with the peptide-binding regions of Ydj1, promoting the formation of tau-Ydj1 binary condensates. Additionally, we show that the underlying network of interactions governing these condensates can be further tuned by RNA. Our results underscore an intriguing interplay of molecular drivers that govern chaperone-associated phase separation, with broader implications for the chaperoning of a wide range of intrinsically disordered proteins involved in physiology and disease.

biophysics↗

bioRxiv2024

DNA barcoding and species delimitation based on four Chloroplast loci to identify species within the Elaeocarpaceae family

AbstractDNA barcoding is an indispensable taxonomic tool for plant species identification. The present research successfully amplified the four coding regions of plastid namely; matK, rpoB, ndhJ, and accD, sequenced, and submitted it to NCBI Genbank after verification. This study evaluated the significance of single (matK, rpoB, ndhJ, and accD) and two-locus plastid loci (rpoB+matK, ndhJ+matK, accD+matK) and examined their abilities for species identification and phylogenetic construction of Elaeocarpaceae plants. The average aligned length for matK, rpoB, ndhJ, accD, ndhJ+matK, rpoB+matK, and accD+matK was 395 bp, 538 bp, 477 bp, 254 bp, 872 bp, 937 bp, and 649 bp, respectively. The highest substitution rate was recorded in the rpoB (18.47%), followed by ndhJ (17.38%), accD (14.00%), and matK (11.23%). The number of variable sites, segregating sites (S), nucleotide diversity (Pi), and mutations (Eta) were observed to be highest in the matK region. Evolutionary relationship based on the Neighbor-joining method demonstrated that candidate barcode sequences were competent for identifying Crinodendron, Elaeocarpus, Sloanea, and Vallea species. A significant barcoding gap was identified in two barcoding regions (matK and ndhJ+matK). The species-specific barcodes for the genus Elaeocarpus were generated based on Single Nucleotide Polymorphism (SNP) analysis. This study offers novel strategies for effectively identifying species within Elaeocarpaceae and lays the foundation for germplasm conservation and utilization.

bioinformatics↗

bioRxiv2024

Intermolecular Energy Migration via HomoFRET Captures the Modulation in the Material Property of Phase-Separated Biomolecular Condensates

Biomolecular condensation via phase separation of proteins and nucleic acids has emerged as a crucial mechanism underlying the spatiotemporal organization of cellular components into functional membraneless organelles. However, aberrant maturation of these dynamic, liquid-like assemblies into irreversible gel-like or solid-like aggregates is associated with a wide range of fatal neurodegenerative diseases. New tools are essential to dissect the changes in the internal material properties of these biomolecular condensates that are often modulated by a wide range of factors involving the sequence composition, truncations, mutations, post-translational modifications, and the stoichiometry of nucleic acids and other biomolecules. Here, we employ homo-Forster Resonance Energy Transfer (homoFRET) as a proximity ruler to study intermolecular energy migration that illuminates the molecular packing in the nanometric length-scale within biomolecular condensates. We used the homoFRET efficiency, measured by a loss in the fluorescence anisotropy due to rapid depolarization, as a readout of the molecular packing giving rise to material properties of biomolecular condensates. Using single-droplet anisotropy imaging, we recorded spatially-resolved homoFRET efficiencies of condensates formed by fluorescent protein-tagged Fused in Sarcoma (FUS). By performing single-droplet picosecond time-resolved anisotropy measurements, we were able to discern various energy migration events within the dense network of polypeptide chains in FUS condensates. Our homoFRET studies also captured the modulation of material properties by RNA, ATP, and post-translational modification. Additionally, we utilized mammalian cell lines stably expressing FUS to study nuclear FUS and oxidative stress-induced stress granule formation in the cytoplasm. Our studies demonstrate that spatially-resolved homoFRET methodology offers a potent tool for studying intracellular phase transitions in cell physiology and disease.

biophysics↗

bioRxiv2024

Regional specialization manifests in the reliability of neural population codes

The brain has the remarkable ability to learn and guide the performance of complex tasks. Decades of lesion studies suggest that different brain regions perform specialized functions in support of complex behaviors1-3. Yet recent large-scale studies of neural activity reveal similar patterns of activity and encoding distributed widely throughout the brain4-6. How these distributed patterns of activity and encoding are compatible with regional specialization of brain function remains unclear. Two frontal brain regions, the dorsal medial prefrontal cortex (dmPFC) and orbitofrontal cortex (OFC), are a paradigm of this conundrum. In the setting complex behaviors, the dmPFC is necessary for choosing optimal actions2,7,8, whereas the OFC is necessary for waiting for3,9 and learning from2,7,9-12 the outcomes of those actions. Yet both dmPFC and OFC encode both choice- and outcome-related quantities13-20. Here we show that while ensembles of neurons in the dmPFC and OFC of rats encode similar elements of a cognitive task with similar patterns of activity, the two regions differ in when that coding is consistent across trials ("reliable"). In line with the known critical functions of each region, dmPFC activity is more reliable when animals are making choices and less reliable preceding outcomes, whereas OFC activity shows the opposite pattern. Our findings identify the dynamic reliability of neural population codes as a mechanism whereby different brain regions may support distinct cognitive functions despite exhibiting similar patterns of activity and encoding similar quantities.

neuroscience↗

bioRxiv2024

Prediction of Post Traumatic Epilepsy using MRI-based Imaging Markers

Post-traumatic Epilepsy (PTE) is a debilitating neurological disorder that develops after traumatic brain injury (TBI). Despite the high prevalence of PTE, current methods for predicting its occurrence remain limited. In this study, we aimed to identify imaging-based markers for the prediction of PTE using machine learning. Specifically, we examined three imaging features: lesion volumes and resting-state fMRI-based measures of functional connectivity and amplitude of low-frequency fluctuation (ALFF). We employed three machine learning methods, namely, kernel support vector machine (KSVM), random forest, and a neural network, to develop predictive models. Our results showed that the KSVM classifier, with all three feature types as input, achieved the best prediction accuracy of 0.78 AUC (Area Under the Receiver Operating Characteristic (ROC) curve) using nested cross-validation. Furthermore, we performed voxel-wise and lobe-wise group difference analyses to investigate the specific brain regions and features that the model found to be most helpful in distinguishing PTE from non-PTE populations. Our statistical analysis uncovered significant differences in bilateral temporal lobes and cerebellum between PTE and non-PTE groups. Overall, our findings demonstrate the complementary prognostic value of MR-based markers in PTE prediction and provide new insights into the underlying structural and functional alterations associated with PTE.

neuroscience↗

bioRxiv2023

Phytochemical Characterization of Bio-active Compounds in Hydroethanolic Extract of Elaeocarpus ganitrus leaves using HPLC, LC-MS, and HPTLC Analyses

Bioactive compounds have various applications in different industries, including food, pharmaceutical, and cosmetic industries, demonstrating the need to identify the best-standardized technique to screen the phytochemical profile of medicinal plants. This study aimed to characterize the bioactive compounds in the hydroethanolic extracts of Elaeocarpus ganitrus leaves using various analytical techniques: HPLC, LC-MS, and HPTLC. Air-dried leaves of E. ganitrus were extracted with 70% ethanol. The phytochemical composition of crude extracts was analyzed by the High performance liquid chromatography (HPLC) method, and a total of 93 compounds, including 46 flavonoids, 17 phenols, 14 polyphenols, 3 phenolic acid, 3 phenolic glycosides, 2 flavonoid glycosides, 2 glycosides, 2 phenylpropanoid glycoside, 1 hydroxycinnamic acid, 1 lignan, 1 tannin, and 1 terpene glycoside were detected and quantified. The Liquid chromatography mass spectrometry (LC-MS) analyses identified 11 major eleven compounds: quercetin (803.0215 {micro}g/L), gallic acid (726.13 {micro}g/L), ferulic acid (652.34 {micro}g/L), chlorogenic acid (651.021{micro}g/L), pinocembrin (264.11 {micro}g/L), p-aminobenzoic acid (251.021 {micro}g/L), epicatechin (246.02 {micro}g/L), catechin (161.51 {micro}g/L), caffeic acid (123.31 {micro}g/L), syringaldehyde (116.31 {micro}g/L), and naringenin (106.31 {micro}g/L). The chemical fingerprinting was carried out by high performance thin layer chromatography (HPTLC), and HPTLC fingerprint qualitatively revealed a predominant amount of gallic acid (48.64 %), curcumin (15.21 %), caffeic acid (12.19 %) and cinnamic acid (6.50 %). A significant amount of bioactive constituents in a hydroethanolic extract of E. ganitrus leaves indicates the plants therapeutic potential, including antioxidant, anti-inflammatory, antidiabetic, anticancer, neuroprotective, and cardio-protective activities.

biochemistry↗

bioRxiv2023

NVX-CoV2373 ancestral and NVX-CoV2540 BA.5 protein nanoparticle vaccines protect against Omicron BA.5 variant in Syrian hamsters

The emergence of SARS-CoV-2 variants with greater transmissibility or immune evasion properties has jeopardized the existing vaccine and antibody-based countermeasures. Here, we evaluated the efficacy of boosting with the protein nanoparticle NVX-CoV2373 or NVX-CoV2540 vaccines containing ancestral or BA.5 S proteins, respectively, in mRNA-immunized pre-immune hamsters, against challenge with the Omicron BA.5 variant of SARS-CoV-2. Serum antibody binding and neutralization titers were quantified before challenge, and viral loads were measured 3 days after challenge. Compared to an mRNA vaccine boost, NVX-CoV2373 or NVX-CoV2540 induced higher serum antibody binding responses against ancestral Wuhan-1 or BA.5 spike proteins, and greater neutralization of Omicron BA.1 and BA.5 variants. One and three months after vaccine boosting, hamsters were challenged with the Omicron BA.5 variant. NVX-CoV2373 and NVX-CoV2540 boosted hamsters showed reduced viral infection in the nasal washes, nasal turbinates, and lungs compared to unvaccinated animals. Also, NVX-CoV2540 BA.5 boosted animals had fewer breakthrough infections than NVX-CoV2373 or mRNA-vaccinated hamsters. Thus, immunity induced by NVX-CoV2373 or NVX-CoV2540 boosting can protect against the Omicron BA.5 variant in the Syrian hamster model. IMPORTANCEAs SARS-CoV-2 variants continue to emergence, the efficacy of prior and updated COVID-19 vaccines need to be tested. Here, we tested the efficacy of two nanoparticle protein-based vaccines in pre-immune hamsters against a challenge with the BA.5 Omicron variant of SARS-CoV-2. Compared to an mRNA vaccine boost, the nanoparticle vaccine NVX-CoV2373 and NVX-CoV2540 induced higher serum antibody binding and neutralization responses against ancestral Wuhan-1 or BA.5 variants. One and three months after the last immunization, hamsters were challenged with the Omicron BA.5 variant. NVX-CoV2373 and NVX-CoV2540 boosted hamsters showed reduced viral infection in the nasal washes, nasal turbinates, and lungs compared to unvaccinated animals. Animals that received the homologous vaccine, NVX-CoV2540, had fewer breakthrough infections than NVX-CoV2373 or mRNA-vaccinated hamsters. Together, our data shows that the BA.5 nanoparticle vaccine is effective and that it is important to update the COVID-19 vaccine to match currently circulating strains of SARS-CoV-2.

microbiology↗

bioRxiv2023

An individual-based simulation framework exploring the ecology and mechanistic underpinnings of larval crowding in laboratory populations of Drosophila

The study of larval competition in laboratory populations of Drosophila, implemented via the crowding of larval cultures, has contributed greatly to the understanding of the ecology of competition, the evolution of larval competitive ability, and formed the basis of rigorous testing of the theory of density-dependent selection. Earlier studies led to the view that the outcomes of larval competition, and resulting evolutionary consequences of crowding-adaptation, could largely be understood by varying the starting density of individuals in a crowded culture. However, recent studies have shown that the results of adaptation to larval crowding may not be well predicted by the total larval density (i.e., total starting individuals/total volume of food). Cultures raised at the same total density but at different egg number and food volume combinations were shown to have different underlying density-specific fitness functions, and crowding-adaptation in each of these cultures was attained through different evolutionary trajectories as well. A recent study showed that cultures with not just the same density, but the same egg and food volume combination, achieved through food columns of differing diameter and height, could also differ greatly in fitness-related trait outcomes. In that study, the density of larvae in the feeding band (volume of food close to the surface in contact with air, to which larval feeding is largely restricted) was a very important factor in predicting the outcomes of larval competition. Given these recent findings, it is important to understand the overall role of feeding band density, and how it influences density-specific fitness functions in different kinds of crowded cultures. As the older models of larval competition are now insufficient to capture current empirical data, we constructed an individual-based simulation framework informed in part by these more recent findings, in order to better understand the evolutionary ecology and mechanistic underpinnings of larval competition, and predict robust experiments for expanding our understanding of the process of larval competition in Drosophila.

ecology↗

bioRxiv2023

More than just density: the role of egg number, food volume and container dimensions in mediating larval competition in Drosophila melanogaster

Flies of the genus Drosophila have been extensively used as model systems to study competition. Experiments using larval crowding in these species have furthered our understanding of competition ecology, stress-adaptation, density-dependent selection and population dynamics. Historically, larval competition has been induced by crowding the larvae in high density cultures, compared to low-density controls. However, recent studies have shown that two larval cultures having the same total eggs per mL food density, with different absolute quantities of eggs and food, can differ greatly in their density-specific fitness functions. Similarly, populations adapted to two types of cultures achieving the same density through different means, can also evolve different traits. Thus, it is clear that there is more to larval crowding than just eggs/food density, which has until now been the benchmark variable for quantifying larval crowding in Drosophila studies. In the current study, we explore the consequences of implementing crowding in different ways, using a three-way factorial experiment with egg number and food volume, cast into different food column heights or cylindrical vials with different diameters. We find that not just the same density, but cultures having the same egg number and food volume combination but experienced in food columns of varying height and diameter can have very different pre-adult survivorship and development times. We further propose a new variable for quantifying larval crowding - effective density, which is the density within the larval feeding band, a volume of food close to the surface, with access to air, wherein a majority of the larvae feed. We show that effective density is a much better predictor of the outcomes of competition than the popularly used total eggs/food density.

evolutionary biology↗