Biology subjects

Singhal, S.

Publications and source records attributed to Singhal, S..

At least 19 recordsLinked to original sources

bioRxiv2026

In-vitro evaluation of Ozenoxacin and other Antibiotics against Staphylococcus aureus and Streptococcus pyogenes isolated from Skin and Soft Tissue Infections

Staphylococcus aureus and Streptococcus pyogenes are major causative bacteria responsible for skin and soft-tissue infections (SSTIs) such as impetigo. Increasing resistance to commonly used topical antibiotics necessitates evaluation of newer agents for the treatment of skin infections. Ozenoxacin, a novel non-fluorinated topical quinolone, has shown promise, exhibiting potent activity against a wide range of pathogens, including methicillin-resistant Staphylococcus (MRSA) and Streptococcus pyogenes. The present study compared the in vitro activity of ozenoxacin and comparator agents against clinical isolates of Staphylococcus aureus and Streptococcus pyogenes from multiple sources including skin and soft-tissue, wound, abscess, and blood. Ozenoxacin was assessed for in vitro antimicrobial activity against 109 methicillin-susceptible (MSSA), methicillin-resistant S. aureus (MRSA), and 24 Streptococcus pyogenes isolates by broth microdilution method recommended by the Clinical and Laboratory Standards Institute (CLSI). Ozenoxacin demonstrated potent in-vitro activity against all 109 S. aureus (MIC50/90= 0.125/0.5 {micro}g/ml) and 24 S. pyogenes (MIC50/90= 0.015/0.03 {micro}g/ml) strains. In contrast, higher MICs were observed for fusidic acid and mupirocin among a subset of S. aureus isolates. A comparison of MIC90values demonstrated that ozenoxacin (0.5 {micro}g/ml) was more active against S. aureus isolates than 8 of the 9 comparator agents tested including vancomycin and linezolid (MIC90= 2 & 4 {micro}g/ml) respectively. In vitro studies of ozenoxacin showed potency against staphylococci and streptococci including resistant S. aureus strains. These findings support its role as an effective first-in-class quinolone topical therapeutic option in the management of various SSTIs.

microbiology↗

bioRxiv2026

Gene Flow Creates Fuzzy Species Boundaries in Fence Lizards

Species delimitation is a fundamental challenge in systematic biology, particularly for geographically variable taxa with hierarchical population structure and gene flow. Migration-aware coalescent models provide a powerful framework for investigating lineage divergence and accurately defining species boundaries. In this study, we combine statistical evaluations of gene flow with phylogenetic and population structure analyses to delimit species of fence lizards within the Sceloporus undulatus complex, a group characterized by extensive population subdivision, mitochondrial DNA introgression, and nuclear gene flow. We find that the undulatus complex exhibits uneven variation in genetic, morphological, and bioclimatic traits, resulting in variable distinctiveness among groups. In some cases, species boundaries are recognized by clear genetic discontinuities without gene flow. In others, shallow divergence, paraphyly, and gene flow produce leaky boundaries and fuzzy species limits. Mitochondrial introgression is extensive and concentrated at species boundaries, whereas nuclear gene flow occurs between only a few species and at much lower levels than within species. Neither within-species populations or species are substantially diverged across morphology or bioclimatic space, highlighting the limited utility of these traits for diagnosing species in this group. By integrating estimates of gene flow with phylogenetic and population structure analyses, this study provides a robust and biologically meaningful revised taxonomic framework for the undulatus complex that identifies independently evolving lineages as species.

evolutionary biology↗

bioRxiv2025

Survival of thermostable {varphi}6 genotypes in acidic, basic, and UV environments

Mutations can facilitate viral resistance to a single extreme environment. But it is unknown how often these mutations confer resistance to other extreme environments to which the viruses have not been previously exposed. Here, we focus on how prior adaptation to thermal stress affects viral survival during exposure to acidic, basic, and UV conditions. We exposed four genotypes (3 single mutants and an unmutated ancestor) of the bacteriophage {Phi}6 with varying thermostability (low, high, or ancestral) to acid (pH 4) for 2 minutes, to base (pH 11) for 16 hours, or to UV radiation for 1 minute. We hypothesized the most thermostable genotype would also have higher survival in pH and UV stress. Unexpectedly, the least thermostable genotype demonstrated the highest survival in acidic, basic, and UV conditions, while the most thermostable genotype tended to show the lower survival in these environments. These results suggest that mutations that increase phage thermostability may not always increase pH or UV stability. Rather, molecular mechanisms of stability may depend on the environment. Investigating the survival of {Phi}6 in other adverse environments could provide further information on molecular mechanisms of stability and viral survival strategies.

microbiology↗

bioRxiv2025

Founders predict trait evolution and population dynamics after evolutionary rescue

Evolutionary rescue helps populations survive environmental change, but the phenotypic and demographic factors associated with rescue dynamics and its long-term effects remain unclear. We experimentally evolved 10 wild-collected populations of flour beetles from across India in a suboptimal corn resource for 70 generations (>5 years), collecting >10,000 population census points book-ended by measurements of fitness-related traits for 30 experimental lines. Despite clear ancestral trait differences, all lines showed highly parallel evolutionary rescue within 20 generations. Long-term average population size varied across source populations and was positively correlated with ancestral development rate, which increased convergently across populations and emerged as the single best predictor of population performance during and after evolutionary rescue. Notably, specific demographic events during rescue (such as the rate of population decline and recovery) were uncorrelated both with ancestral trait distributions and post-rescue adaptation. Our results support prior work showing founder traits as key predictors of adaptation, and highlight their role in long-term adaptation and trait evolution following evolutionary rescue. SIGNIFICANCE STATEMENTUnderstanding how populations adapt to sudden environmental change is vital given accelerating biodiversity declines, the rise of antimicrobial resistance and climate change. We chart evolutionary rescue -- where rapid adaptation prevents extinction -- in flour beetles across 70 generations. Using >10,000 census points and measuring fitness in ancestors, their offspring and in evolved lines, we show that larval development rate is the strongest correlate of long-term population success across diverse wild-collected populations. The effect of ancestral variation is dynamic and disassociated from finer-grained details of the rescue. All populations show highly parallel evolutionary rescue, with convergent evolution in key traits. These findings have direct implications for predicting species survival after environmental change, ranging from conservation to pest and pathogen management.

evolutionary biology↗

bioRxiv2025

Hybrid zone analysis using coalescent-based estimates of introgression and migration

Hybrid zones can serve as natural experiments allowing us to investigate the evolutionary consequences of introgression between distinct populations with divergent genomic backgrounds. Modeling hybrid zones using a coalescent framework can provide critical insights into the historical demography of populations, including population divergence times, population sizes, introgression proportions, migration rates, and the timing of hybrid zone formation. We used coalescent analyses to test whether a hybrid zone between Plateau Fence Lizard (Sceloporus tristichus) populations in Arizona formed recently because of human-induced landscape alterations or originated during Pleistocene climatic shifts. Introgression analysis places the divergence time between the parental populations at approximately 140 kya and their secondary contact and hybridization at approximately 10 kya at the end of the Pleistocene. Introgression proportions for hybrid populations are correlated with their geographic distance from the parental populations, a pattern that is repeated with admixture proportions and hybrid index values. The multispecies coalescent with migration model supports asymmetric migration rates with a bias for gene flow moving towards the northern end of the hybrid zone. The direction of this asymmetry is consistent with spatial cline analyses that suggest a slow but steady northward shift of the center of the hybrid zone. When analyzing hybrid populations sampled along a linear transect, coalescent methods can provide novel insights into the evolutionary history of hybrid zone formation that complement existing spatial and genomic methods.

evolutionary biology↗

bioRxiv2024

Genome assembly and annotation of the red flour beetle (Tribolium castaneum) from India

The largest insect order, Coleoptera, includes several economically important beetles that also serve as major model species for biological research. Perhaps foremost among these is the red flour beetle, a global pest of stored grains and flour whose genome was sequenced in 2008. However, the currently available reference genome (Tcas5.2) is incomplete, fragmented and contains many gaps, and the Y chromosome is not assembled. Here we present inTcas1, an updated genome assembly and annotation of T. castaneum collected from India, assembled using both short and long read sequencing, and annotated using two transcriptome datasets. We report that inTcas1 has fewer gaps, less fragmentation, and many new genes and new isoforms of previously annotated genes. This new resource provides a useful update, comparison, and reference for new beetle genome assemblies. The first Y chromosome assembly for this species also provides critical data to study the evolution of insect sex chromosomes and sex determination systems. SIGNIFICANCEWe present here an improved T. castaneum genome assembly (inTcas1) for beetles sampled from India, including the first Y chromosome of this important pest and laboratory model species. The new genome should facilitate more comprehensive analysis of Coleoptera genome and transcriptome datasets, especially beetle populations from Asia - the previously available genome, Tcas5.2, was assembled using the GA2 strain from USA. The updated genome should also facilitate analyses of genome evolution, including sex determination and sex chromosome dynamics; and the new gene annotations can expand the genetic toolkit for this beetle.

genomics↗

bioRxiv2024

pipesnake : Generalized software for the assembly and analysis of phylogenomic datasets from conserved genomic loci

MotivationPhylogenetics has moved into the era of genomics, incorporating enormous volumes of data to study questions at both shallow and deep scales. With this increase in information, phyloge-neticists need new tools and skills to manipulate and analyze these data. To facilitate these tasks and encourage reproducibility, the community is increasingly moving towards automated workflows. ResultsHere we present pipesnake, a phylogenomics pipeline written in Nextflow for the processing, assembly, and phylogenetic estimation of genomic data from short-read sequences. pipesnake is an easy to use and efficient software package designed for this next era in phylogenetics. AvailabilityThe quick brown fox jumps over the lazy dog. Contactexample@example.org Supplementary informationpipesnake is written in Nextflow and freely available from https://github.com/AusARG/pipesnake alongside comprehensive documentation and a wiki/tutorial. The pipeline is containerized and deployable via Docker, Singularity, and Conda making it easy to run on different compute infrastructures.

bioinformatics↗

bioRxiv2023

Circuit and cell-specific contributions to decision making involving risk of explicit punishment in male and female rats.

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA[->]NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA[->]NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.

neuroscience↗

bioRxiv2022

Molecular early burst associated with the diversification of birds at the K-Pg boundary

Complex patterns of genome and life-history evolution associated with the end-Cretaceous (K- Pg) mass extinction event limit our understanding of the early evolutionary history of crown group birds [1-9]. Here, we assess molecular heterogeneity across living birds using a technique enabling inferred sequence substitution models to transition across the history of a clade [10]. Our approach identifies distinct and contrasting regimes of molecular evolution across exons, introns, untranslated regions, and mitochondrial genomes. Up to fifteen shifts in the mode of avian molecular evolution map to rapidly diversifying clades near the Cretaceous-Palaeogene boundary, demonstrating a burst of genomic disparity early in the evolutionary history of crown birds [11-13]. Using simulation and machine learning techniques, we show that shifts in developmental mode [14] or adult body mass [4] best explain transitions in the mode of nucleotide substitution. These patterns are related, in turn, to macroevolutionary shifts in the allometric scaling relationship between basal metabolic rate and body mass [15, 16]. In agreement with theoretical predictions, this scaling relationship appears to have weakened across the end-Cretaceous transition. Overall, our study provides evidence that the Chicxulub bolide impact [17] triggered integrated patterns of evolution across avian genomes, physiology, and life history that structured the evolutionary potential of modern birds.

evolutionary biology↗

bioRxiv2022

A novel fluorobenzothiazole RBx 10080758 as a dual inhibitor against bacterial GyraseB (GyrB) and Topoisomerase IV (parE) of Gram-positive pathogens causing skin and respiratory infections

Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential opportunity to combat the drug resistance. In the present study, we extensively investigated the efficacy of RBx 10080758, a novel fluorobenzothiazole, against skin and respiratory infections caused by Staphylococci and Streptococci in in vitro and in vivo models. RBx 10080758 showed a potent IC50 of 0.06 M against Gyrase and Topoisomerase IV and also exhibited a strong whole cell in vitro activity with MIC ranges of 0.015-0.06, 0.015-0.03, 0.008-0.03, 0.008-0.03, 0.008-0.0.06, 0.015-0.06 g/ml against Staphylococcus. aureus, Streptococcus pneumoniae, Coagulase negative Staphylococci, Streptococcus viridans, Streptococcus pyogenes and Enterococcus, respectively. As expected from the novel class of molecule, it retains potent even against linezolid and vancomycin resistant strains. Interesting, in mouse systemic infection 10 mg/kg, IV dose protected 100% mice from lethal infections. In rat thigh infection model with MRSA WCUH29 at 45 mg/kg exhibited >3-log10 cfu reduction in thigh muscles. RBx 10080758 displayed potent in vitro and in vivo activity against a panel of MDR Gram-positive bacteria. As a novel chemical class, the fluorobenzothiazoles have the potential to become clinically viable antibiotics, to address the drug resistance problem by its unique dual targeting mechanism of action.

microbiology↗

bioRxiv2022

Concurrent separation of phase-locked and non-phase-locked activity

Brain dynamics recorded via electroencephalography (EEG) is conceptualized as a sum of two components, "phase-locked" and "non-phase-locked" to the stimulus. Both activities are understood to be stemming from different neuronal mechanisms and hence accurately characterizing them is of immense importance in neuroscientific studies. Here, we discuss the drawbacks of currently used methods to separate the phase-locked and non-phase-locked activity and propose a new method that decomposes the two components simultaneously. First, we demonstrate that single-trial separation of phase-locked and non-phase-locked power is an ill-posed problem. Second, using simulations where ground truth validation is possible, we elucidate the drawbacks of the widely used averaging method and efficacy of the proposed concurrent phaser method (CPM). Using two experimental datasets, audio oddball EEG data and auditory steady-state responses (ASSR) we show how the empirical signal-to-noise estimates warrant the usage of CPM to separate phase-locked and non-phase-locked activity.

neuroscience↗

bioRxiv2022

Large-scale systematic feasibility study on the pan-cancer predictability of multi-omic biomarkers from whole slide images with deep learning

We assessed the pan-cancer predictability of multi-omic biomarkers from haematoxylin and eosin (H&E)-stained whole slide images (WSI) using deep learning (DL) throughout a systematic study. A total of 13,443 DL models predicting 4,481 multi-omic biomarkers across 32 cancer types were trained and validated. The investigated biomarkers included a broad range of genetic, transcriptomic, proteomic, and metabolic alterations, as well as established markers relevant for prognosis, molecular subtypes and clinical outcomes. Overall, we found that DL can predict multi-omic biomarkers directly from routine histology images across solid cancer types, with 50% of the models performing at an area under the curve (AUC) of more than 0.633 (with 25% of the models having an AUC larger than 0.711). A wide range of biomarkers were detectable from routine histology images across all investigated cancer types, with a mean AUC of at least 0.62 in almost all malignancies. Strikingly, we observed that biomarker predictability was mostly consistent and not dependent on sample size and class ratio, suggesting a degree of true predictability inherent in histomorphology. Together, the results of our study show the potential of DL to predict a multitude of biomarkers across the omics spectrum using only routine slides. This paves the way for accelerating diagnosis and developing more precise treatments for cancer patients.

cancer biology↗

bioRxiv2022

Evaluation of a predictive method for the H&E-based molecular profiling of breast cancer with deep learning

We present a public validation of PANProfiler (ER, PR, HER2), an in-vitro medical device (IVD) that predicts the qualitative status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) by analysing the hematoxylin and eosin (H&E)-stained tissue scan. In public validation on 648 (ER), 648 (PR) and 560 (HER2) unseen cases with known biomarker status, the device achieves an accuracy of 87% (ER), 83% (PR) and 87% (HER2). The validation offers early evidence of the ability to predict clinically relevant breast biomarkers from an H&E slide in a relevant clinical setting.

cancer biology↗

bioRxiv2020

Diversification, disparification, and hybridization in the desert shrubs Encelia

O_LIThere are multiple hypotheses for the spectacular plant diversity found in deserts. We explore how different factors, including the roles of ecological opportunity and selection, promote diversification and disparification in Encelia, a lineage of woody plants in the deserts of the Americas. C_LIO_LIUsing a nearly complete species-level phylogeny along with a broad set of phenotypic traits, we estimate divergence times and diversification rates, identify instances of hybridization, quantify trait disparity, and assess phenotypic divergence across environmental gradients. C_LIO_LIWe show that Encelia originated and diversified recently (mid-Pleistocene) and rapidly, with rates comparable to notable adaptive radiations in plants. Encelia probably originated in the hot deserts of North America, with subsequent diversification across steep environmental gradients. We uncover multiple instances of gene flow between species. The radiation of Encelia is characterized by fast rates of phenotypic evolution, trait lability, and extreme disparity across environments and between species-pairs with overlapping geographic ranges. C_LIO_LIEncelia exemplifies how interspecific gene flow in combination with high trait lability can enable exceptionally fast diversification and disparification across steep environmental gradients. C_LI

evolutionary biology↗

bioRxiv2020

Natural selection maintains species despite widespread hybridization in the desert shrub Encelia

Natural selection is an important driver of genetic and phenotypic differentiation between species. A powerful way to test the role of natural selection in the formation and maintenance of species is to study species complexes in which potential gene flow is high but realized gene flow is low. For a recent radiation of New World desert shrubs (Encelia: Asteraceae), we use fine-scale geographic sampling and population genomics to determine patterns of gene flow across two hybrid zones formed between two independent pairs of species with parapatric distributions. After finding evidence for extremely strong selection at both hybrid zones, we use a combination of field experiments, high-resolution imaging, and physiological measurements to determine the ecological basis for selection at one of the hybrid zones. Our results identify multiple ecological mechanisms of selection (drought, salinity, herbivory, and burial) that together are sufficient to maintain species boundaries despite high rates of hybridization. Given that multiple pairs of species hybridize at ecologically divergent parapatric boundaries in the adaptive radiation of Encelia, such mechanisms may maintain species boundaries throughout this group. SIGNIFICANCE STATEMENTIn Baja California, the deserts meet the coastal dunes in a narrow transition visible even from satellite images. We study two species pairs of desert shrubs (Encelia) that occur across this transition. Although these species can interbreed, they remain distinct. Using a combination of genetics, field experiments, 3D-imaging, and physiological measurements, we show that natural selection counteracts the homogenizing effects of gene exchange. The different habitats of these species create multiple mechanisms of selection - drought, salinity, herbivory, and burial, which together maintain these species in their native habitats and their hybrids in intermediate habitats. This study illustrates how environmental factors influence traits and fitness and how this in turn maintain species, highlighting the importance of natural selection in speciation.

evolutionary biology↗

bioRxiv2019

A tale of winglets: evolution of flight morphology in stick insects

The evolutionary transition between winglessness and a full-winged morphology requires selective advantage for intermediate forms. Conversely, repeated secondary wing reductions among the pterygotes indicates relaxation of such selection. However, evolutionary trajectories of such transitions are not well characterized. The stick insects (Phasmatodea) exhibit diverse wing sizes at both interspecific and intersexual levels, and thus provide a system for examining how selection on flight capability, along with other selective forces, drives the evolution of flight-related morphology. Here, we examine variation in relevant morphology for stick insects using data from 1100+ individuals representing 765 species. Although wing size varies along a continuous spectrum, taxa with either long or miniaturized wings are the most common, whereas those with intermediate-sized wings are relatively rare. In a morphological space defined by wing and body size, the aerodynamically relevant parameter termed wing loading (the average pressure exerted on the air by the wings) varies according to sex-specific scaling laws; volant but also flightless forms are the most common outcomes in both sexes. Using phylogenetically-informed analyses, we show that relative wing size and body size are inversely correlated in long-winged insects regardless of sexual differences in morphology and ecology. These results demonstrate the diversity of flight-related morphology in stick insects, and also provide a general framework for addressing evolutionary coupling between wing and body dimensions. We also find indirect evidence for a fitness valley associated with intermediate-sized wings, suggesting relatively rapid evolutionary transitions between wingless and volant forms.

evolutionary biology↗

bioRxiv2019

Risk of complications among diabetics self-reporting oral health status in Canada: A population-based cohort study

BackgroundPeriodontitis has persistently been associated with diabetes and poor health outcomes. While clear associations have been identified for the diabetes-oral health link, less is known about the implications of poor oral health on incident complications of diabetes. This study sought to investigate the risk of diabetes complications associated with self-reported \"poor to fair\" and \"good to excellent\" oral health status among diabetics living in Ontario, Canada.\n\nMethodsThis cohort study was undertaken of diabetics from the Canadian Community Health Survey (2003 and 2007-8). Self-reported oral health was linked to electronic health records at the Institute for Clinical Evaluative Sciences. Participants under the age of 40, missing self-reported oral health and those who could not be identified in linked databases were excluded (N=5,183). A series of Cox Proportional hazard models were constructed to determine the risk of diabetes complications. Participants who did not experience any diabetes complication were censored at time of death or at the study termination date (March 31, 2016). Models were adjusted for age and sex, followed by social characteristics and behavioural factors.\n\nResultsDiabetes complications differed by self-reported oral health. For those reporting \"poor to fair\" oral health, the hazard of a diabetes complication was 30% greater (HR 1.29 95%CI 1.03, 1.61) than those reporting \"good to excellent\" oral health.\n\nConclusionsOur findings indicate that oral health status is associated with increased risk for complications among diabetics, after adjusting for a wide range of confounders. Examining oral health and the risk for diabetes complications from a broader perspective including socio-behavioural and biological pathways is principal for informing policies and interventions that aim to mitigate the burdens of poor systemic health.

epidemiology↗

bioRxiv2019

Memory-driven computing accelerates genomic data processing

Next generation sequencing (NGS) is the driving force behind precision medicine and is revolutionizing most, if not all, areas of the life sciences. Particularly when targeting the major common diseases, an exponential growth of NGS data is foreseen for the next decades. This enormous increase of NGS data and the need to process the data quickly for real-world applications requires to rethink our current compute infrastructures. Here we provide evidence that memory-driven computing (MDC), a novel memory-centric hardware architecture, is an attractive alternative to current processor-centric compute infrastructures. To illustrate how MDC can change NGS data handling, we used RNA-seq assembly and pseudoalignment followed by quantification as two first examples. Adapting transcriptome assembly pipelines for MDC reduced compute time by 5.9-fold for the first step (SAMtools). Even more impressive, pseudoalignment by near-optimal probabilistic RNA-seq quantification (kallisto) was accelerated by more than two orders of magnitude with identical accuracy and indicated 66% reduced energy consumption. One billion RNA-seq reads were processed in just 92 seconds. Clearly, MDC simultaneously reduces data processing time and energy consumption. Together with the MDC-inherent solutions for local data privacy, a new compute model can be projected pushing large scale NGS data processing and primary data analytics closer to the edge by directly combining high-end sequencers with local MDC, thereby also reducing movement of large raw data to central cloud storage. We further envision that other data-rich areas will similarly benefit from this new memory-centric compute architecture.

bioinformatics↗