Biology subjects

Viswanathan, A.

Publications and source records attributed to Viswanathan, A..

16 recordsLinked to original sources

bioRxiv2026

Paired Tumor Biopsies Reveal Spatiotemporal Myeloid Remodeling After Local Chemotherapy in Glioblastoma

BackgroundStandard-of-care chemotherapy for glioblastoma induces inflammation that may contribute to disease recurrence. Although recurrent tumors are enriched with myeloid cells, the early cellular response to chemotherapy and the mechanisms that initiate this inflammatory remodeling remain poorly understood. In particular, it is unknown how neoplastic and tumor-associated myeloid populations respond during the immediate post-treatment period, and whether tumor-associated myeloid cells directly experience chemotherapy-induced genotoxic stress that contributes to inflammatory state transitions. MethodsWe performed sequencing-based analysis of neoplastic and immune populations following topotecan exposure using multiple complementary model systems and time points. We first analyzed MRI-localized, paired pre- and post-treatment biopsies from a first-in-human trial of 28-day convection enhanced delivery (CED) of topotecan (n=5) using cell-type-deconvolved bulk-RNA-sequencing and immunofluorescence. We then treated syngeneic murine gliomas using an in vivo model of CED-topotecan and measured acute 3-day and 7-day treatment responses by single cell RNA-sequencing. We additionally conducted sequencing analysis of patient-derived slice cultures and in vitro human microglial and glioma cell lines following 24-hour topotecan treatment. ResultsIn paired human biopsies, CED-topotecan induced spatially restricted transcriptional remodeling within the infusion zone, characterized by suppression of proliferative tumor programs and enrichment of inflammatory, interferon, hypoxia, and mesenchymal signatures. Cell-type deconvolution and immunofluorescence linked this response to myeloid remodeling, including enrichment of monocyte-derived tumor-associated macrophage states, increased MARCO-positive myeloid populations, and pH2AX-positive genotoxic stress within Iba1-positive myeloid cells. In the murine CED model, topotecan prolonged survival and reduced tumor cellularity, while also inducing inflammatory and DNA-damage programs in tumor-associated macrophages that evolved by 7-days toward hypoxia, angiogenesis, TGF-{beta} signaling, and mesenchymal/tissue-remodeling programs. Human slice culture and in vitro microglial systems confirmed stress-coupled inflammatory and DNA-damage responses in human myeloid cells. ConclusionsChemotherapy exposure induces a spatially structured inflammatory myeloid response characterized by early genotoxic stress and inflammatory activation, with later emergence of mesenchymal and tissue-remodeling macrophage programs. Across model systems, our analysis supports a model in which chemotherapy-associated damage in both tumor and myeloid cells contributes to an evolving inflammatory microenvironment after treatment.

neuroscience↗

bioRxiv2026

Overweight status drives early tumor microenvironment reprogramming in pancreatic ductal adenocarcinoma: a cell-type-resolved Bayesian hierarchical modeling and interactome analysis

Obesity significantly increases the risk of pancreatic ductal adenocarcinoma, yet a comprehensive understanding of obesity-driven tumor microenvironment remodeling remains incomplete. We developed a cell-type-resolved transcriptomic model using bulk RNA sequencing data from the Clinical Proteomic Tumor Analysis Consortium cohort (n=140) stratified by body mass index. A custom functional gene signature database covering 65 immune and stromal cell types was manually constructed and validated through large-language model-assisted review. Cell-type-specific expression profiles were derived using BayesPrism deconvolution with matched single-cell RNA sequencing references, enabling high-resolution quantification of signature activity within each cell type. Body mass index-associated signatures were identified using a machine learning framework. Bulk pathway analysis showed deterioration of extracellular matrix homeostasis and primary immunodeficiency pathways with rising body mass index. Bayesian hierarchical modeling revealed cell-type-specific, non-linear dynamics: stromal populations in overweight individuals underwent coordinated extracellular matrix remodeling and inflammatory signaling that stabilized rather than intensified in obesity, while CD8-positive T cells showed dose-dependent activation progressing to chronic exhaustion. Spatial analysis showed that stromal-trapped CD8-positive T cells were positioned progressively closer to the cytokeratin-positive tumor boundary with rising body mass index. These findings establish overweight status as a critical tipping point in tumor microenvironment reprogramming, suggesting that early metabolic interventions may prevent irreversible microenvironmental deterioration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/721695v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1c56c76org.highwire.dtl.DTLVardef@53b7e2org.highwire.dtl.DTLVardef@4d7b86org.highwire.dtl.DTLVardef@e8d403_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Electrophysiologically Targeted Biopsies Reveal the Transcriptional Landscape of Focal Epilepsy

Up to 30% of patients with epilepsy have intractable seizures, yet the mechanisms of focal ictogenesis remain unclear. Tissue involvement in ictal regions is heterogeneous, with different regions playing distinct roles in ictogenesis, seizure propagation, and resistance to spread. These roles are reflected in electrophysiologic differences between the seizure focus and the ictal penumbra, where evidence of synaptic spread is present but excitatory firing is constrained by largely intact inhibition. Investigation of the disruption of the normal interplay between excitatory and inhibitory activity, thought to underlie ictogenesis across a range of epilepsy etiologies, is limited by network complexity and cellular heterogeneity in human tissue samples. In this study, we relate cellular and molecular alterations to excitatory-inhibitory disruption in network dynamics defined by electrophysiologic features. This work may aid in the identification of clinically relevant tissue biomarkers and support novel preclinical therapeutic approaches for treatment-resistant focal epilepsy disorders. We developed a novel intracranial EEG guided, MRI-localized approach to sample paired biopsies from 11 patients with drug-resistant focal epilepsy with diverse etiologies, which were then studied using single-nucleus RNA sequencing (snRNAseq) and immunohistochemistry (IHC). EEG recorded from stereotactically implanted depth arrays (sEEG) was used to identify regions of epileptic involvement, based on findings from prior simultaneous clinical and microelectrode recordings. This approach addresses the intrinsic heterogeneity due to etiology and cortical architecture through paired, within-patient comparisons. We identified distinct cell-type specific transcriptional signatures that differentiate cellular populations in the seizure focus and ictal penumbra in intractable focal epilepsies. Our findings provide a link between tissue composition and gene expression that correlate with electrographic features in a heterogeneous seizure landscape. Our findings support common pathways of seizure generation and spread that are conserved across disease etiologies. Relative depletion of interneuron populations in the seizure focus supports the hypothesis of disrupted inhibition as a driver of epileptiform activity in the seizure focus. The enrichment of plasticity-associated gene signatures in the penumbra suggests a complex interaction of these regions with the seizure focus, as well as the role of the penumbra in enabling or limiting seizure expansion. This study provides a novel methodology for tissue sampling in epilepsy and uncovers biologically relevant tissue signatures that provide grounds for future work in targeting cellular and molecular alterations present in focal epilepsies.

neuroscience↗

bioRxiv2025

Convection-enhanced delivery of dexamethasone in glioma suppresses myeloid inflammation while avoiding systemic toxicities

Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration of dexamethasone via convection-enhanced delivery (CED) to maximize intratumoral anti-inflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In two glioma mouse models, continuous intraparenchymal infusion of dexamethasone was well tolerated with no adverse effects. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. Single-nucleus RNA sequencing (snRNA-seq) and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell (iPSC)-derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. This inflammatory suppression was recapitulated in both immortalized microglial (HMC3) and macrophage (THP1) cell lines. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves control of inflammation without the systemic adverse effects associated with standard systemic dexamethasone therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.

cancer biology↗

bioRxiv2025

What's next for Indian Ornithology? 101 key research questions

India has a rich history of ornithology, and bird research in this field has expanded considerably in recent decades, spurred by a growing number of birdwatchers and ornithologists. Despite this progress, critical gaps remain. This paper highlights key areas where further research is needed and identifies pressing questions that will shape Indian ornithology in the coming years. Drawing from diverse inputs, we present a curated list of 101 research questions spanning across the various disciplines in ornithology - Natural History, Physiology and Disease Ecology, Behaviour, Population and Community Ecology, Habitat Ecology, Macroecology and Biogeography, Population Genetics and Evolution, Applied/Economic Ornithology and Conservation. The list was compiled through a multi-stage process, starting with a public open call for questions, followed by review and curation by a smaller panel of subject specialists. Each question was independently scored by a panel of experts based on three criteria: generality, novelty, and relevance. To account for variation in scoring styles, scores were normalised using Z-scores. The top 101 research questions were then selected based on these standardised scores. Each question is accompanied by an annotation that describes the significance of the question, and highlights opportunities to address it. While our list of research questions highlights significant research priorities, it is not intended to be exhaustive. Rather, it reflects the perspectives of those involved in its curation, who deemed these questions particularly relevant and impactful towards advancing Indian ornithology. We expect these questions to spark new project ideas among students, researchers, and citizen scientists, while guiding funders, managers, and policymakers toward priority research areas.

ecology↗

bioRxiv2025

Uttroside B, a US FDA-designated Orphan drug, mitigates thedevelopment of hepatocellular carcinoma and its pulmonary metastasis via EGFR/ERK-mediated inhibition of SREBP-1 and STAT-3

Hepatocellular carcinoma (HCC) is a highly aggressive tumor with rapid propensity for extrahepatic metastasis, which critically limits the long-term clinical benefits of conventional chemotherapeutics and decreases the overall survival rate of patients. Our previous findings on the exceptional anti-HCC potential and pharmacological safety of uttroside B (Utt-B) have gained multiple international patents and the compound has been designated as an Orphan Drug against HCC by the US FDA. The current study substantiates the pharmacodynamics of Utt-B and is the first report to date on the anti-metastatic potential of the compound against HCC. Herein, we demonstrate the role of EGFR/ERK signaling axis and their downstream targets SREBP-1 and STAT-3, the key regulators of HCC development and the pulmonary metastasis, respectively, in orchestrating the anti-HCC and anti-metastatic potential of Utt-B. This is evidenced by the abrogation of the cytotoxic and pro-apoptotic effects of Utt-B upon pharmacological inhibition of this signaling axis. Orthotopic xenograft studies validated that Utt-B treatment restricted the development of tumors via the down-regulation of EGFR/ERK axis. Notably, Utt-B diminishes the migratory and invasive properties of liver cancer cells in vitro and impedes the pulmonary metastasis of HCC, in vivo. Taken together, the current findings attest to the exceptional therapeutic potential of Utt-B against primary and metastatic HCC and highlight its potential as a candidate drug to be evaluated in the clinics for the benefit of HCC patients having limited prognosis and therapeutic options.

cancer biology↗

bioRxiv2025

Subtle Cellular Phenotypes Inform Pathological and Benign Genetic Mutants in the Iduronidase-2 Sulfatase Gene

As with most enzyme-storage disorders, DNA testing at an early age is critical for identifying genetic variants and their impact on disease burden. Still, most variants in genes such as Iduronate-2-sulfatase, IDS, are Variants of Uncertain Significance (VUS). In patients presenting with Hunter Syndrome, clinical testing for IDS enzyme activity has been the mainstay to determine whether a variant is likely damaging. However, these enzyme assays are unable to predict disease severity or neuronal toxicity and may be missing many aspects of IDS pathology. In this study, we have developed an image-based assay using genome-engineered cells with IDS mutations to identify if a specific mutation causes lysosomal and membrane disruptions that characterize the disease. Specifically, we generate twelve mutant cell lines and document both the biochemical changes in IDS activity and the reproducible phenotypic differences therein. Next, we examine two patient-derived cell lines and find the same phenotypic differences in these lines compared to parental controls. The phenotypic changes are measured on a specific scale, which we term the PathScoreLC. To determine whether the observed changes are specific to IDS, we reintroduce a recombinant version of the IDS enzyme (rhIDS) to rescue both the biochemical and phenotypic changes of these cells. Interestingly, even after 120 hours, rescue is present, but not all the cells return to normal, which may also reflect the pathological state. Finally, we examine the gene expression differences and find that recombinant enzyme is not sufficient to induce transcriptional changes in the mutant lines at the time points studied. Overall, these cell-based lysosomal and membrane phenotypes may be key to quickly and accurately profiling clinical variants in the IDS gene.

cell biology↗

bioRxiv2024

State of India's Birds 2023: A framework to leverage semi-structured citizen science for bird conservation

Birds and their habitats are threatened with extinction around the world. Regional assessments of the State of Birds are a vital means to prioritize data-driven conservation action by informing national and global policy. Such evaluations have traditionally relied on data derived from extensive, long-term, systematic surveys that require significant resources, limiting their feasibility to a few regions in the world. In the absence of such structured long-term datasets, semi-structured datasets have recently emerged as a promising alternative in other regions around the world. Semi-structured data are generated and uploaded by birdwatchers to citizen science platforms like eBird. Such data contain inherent biases because birdwatchers are not required to adhere to a fixed protocol. An evaluation of the status of birds from semi-structured data is therefore a difficult task that requires careful curation of data and the use of robust statistical methods to reduce errors and biases. In this paper, we present a methodology that was developed for this purpose, and was applied to produce the comprehensive State of Indias Birds (SoIB) 2023 report. SoIB 2023 assessed the status of 942 bird species in India by evaluating each species based on three metrics: 1) long-term change: change in abundance between the year 2022 and the year-interval pre-2000; 2) current annual trend: mean annual change in abundance from 2015 to 2022; and 3) distribution range size. We found evidence that 204 species have declined in the long term, and 142 species are currently declining. We present and discuss important insights about Indias birds that can guide research and conservation action in the region. We hope that the detailed methodology described here can act as a blueprint to produce State of Birds assessments from semi-structured citizen science datasets and springboard conservation action in many other regions where structured data is lacking but strong communities of birders exist. Open Research StatementThe primary data are already publicly available on eBird (Sullivan et al. 2014), and other data are already published in a GitHub repository (stateofindiasbirds 2024).

ecology↗

bioRxiv2024

Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition

Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via RiboTag, morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

neuroscience↗

bioRxiv2023

Birdwatchers' resilience to perturbation in India buffers citizen science from pandemic-induced biases

Most systematic projects to monitor bird populations, like breeding bird surveys, require large and coordinated volunteer networks that are lacking in many parts of the world such as the Global South. Data from less systematic citizen science (CS) programmes offer an alternative to data from systematic initiatives in these regions, but the semi-structured nature of such data also presents several challenges. The utility of semi-structured CS data to monitor bird species abundance is contingent on how, where, and how comparably birdwatchers watch birds, year on year. Trends inferred directly from the data can be confounded during years when birdwatchers may behave differently, such as during the COVID-19 pandemic. We wanted to ascertain how the data uploaded from India to one such CS platform, eBird, was impacted by this deadliest global pandemic of the 21st century. To understand whether eBird data from the pandemic years in India is useful and comparable to data from adjacent years, we explored several quantitative and qualitative aspects of the data (such as birdwatcher behaviour) at multiple spatial and temporal scales. We found no negative impact of the pandemic on data generation. Data characteristics changed largely only during the peak pandemic months characterised by high fatality rates and strict lockdowns, possibly due to decreased human mobility and social interaction. It remained similar to the adjacent years during the rest of this restrictive period, thereby reducing the impact of the aberrant peak months on any annual inference. Moreover, impacts on data characteristics varied widely across states in India, resulting in no strong consistent trend at the national level--unlike results from elsewhere in the world. Our findings show that birdwatchers in India as contributors to CS were resilient to disturbance, and that the effects of the pandemic on birdwatching effort and birdwatcher behaviour are highly scale- and context-dependent. In summary, eBird data in India from the pandemic years remains useful and interpretable for most large-scale applications, such as abundance trend estimation, but will benefit from preliminary data quality checks when utilised at a fine scale. Lay summaryO_LICitizen science platforms like eBird comprise vast repositories of data generated by casual birdwatching. C_LIO_LISuch data are vital to understanding bird population trends, but their usability reduces when birdwatchers change where, when and how much they watch birds from year to year. C_LIO_LIGiven the impact of the COVID-19 pandemic on our everyday lives, we wondered whether it also impacted the way people reported birds, thereby reducing the usability of the data in trend analyses. C_LIO_LIWe analysed data uploaded to eBird from India, and found that the impacts of the pandemic on this data were largely restricted to April and May in 2020, and to a lesser C_LIO_LIextent in 2021. During these months that coincided with the greatest health impacts, birdwatchers avoided travel, groups and public spaces. C_LIO_LIBirdwatchers were resilient; they bounced back soon after these difficult periods, and started birding like they had done before the pandemic. C_LIO_LIBecause the impact was limited to short periods and few regions, we conclude that eBird data from India during the pandemic still remains useful for analyses of bird abundance trends. C_LI

ecology↗

bioRxiv2023

Host-pathogen-vector continuum in a changing landscape: Drivers of Bartonella prevalence and evidence of historic spillover in a tropical multi-host community

Small mammals and their ectoparasites present a unique system to investigate the eco-epidemiology of multi-host vector-borne pathogens and identify specific bacterial spillover determinants. We applied ecological and evolutionary analyses in a rainforest-human-use mosaic to investigate Bartonella spp. across small mammal and ectoparasite communities. We observed substantial overlap among small mammal communities in different habitat types, predominantly driven by habitat generalists. Most ectoparasites were generalists, infecting multiple hosts. We observed high Bartonella prevalence at both study sites -a forest-plantation mosaic (47.4%) and a protected area (28.8%). Seven of the ten ectoparasite species sampled were also positive for Bartonella, following prevalence trends in their hosts. A generalised linear model revealed an independent association between aggregated ectoparasite load in hosts and Bartonella prevalence, implicating ectoparasites in transmission. Bartonella lineages from small mammals were host-specific, while ectoparasites carried Bartonella associated with other small mammal hosts, indicating the potential for cross-species transmission. Phylogenetic ancestral trait reconstruction of Bartonella haplotypes suggest historic spillover events in the small mammal community, validating the potential for contemporary spillover events. These results highlight the necessity to disentangle the complex relationship between hosts, ectoparasites, and pathogens to understand the zoonotic implications of undetected spillover events in such multi-host communities.

ecology↗

bioRxiv2021

Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in PSC.

ObjectiveConflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: Define complex interactions between resident microbes and their association in PSC patients by studying antibiotic-treated specific pathogen-free (SPF) and germ-free (GF) multi-drug-resistant 2 deficient (mdr2-/-) mice. DesignWe measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, fecal 16s rRNA gene profiling, and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients. ResultsGF mdr2-/- mice had exaggerated hepatic inflammation and fibrosis with 100% mortality by 8 weeks; early SPF autologous stool transplantation rescued liver-related mortality. Broad-spectrum antibiotics and vancomycin alone accelerated disease in weanling SPF mdr2-/- mice, indicating that vancomycin-sensitive resident microbiota protect against hepatobiliary disease. Vancomycin treatment selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased cytolysin-expressing E. faecalis and E. coli liver translocation; colonization of gnotobiotic mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated liver inflammation and mortality. Lachnospiraceae colonization of antibiotic pre-treated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, while Lachnospiraceae-produced SCFA decreased fibrosis. Fecal E. faecalis/ Enterobacteriaceae was positively and Lachnospiraceae was negatively associated with PSC patients clinical severity Mayo risk scores. ConclusionsWe identified specific functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical outcomes. These insights may guide personalized targeted therapeutic interventions in PSC patients.

microbiology↗

bioRxiv2021

Genomic evidence for inbreeding depression and purging of deleterious genetic variation in Indian tigers

Increasing habitat fragmentation leads to wild populations becoming small, isolated, and threatened by inbreeding depression. However, small populations may be able to purge recessive deleterious alleles as they become expressed in homozygotes, thus reducing inbreeding depression and increasing population viability. We used whole genomes sequencing from 57 tigers to estimate individual inbreeding and mutation loads in a small-isolated, and two large-connected populations in India. As expected, the small-isolated population had substantially higher average genomic inbreeding (FROH=0.57) than the large-connected (FROH=0.35 and FROH=0.46) populations. The small-isolated population had the lowest loss-of-function mutation load, likely due to purging of highly deleterious recessive mutations. The large populations had lower missense mutation loads than the small-isolated population, but were not identical, possibly due to different demographic histories. While the number of the loss-of-function alleles in the small-isolated population was lower, these alleles were at high frequencies and homozygosity than in the large populations. Together, our data and analyses provide evidence of (a) high mutation load; (b) purging and (c) the highest predicted inbreeding depression, despite purging, in the small-isolated population. Frequency distributions of damaging and neutral alleles uncover genomic evidence that purifying selection has removed part of the mutation load across Indian tiger populations. These results provide genomic evidence for purifying selection in both small and large populations, but also suggest that the remaining deleterious alleles may have inbreeding associated fitness costs. We suggest that genetic rescue from sources selected based on genome-wide differentiation should offset any possible impacts of inbreeding depression. Significance statementHabitat fragmentation is sequestering species into small and isolated populations with high chances of extinction. But are small and isolated populations at risk of extinction from inbreeding depression, or does inbreeding and purging of deleterious alleles reduce such threat? Using whole genomes from several wild Indian tiger populations, we provide evidence supporting purging of highly deleterious variants in a small isolated population. However, our analyses also indicate that the remaining highly deleterious alleles are at high frequencies, suggesting continued inbreeding depression despite some successful purging. We discuss the implications of our results for conservation, including possible genomics-informed genetic rescue strategies.

evolutionary biology↗

bioRxiv2019

Unsupervised Clustering Reveals Spatially Varying Single Neuronal Firing Patterns in the Subthalamic Nucleus of Patients with Parkinson's Disease

IntroductionSubthalamic nucleus (STN) is an effective target for deep brain stimulation (DBS) to reduce the motor symptoms of Parkinsons disease (PD). It is important to identify firing patterns within the structure for a better understanding of the electro-pathophysiology of the disease. Using recently established metrics, our study aims to autonomously identify the discharge patterns of individual cells and examine their spatial distribution within the STN. MethodsWe recorded single unit activity (SUA) from 12 awake PD patients undergoing a standard clinical DBS surgery. Three extracted features from raw SUA (local variation, bursting index and prominence of peak) were used with k-means clustering to achieve the aforementioned unsupervised grouping of firing patterns. Results279 neurons were isolated and four distinct firing patterns were identified across patients: tonic (11%), irregular (55%), periodic (9%) and non-periodic bursts (25%). The mean firing rates for irregular discharges were significantly lower (p<0.05) than the rest. Tonic firings were significantly ventral (p<0.05) while periodic (p<0.05) and non-periodic (p<0.01) bursts were dorsal. The percentage of periodically bursting neurons in dorsal region and entire STN were significantly correlated with off state UPDRS tremor scores (r=0.51, p=0.04) and improvement in bradykinesia and rigidity (r=0.57, p=0.02) respectively. ConclusionStrengthening the application of unsupervised clustering for firing patterns of individual cells, this study shows a unique spatial affinity of tonic activity towards the ventral and bursting activity towards the dorsal region of STN in PD patients. This spatial preference, together with the correlation of clinical scores, can provide a clue towards understanding Parkinsonian symptom generation.

neuroscience↗

bioRxiv2018

Spatial signature of white matter hyperintensities in stroke patients

PurposeWhite matter hyperintensity (WMH) is a common phenotype across a variety of neurological diseases, particularly prevalent in stroke patients; however, vascular territory dependent variation in WMH burden has not yet been identified. Here, we sought to investigate the spatial specificity of WMH burden in patients with acute ischemic stroke (AIS). Materials and MethodsWe created a novel age-appropriate high-resolution brain template and anatomically delineated the cerebral vascular territories. We used WMH masks derived from the clinical T2 FLAIR MRI scans and spatial normalization of the template to discriminate between WMH volume within each subjects anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA) territories. Linear regression modeling including age, sex, common vascular risk factors, and TOAST stroke subtypes was used to assess for spatial specificity of WMH volume (WMHv) in a cohort of 882 AIS patients. ResultsMean age of this cohort was 65.23{+/-}14.79 years, 61.7% were male, 63.6% were hypertensive, 35.8% never smoked. Mean WMHv was 11.58c +/-13.49 cc. There were significant differences in territory-specific, relative to global, WMH burden. In contrast to PCA territory, age (0.018{+/-}0.002, p<0.001) and small-vessel stroke subtype (0.212{+/-}0.098, p<0.001) were associated with relative increase of WMH burden within the anterior (ACA and MCA) territories, whereas male sex (-0.275{+/-}0.067, p<0.001) was associated with a relative decrease in WMHv. ConclusionsOur data establish the spatial specificity of WMH distribution in relation to vascular territory and risk factor exposure in AIS patients and offer new insights into the underlying pathology.

neuroscience↗

bioRxiv2017

Patchiness and scale-free correlations: characterising criticality in ecosystems.

I.O_LIIn diverse ecosystems, organisms cluster together in such a manner that the frequency distribution of cluster sizes is a power-law function. Spatially-explicit models of ecosystems suggest that loss of such power-law clustering may indicate loss of ecosystem resilience. Hence, it is hypothesised that spatial clustering properties in ecosystems - which can be readily measured using remotely-sensed high-resolution data - can help infer proximity to ecosystem thresholds and may even provide early warning signals of ecosystem collapse. Recent empirical and simulation studies, however, dont find consistent relationships between spatial clustering and ecosystem resilience. Furthermore, how spatial clustering metrics relate to other well-known early warning signals of ecosystems collapse, specifically the phenomenon of critical slowing down (CSD), remains unclear. C_LIO_LIWe synthesize the literature on cluster sizes in empirical and theoretical studies that show how local interactions (especially, positive feedback) among organisms can cause power-law clustering. In addition, we analyse a minimal spatial model of ecosystem transitions that allows us to disentangle the role of environmental stressor and positive feedback on spatial patterns and ecosystem resilience. C_LIO_LIOur literature synthesis reveals that empirically observed power-law clustering in ecosystems is parsimoniously explained by local positive feedback. Our synthesis together with model analysis demonstrates that, depending on the strength of positive feedback, emergence of power-law clustering can occur at any distance from the critical threshold of ecosystem collapse. In fact, we find that for systems with strong positive feedbacks, which are most likely to exhibit abrupt transitions, loss of power-law clustering may not even occur prior to ecosystem thresholds. We also argue that cluster-size distributions are unrelated to the phenomenon of CSD. C_LIO_LIWe demonstrate that, due to CSD, a power-law feature does occur near critical thresholds but in a different quantity; specifically, a power-law decay of spatial correlations of ecosystem state. C_LIO_LIWe conclude that loss of power-law clustering cannot be used as a reliable indicator of ecosystem resilience. Our synthesis and model analyses highlights links between local positive feedback, emergent spatial properties and how they may be used to interpret ecosystem resilience. C_LI

ecology↗