Biology subjects

Nair, A.

Publications and source records attributed to Nair, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2021

Single-cell foundations of live social gaze interaction in the prefrontal cortex and amygdala

Social gaze interaction powerfully shapes interpersonal communication in humans and other primates. However, little is known about the neural underpinnings of these social behavioral exchanges. Here, we studied neural responses associated with naturalistic, face-to-face, social gaze interactions between pairs of macaques. We examined spiking activity in a large number of neurons spanning four different brain regions involved in social behaviors - the amygdala, orbitofrontal cortex, anterior cingulate cortex, and dorsomedial prefrontal cortex. We observed widespread single-cell representations of social gaze interaction functionalities in these brain regions - social discriminability, social gaze monitoring, and mutual eye contact selectivity. Many of these neurons discriminated looking at social versus non-social stimuli with rich temporal heterogeneity, or parametrically tracked the gaze positions of oneself or the conspecific. Furthermore, many neurons displayed selectivity for mutual eye contact as a function of the initiator or follower of mutual gaze events. Crucially, a significant proportion of neurons coded for more than one of these three signatures of social gaze interaction, supporting the recruitment of partially overlapping neuronal ensembles. Our findings emphasize integrated contributions of the amygdala and prefrontal circuits within the social interaction networks in processing real-life social interactions.

neuroscience↗

bioRxiv2021

Abnormal function in dentate nuclei precedes the onset of psychosis: a resting-state fMRI study in high-risk individuals

ObjectiveThe cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into three functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN precede the onset of psychosis in individuals at risk of developing schizophrenia. MethodsWe used the MRI dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N=144), with longitudinal follow-up to determine which subjects developed a psychotic episode within one year of their fMRI scan (converters N=23). Analysis used the three functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis. ResultsRsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the three functional territories of the DN that were evaluated. ConclusionsWe show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.

neuroscience↗

bioRxiv2021

A functional logic for neurotransmitter co-release in the cholinergic forebrain pathway

The forebrain cholinergic system has recently been shown to co-release both acetylcholine and GABA. We have discovered that such co-release by cholinergic inputs to the claustrum differentially affects neurons that project to cortical versus subcortical targets. The resulting changes in neuronal gain toggles network efficiency and discriminability of output between two different projection subcircuits. Our results provide a potential logic for neurotransmitter co-release in cholinergic systems.

neuroscience↗

bioRxiv2021

Functional modules within a distributed neural network control feeding in a model medusa

Jellyfish are free-swimming, radially symmetric organisms with complex behaviors that arise from coordinated interactions between distinct, autonomously functioning body parts. This behavioral complexity evolved without a corresponding cephalization of the nervous system. The systems-level neural mechanisms through which such decentralized control is achieved remain unclear. Here, we address this question using the jellyfish, Clytia, and present it as a new neuroscience model. We describe a coordinated, asymmetric behavior in which food is passed from the umbrellar margin to the central mouth via directed margin folding. Using newly developed transgenic jellyfish lines to ablate or image specific neuronal subpopulations, we find, unexpectedly, that margin folding reflects the local activation of neural subnetworks that tile the umbrella. Modeling suggests that this structured ensemble activity emerges from sparse, local connectivity rules. These findings reveal how an organismal behavior can emerge from local interactions between functional modules in the absence of a central brain.

neuroscience↗

bioRxiv2021

Timing of selective basal ganglia white matter loss in Huntington's disease

ObjectivesTo investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (WM) loss begins in premanifest Huntingtons disease (preHD), and which striatal and thalamic sub-region WM tracts are most vulnerable. MethodsWe performed fixel-based analysis, which allows resolution of crossing WM fibres at the voxel level, on diffusion tractography derived WM tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. ResultsWe found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntingtons disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. ConclusionsOur findings suggest that the initiation of disease modifying therapies 25 years before onset could protect these important brain networks from undergoing neurodegeneration and highlight selectively vulnerable sub-regions of the striatum and thalamus that may be important targets for future therapies.

neuroscience↗

bioRxiv2021

Spatio-temporal analysis identifies hotspots of marine mammal strandings along the Indian coastline: implications for developing a National Marine Mammal Stranding Response and Management policy

Marine mammal strandings provide vital information on their life histories, population health and status of marine ecosystems. Opportunistic reporting of strandings serve as a potent low-cost tool for conservation monitoring of these highly mobile species. We present the results of spatio-temporal analyses of marine mammal stranding events to identify hotpots along Indian coastline. We collated data over a long-time frame (~270 years) available from various open access databases, reports and publications. Given the inadequacy in data collection over these years, we grouped data into four major groups viz. baleen whales, toothed whales, small cetaceans and dugongs. Further, we described the trends in data for marine mammal sightings, incidental mortalities, induced mortalities and stranding events using the last group for spatio-temporal analysis. Annual strandings along the Indian coast has increased considerably in the recent years (11.25 {+/-} 9.10 strandings/ year), peaking in the last two years (2015-17, mean = 27.66{+/-}12.03 strandings /year). We found that number of strandings spiked in June- September along the west coast and December- January along the east coast. We identified several sections of coastline which have consistently received comparatively higher number of stranded animals (0.38 - 1.82 strandings/km) throughout the study period. Use of novel geospatial tool Emerging Hotspot Analysis revealed new and consecutive hotspots along the north-west coast, and sporadic hotspots along the south-east coast. Despite the challenges of working with an opportunistic database, this study highlights critical areas to be prioritized for monitoring marine mammal strandings in the country. We recommend establishing regional marine mammal stranding response centres at the identified hotspots coordinated by a National Stranding Monitoring Centre with adequate funding support. Regular conduct of stranding response programs for field veterinarians, frontline personnel focused around identified stranding hotspots would help develop a comprehensive picture of marine mammal populations in Indian waters.

ecology↗

bioRxiv2020

Improved chromosome level genome assembly of the Glanville fritillary butterfly (Melitaea cinxia) based on SMRT Sequencing and linkage map.

The Glanville fritillary (Melitaea cinxia) butterfly is a long-term model system for metapopulation dynamics research in fragmented landscapes. Here, we provide a chromosome level assembly of the butterflys genome produced from Pacific Biosciences sequencing of a pool of males, combined with a linkage map from population crosses. The final assembly size of 484 Mb is an increase of 94 Mb on the previously published genome. Estimation of the completeness of the genome with BUSCO, indicates that the genome contains 93 - 95% of the BUSCO genes in complete and single copies. We predicted 14,830 gene models using the MAKER pipeline and manually curated 1,232 of these gene models. The genome and its annotated gene models are a valuable resource for future comparative genomics, molecular biology, transcriptome and genetics studies on this species.

genomics↗

bioRxiv2020

A novel regulatory element upstream of TNFAIP3 promoter may be influenced by SLE risk variants

Almost all of Genome Wide Association Studies (GWAS) hits come from non-coding DNA elements. Data from chromatin interaction analyses suggest a long-range interaction with a putative enhancer upstream of TNFAIP3. Disrupting the enhancer may impair TNFAIP3 expression and enhance SLE risk. Two variants, rs10499197 and rs58905141 carried on the SLE risk haplotype are situated near this enhancer and could affect its function. Cloning the regulatory region surrounding rs10499197 into an expression plasmid containing a CRISPR-Cas9 backbone, and then performing a genome editing assay, we found that the variant is located near an enhancer. And any changes to the SNP region might impair enhancer and its ability to regulate TNFAIP3 expression.

bioinformatics↗

bioRxiv2020

Towards Building a Smart Kidney Atlas: Network-based integration of multimodal transcriptomic, proteomic, metabolomic and imaging data in the Kidney Precision Medicine Project

AO_SCPLOWBSTRACTC_SCPLOWKidney Precision Medicine Project (KPMP) is building a spatially-specified human tissue atlas at the single-cell resolution with molecular details of the kidney in health and disease. Here, we describe the construction of an integrated reference tissue map of cells, pathways and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 55 subjects. We use single-cell and -nucleus transcriptomics, subsegmental laser microdissection bulk transcriptomics and proteomics, near-single-cell proteomics, 3-D nondestructive and CODEX imaging, and spatial metabolomics data to hierarchically identify genes, pathways and cells. Integrated data from these different technologies coherently describe cell types/subtypes within different nephron segments and interstitium. These spatial profiles identify cell-level functional organization of the kidney tissue as indicative of their physiological functions and map different cell subtypes to genes, proteins, metabolites and pathways. Comparison of transcellular sodium reabsorption along the nephron to levels of mRNAs encoding the different sodium transporter genes indicate that mRNA levels are largely congruent with physiological activity.This reference atlas provides an initial framework for molecular classification of kidney disease when multiple molecular mechanisms underlie convergent clinical phenotypes.

bioinformatics↗

bioRxiv2020

Altered Thalamocortical Connectivity in Six-Week Old Infants at High Familial Risk for Autism Spectrum Disorder

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and lowrisk controls (LR). Resting-state functional connectivity (rs-fcMRI) and diffusion tensor imaging (DTI) data were acquired 52 six-week-old infants. Functional connectivity was examined between six cortical seeds -prefrontal, motor, somatosensory, temporal, parietal, and occipital regions- and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared to LR infants. Notably, aberrant rs-fcMRI and DTI connectivity indices at 6 weeks predicted atypical social development between 6 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as six weeks of age, providing a possible early marker of risk for ASD.

neuroscience↗

bioRxiv2020

Stability of Begomoviral pathogenicity determinant βC1 is modulated by mutually antagonistic SUMOylation and SIM interactions

To successfully invade new hosts, to break host resistance as well as to move within and between plant cells, viruses and their satellites have evolved a coordinated network of protein interactions. {beta}C1 protein encoded by specific geminiviral satellites acts as a key pathogenicity determinant. {beta}C1 from diverse viruses undergo multiple post-translational modifications (PTMs) such as ubiquitination and phosphorylation. However, the relevance of these and other layers of PTMs in host-geminiviral interactions has not been fully understood. Here we identified the significance of a novel layer of PTMs in Synedrella yellow vein clearing virus (SyYVCV) encoded {beta}C1 protein having well conserved SUMOylation and SUMO-interacting motifs (SIMs). We observed that SyYVCV {beta}C1 undergoes SUMOylation in host plants as a defensive strategy against ubiquitin mediated degradation. On the contrary, SIMs encoded in {beta}C1 mediate degradation of {beta}C1. Both these PTMs are also essential for the function of {beta}C1 protein since SIM and SUMOylation motif mutants failed to promote pathogenicity and viral replication in vivo. In addition, SUMOylation in different motifs of {beta}C1 led to functionally distinct outcomes, regulating the stability and function of the {beta}C1 protein, as well as increased global SUMOylation of host proteins. Our results indicate the presence of a novel mechanism mediating a fine balance between defence and counter-defence in which a SIM site is competitively sought for degradation and as a counter defense, {beta}C1 undergoes SUMOylation to escape from its degradation. Summary Statement{beta}C1 viral protein has evolved counter-defensive strategies to perturb host protein degradation pathways

plant biology↗

bioRxiv2020

The ΔF508 CFTR defect: molecular mechanism of suppressor mutation V510D and the contribution of transmembrane helix unraveling

Cystic fibrosis (CF) results from mutations within the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a transmembrane chloride channel found on the apical surface of epithelial cells. The most common CF-causing mutation results in a deletion of phenylalanine 508 ({Delta}F508-CFTR), a residue normally found within the NBD1 domain. Loss of F508 causes NBD1 to be less thermodynamically stable and prevents proper tertiary folding of CFTR. As a result, CFTR is not properly trafficked to the cell surface. Recently, progress has been made towards the development of small molecule "correctors" that can restore CFTR tertiary structure and stabilize the channel to overcome the instability inherent in {Delta}F508-CFTR. However, the resultant improvement in channel activity has been modest, and the need for potent correctors remains. To fully inform such efforts, a better understanding of the molecular pathology associated with {Delta}F508-CFTR is required. Here we present a comprehensive study of the impact of F508 deletion on both purified NBD1 and full-length CFTR. Through the use of homology modeling, molecular dynamics simulations, mutational analysis, biochemical, biophysical and functional characterization studies, we obtained insight into how the {Delta}F508 mutation may lead to helical unraveling of transmembrane domains 10 and 11 (TM10, TM11), and how the known suppressor mutations V510D and R1070W, as well as novel second site suppressor mutations (SSSMs) identified in this work, may act to rescue {Delta}F508-CFTR maturation and trafficking.

biochemistry↗

bioRxiv2020

Nutritional stress alone can control in vitro tumor formation and its invasive nature

The metastatic nature is an inherent property of the tumor. However, the effect of the environmental stress conditions on tumor microcosm in the context of metastasis needs to be analyzed. This work is proposed to analyze the tumor behavior under multiple metabolic stress conditions, such as deprivation of glucose, protein, and oxygen. The spheroid proliferation rate is observed to be influenced profoundly by the stress level where minimal stress produces compact spheroid and severe stress makes unstable aggregate like structures. It is observed that the non-invasive cancer cells cannot form spheroids under extreme stress. Stress conditions influence the mRNA levels of hypoxic, angiogenic and ECM deformation specific gene clusters. Spheroid reversal assay reveals the quiescent nature of the stressed spheroids under continuous stress conditions. However, after the rescue, the stressed spheroids were found to opt for different migration modalities. Extremely stressed non-invasive spheroids display atypical sprout-like growth within the invasion matrix and severely stressed spheroids can control the migration pattern of mesenchymal stem cells. Thus, it is concluded that multiple nutritional stress influences the spheroid formation and physiology along with the conversion of a non-invasive spheroid into quasi-invasive one.

cancer biology↗

bioRxiv2020

Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A 1 Infection via Akt1

Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that it increases the mortality of bacterial pneumonia in mice. Here, we show that normoxic hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus (IAV). Elevated CO2 increased IAV replication and inhibited antiviral gene and protein expression in macrophages in vivo and in vitro. Hypercapnia potentiated IAV-induced activation of Akt, while specific pharmacologic inhibition or shRNA knockdown of Akt1 in alveolar macrophages blocked hypercapnias effects on IAV growth and the macrophage antiviral response. Our findings suggest that targeting Akt1 or downstream pathways through which elevated CO2 signals could enhance macrophage antiviral host defense and improve clinical outcomes in hypercapnic patients with advanced lung disease.

immunology↗

bioRxiv2020

Redox-active cysteines in TGACG-BINDING FACTOR 1 (TGA1) do not play a role in salicylic acid- or pathogen-induced expression of TGA1-regulated target genes in Arabidopsis thaliana

O_LISalicylic acid (SA) is an important signaling molecule of the plant immune system. C_LIO_LISA biosynthesis is indirectly modulated by the closely related transcription factors TGA1 (TGACG-BINDING FACTOR 1) and TGA4. They activate expression of SARD1 (SYSTEMIC ACQUIRED RESISTANCE DEFICIENT1), the gene product of which regulates the key SA biosynthesis gene ICS1 (ISOCHORISMATE SYNTHASE 1). C_LIO_LISince TGA1 interacts with the SA receptor NPR1 (NON EXPRESSOR OF PATHOGENESIS-RELATED GENES 1) in a redox-dependent manner and since the redox state of TGA1 is altered in SA-treated plants, TGA1 was assumed to play a role in the NPR1-dependent signaling cascade. Here we identified 193 out of 2090 SA-induced genes that require TGA1/TGA4 for maximal expression after SA treatment. One robustly TGA1/TGA4-dependent gene encodes for the SA hydroxylase DLO1 (DOWNY MILDEW RESISTANT 6-LIKE OXYGENASE 1) suggesting an additional regulatory role of TGA1/TGA4 in SA catabolism. C_LIO_LIExpression of TGA1/TGA4-dependent genes in mock/SA-treated or Pseudomonas-infected plants was rescued in the tga1 tga4 double mutant after introduction of a mutant genomic TGA1 fragment encoding a TGA1 protein without any cysteines. Thus, the functional significance of the observed redox modification of TGA1 in SA-treated tissues has remained enigmatic. C_LI SIGNIFICANCE STATEMENTPrevious findings demonstrating a redox-dependent interaction between transcription factor TGA1 and NPR1 attracted considerable attention. Here we show that TGA1 can act in the NPR1- and SA-dependent signaling cascade, but that its SA-regulated redox-active cysteines do not affect its function in this process.

molecular biology↗

bioRxiv2019

Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism.

The diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented. HighlightsO_LILate life metformin treatment limits cell survival and shortens lifespan. C_LIO_LIMetformin exacerbates aging-associated mitochondrial dysfunction causing fatal ATP exhaustion. C_LIO_LIOld cells fail to upregulate glycolysis as a compensatory response to metformin. C_LIO_LIThe dietary restriction (DR) mimetic response to metformin is abrogated in old animals. C_LIO_LIPKA and not AMPK pathway instigates the early life DR response to metformin. C_LIO_LIStabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. C_LI

physiology↗

bioRxiv2019

Frequency of MicroRNA Response Elements Identifies Pathologically Relevant Signaling Pathways in Cancers

Complex interactions between mRNAs and microRNAs influence cellular functions. The interactions between mRNA and microRNAs also determine the post-transcriptional availability of free mRNAs and unbound microRNAs. The microRNAs bind to one or more microRNA Response Elements (MREs) predominantly located on the 3untranslated regions (3UTR) of mRNAs. In this study, we leveraged MRE sites and their frequencies in transcriptomes of cancer and matched normal tissues to obtain insights into disease-specific interactions between mRNAs and microRNAs. Toward this, we developed a novel bioinformatics method called ReMIx that utilizes RNA-Seq data to quantify MRE frequencies at 3UTR of genes across the transcriptome. We applied ReMIx to The Cancer Genome Atlas (TCGA) Triple Negative (TN) breast cancer tumor-normal adjacent pairs (N=13) and identified distinctly and differentially expressed MREs specific to the TN tumors. Novel data generated by ReMIx identified candidate mRNAs and microRNAs in the MAPK signaling cascade of the TN tumors. We further analyzed the MAPK endogenous RNA network to establish regulatory microRNA partners, along with interacting protein-coding mRNAs that influence and modulate MAPK signaling in TN breast cancers.

bioinformatics↗

bioRxiv2018

The first draft genomes of the ant Formica exsecta, and its Wolbachia endosymbiont reveal extensive gene transfer from endosymbiont to host.

The wood ant Formica exsecta (Formicidae; Hymenoptera), is a common ant species throughout the Palearctic region. The species is a well established model for studies of ecological characteristics and evolutionary conflict. In this study, we sequenced and assembled draft genomes for Formica exsecta and its endosymbiont Wolbachia. The draft F. exsecta genome is 277.7 Mb long; we identify 13,767 protein coding genes for which we provide gene ontology, and protein domain annotations. This is also the first report of a Wolbachia genome from ants, and provides insights into the phylogenetic position of this endosymbiont. We also identified multiple horizontal gene transfer events (HGTs) from Wolbachia to F. exsecta. Some of these HGTs have also occurred in parallel in multiple other insect genomes, highlighting the extent of HGTs in eukaryotes. We expect that the F. exsecta genome will be valuable resource in further exploration of the molecular basis of the evolution of social organization.

genomics↗