Biology subjects

Yadav, N.

Publications and source records attributed to Yadav, N..

31 records · Page 2Linked to original sources

bioRxiv2024

Estrus-Tracking Cortical Neurons Integrate Social cues and Reproductive states to Adaptively Control Sexually Dimorphic Sociosexual Behaviors

Female sociosexual behaviors, essential for survival and reproduction, are adaptively modulated by ovarian hormones. However, the neural mechanisms integrating internal hormonal states with external social cues to guide these behaviors remain poorly understood. Here we identified primary estrous-sensitive Cacna1h-expressing medial prefrontal (mPFCCacna1h+) neurons that orchestrate adaptive sociosexual behaviors. Bidirectional manipulation of mPFCCacna1h+ neurons drives opposite-sex-directed behavioral shifts between estrus and diestrus females. In males, these neurons serve opposite functions compared to estrus females, mediating sexually dimorphic effects via anterior hypothalamic outputs. Miniscope imaging reveals mixed-representation of self-estrous states and social target sex in distinct mPFCCacna1h+ subpopulations, with biased-encoding of opposite-sex social cues in estrus females and males. Mechanistically, ovarian hormone-driven upregulation of Cacna1h-encoded T-type calcium channels underlies estrus-specific activity changes and sexual-dimorphic function of mPFCCacna1h+ neurons. These findings uncover a prefrontal circuit that integrates internal hormonal states and target-sex information to exert sexually bivalent top-down control over adaptive social behaviors.

neuroscience↗

bioRxiv2023

Fractal Dimension and Lacunarity Measures of Glioma Subcomponents Provide a Quantitative Platform Discriminative of IDH Status: A Radiogenomics Approach in Gliomas

BackgroundThe presence of structural and geometric variations within gliomas, even among those with similar histologic grades, reflects the phenotypic heterogeneity unique to a genetic and epigenetic landscape. Whole glioma mass comprises of various subcomponents identified on MR imaging: enhancing, nonenhancing, necrosis, and edema fractions in varied fractions across patients. The geometry of whole tumor mass and the glioma subcomponents is highly irregular. Thereby, traditional Euclidean geometry is not suitable for quantifying the geometric dimensions. Here, we employ non-Euclidean geometric measurements: Fractal Dimension and lacunarity of the glioma subcomponents as a discriminator of IDH and MGMT status of gliomas. MethodsFractality and Lacunarity measurements were obtained using the tumor masks generated for enhancing, nonenhancing, and edema subcomponents from the preoperative T1, T1c, and T2-Flair MRI. Fractality and lacunarity measures of each subcomponent were evaluated between IDH mutant and wildtype gliomas. The fractality and lacunarity measures in IDH mutant and wildtype gliomas were further stratified for MGMT methylated and unmethylated gliomas. The fractality and lacunarities were trained and tested using supervised ML modeling as discriminators of IDH and MGMT status. Further, Cox Hazard estimations and the Kaplan-Meir investigations were performed to evaluate the impact of fractality and lacunarity measures of glioma subcomponents on the overall survival of the patients. ResultsIDH wildtype gliomas had [~]2-fold higher fractality for the enhancing subcomponent compared to IDH mutant enhancing subcomponent, while IDH mutant gliomas showed higher fractality for the nonenhancing subcomponent. Furthermore, the edema subcomponent did not differ for fractality or lacunarity measures between IDH mutant and wildtype gliomas. Fractal or lacunarity measures for either of the three subcomponents do not vary across MGMT methylated and unmethylated status with a given IDH mutant or wildtype gliomas. A combination of fractal measures of the enhancing and nonenhancing subcomponents together provided highly accurate and sensitive discrimination of IDH status using the supervised ML models. Moreover, fractality measure [≥] 0.69 for the enhancing subcomponent was associated with shortened patient survival: a fractal dimension value corresponding to that of IDH wild type gliomas. However, fractality and lacunarity estimates were not sensitive for discrimination of MGMT status. ConclusionGlioma structural heterogeneity measured as fractality and lacunarity using routine structural MRI measurements provide a noninvasive quantitative platform definitive of the molecular subtype of gliomas: IDH mutant vs. wildtype. Establishing fractality and/or lacunarity quantities as signatures of prognostic molecular events provides an avenue to bypass the need of biopsy/surgical interventions for decision-making, determining the molecular subtypes and overall clinical management of gliomas. Importance of the StudyThe non-Euclidean geometric measurements such as fractal dimension and lacunarity of enhancing, nonenhancing, and edema subcomponents are potentially unique quantitative metrics, discriminative of IDH status and patient survival. Fractality and Lacunarity estimates using the conventional structural MRI (T1w, T1C, T2, and T2F) provide an easy-to-use quantitative radiogenomics platform for improved clinical decisions, bypassing the need for immediate surgical interventions to ascertain prognostic molecular markers in gliomas, which is likely to improve overall clinical management and outcomes. Key PointsO_LIIncreased fractal dimensions of the enhancing subcomponents in IDH wildtype tumors, suggestive of highly irregular geometry, may potentially serve as a quantitative noninvasive determinant of IDH wildtype tumors. C_LIO_LIA combined fractal estimation of enhancing and nonenhancing subcomponents is the optimal and accurate discriminator of IDH mutant vs. wildtype. C_LIO_LIHigh fractal dimension of enhancing subcomponent and reduced fractality of nonenhancing subcomponent is predictive of shortened patient survival. C_LI

cancer biology↗

bioRxiv2023

MetaVision3D: Automated framework for the Generation of Spatial Metabolome Atlas in 3D

High-resolution spatial imaging is transforming our understanding of foundational biology. Spatial metabolomics is an emerging field that enables the dissection of the complex metabolic landscape and heterogeneity from a thin tissue section. Currently, spatial metabolism highlights the remarkable complexity in two-dimensional space and is poised to be extended into the three-dimensional world of biology. Here, we introduce MetaVision3D, a novel pipeline driven by computer vision techniques for the transformation of serial 2D MALDI mass spectrometry imaging sections into a high-resolution 3D spatial metabolome. Our framework employs advanced algorithms for image registration, normalization, and interpolation to enable the integration of serial 2D tissue sections, thereby generating a comprehensive 3D model of unique diverse metabolites across host tissues at mesoscale. As a proof of principle, MetaVision3D was utilized to generate the mouse brain 3D metabolome atlas (available at https://metavision3d.rc.ufl.edu/) as an interactive online database and web server to further advance brain metabolism and related research.

neuroscience↗

bioRxiv2023

On the road to losing connectivity: Fecal samples provide genome-wide insights into anthropogenic impacts on two large herbivore species in central India

Humans have impacted most of the planet, and the ensuing fragmentation results in small, isolated habitat patches posing a risk of genetic diversity loss, inbreeding and genetic load. Understanding how natural and anthropogenic landscape features affect gene flow among habitat patches is critical for maintaining connectivity. Genome-wide data is required to comprehend the impacts of recent fragmentation, which can be challenging when only non-invasive samples are available. Here, we build upon advancements in conservation genomics to address connectivity of two large herbivores, gaur (Bos gaurus) and sambar (Rusa unicolor) in central India. Given their habitat associations, we expected these species to respond similarly to habitat fragmentation. We used fecal-DNA and methylation-based host-DNA enrichment with modified ddRAD protocol to generate genome-wide single nucleotide polymorphism (SNP) data for 124 Gaur and 99 Sambar individuals. Our findings reveal that gaur populations in central India are fragmented, displaying high genetic differentiation, with drift significantly affecting small populations like Umred-Karhandala Wildlife Sanctuary. Although Sambar shows low genetic structure, another small population, Bor Tiger Reserve is genetically differentiated. Our results suggest that although landcover change and roads restrict animal movement, the extent of this impact varies across the two species. We show that different species, respond differently to landscape features, even with similar habitat associations. We highlight small and isolated populations requiring urgent conservation intervention. Such multi-species approaches enhance our understanding of cross-species connectivity patterns. We suggest shifting from single-species to multi-species holistic conservation approach in rapidly developing landscapes to better manage co-occurring endangered species.

genomics↗

bioRxiv2023

Magnitude and Kinetics of a set of Neuroanatomic Volume and Thickness together with White Matter Hyperintensity is definitive of Cognitive Status and Brain Age

In an aging population, a subset of individuals at a given age group have low white matter hyperintensity (WMH) while another subset has intermediate to high WMH load. WMH load quantification together with comprehensive neuroanatomic volumetry needs to be examined together for establishing a unique precise and optimal number of brain features as a noninvasive indicator of Brain Age and cognitive status. Here, a comprehensive neuroanatomic volumetry together with WMH quantification using longitudinal MRI and cognitive measurements from two aging cohorts have been performed together with machine learning modeling of the quantitative changes with aging to establish Optimal unique brain events discriminative of cognitive status and estimative of Brain Age. A set of Three optimal brain-associated quantities; wherein two are neuroanatomic features Total brain volume; CSF volume, and the third is the extent of microvascular pathology WMH load, provide highly precise discrimination of cognitive status as cognitively normal (CN), impaired (CI) and AD (CI-AD). While medial cortical thinning of Parahippocampal gyrus is an early age event discriminative between CI and CI-AD but loss of hippocampus, gray matter and white matter volume lacks sensitivity to discriminate between CI and CI-AD. The Brain Age estimation using the neuroanatomic volumetry and periventricular and deep WMH load indicates that elevated WMH load in the brain led to an increased Brain Age gap than the brain with low WMH at a given chronological age. Increased Brain Age gap with elevated WMH load at the early age groups is suggestive of profound vascular insult arising from WMH to the brain structure and function.

neuroscience↗

bioRxiv2023

Spatial patterns in the diet of Gyps vultures in India and their implications for conservation

Dietary analyses are particularly useful for developing conservation programmes for species threatened by resource depletion, poisoning and environmental pollution. Gyps vultures in South Asia represent one such case, having undergone a population collapse caused by feeding on carcasses of cattle treated with the non-steroidal anti-inflammatory drug diclofenac. Following a ban on the veterinary use of diclofenac, populations of vultures remain low and mostly concentrated near protected areas. Understanding the role of protected areas in the recovery of these critically endangered species requires analyses of spatial variation in their diet. We used faecal metabarcoding to investigate the spatial variation in the diet of Gyps vultures across four landscapes from sites located inside and outside protected areas. We collected faecal 642 samples, of which 419 yielded adequate molecular data to identify the vulture species and 30 molecular operational taxonomic units corresponding to at least 28 diet species. The diet was dominated by large ungulates and varied across landscapes, protection status and vulture species, with the observed variation largely explained by differential intake of wild and domestic species. Domestic livestock was present in >95% of the samples from central, west and north India, but 77% of the samples had only wild species in south India. This variation was explained by livestock density within 100 km radius of the sampling site. Our results imply that protected areas may not offer a respite from possibility of diclofenac-poisoning across most parts of the country and efforts should continue unabated to remove nephrotoxic drugs from veterinary use.

ecology↗

bioRxiv2023

Iron chelation by deferoxamine as useful adjunct therapeutics in murine tuberculosis.

Dysregulated iron metabolism is reported in tuberculosis patients; therefore, it represents an opportunity for developing host-directed therapeutics. This study monitored the antimycobacterial properties of an iron chelator, i.e., Deferoxamine (DFO/D), and its impact on the transcript and metabolite levels of Mycobacterium tuberculosis (Mtb) in vitro. For in vivo validation, a group of mice received ferric carboxymaltose to create an iron overload condition, and controls were aerosol-infected with Mtb H37Rv. Mtb-infected mice received isoniazid (INH/H) and rifampicin (RIF/R) in combination with or without DFO before tissue-specific CFU assay, liver metabolite screening and iron quantification using mass spectrometry. DFO showed antimycobacterial properties comparable to INH in vitro. DFO treatment deregulated (log2DFO/control>{+/-}1.0) Mtb transcript (n=137) levels, the majority of which encode for iron-containing proteins and proteins involved in stress response. DFO treatment up-regulated Rv3622c (PE32), Rv2353c (PPE39) and Rv3022A (PE29) genes and conditional knocking down of ABC transporter like irtA by anhydrotetracycline (Atc) inducible CRISPR interference (CRISPRi) approach compromised Mtb growth showing their potential involvement in iron metabolism. Global Mtb metabolite analysis using GC-MS identified a set of 5 deregulated metabolites indicating a perturbed pentose phosphate pathway and inositol phosphate metabolism in the host upon DFO treatment. Iron-overloaded mice exhibited significantly higher tissue mycobacterial burden at two weeks post-infection, and the efficacy of INH and RIF were compromised, corroborating with previous reports. Iron chelation by DFO or combined with/adjunct to RIF and INH significantly reduced the lung/tissue mycobacterial burden at four weeks post-treatment, specifically in the first ([~]0.5 log) and second weeks ([~]0.5 log) of treatment. The intracellular pro-inflammatory cytokine levels in the lung CD4+ T cells of INH and RIF-treated groups with or without DFO were similar, suggesting DFO has a direct role in Mtb survival and metabolism rather than improved infection, and the efficacy of INH and RIF were compromised, corroborating with previous reports. DFO adjunct to RIF and INH treatment significantly altered liver arginine biosynthesis, which directly neutralizes ammonia and is immune-supportive. Conventionally, DFO is used for treating acute iron toxicity that is common in thalassemic patients, and this study demonstrates DFO has potential as adjunct therapeutics for tuberculosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/543389v3_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@5066fdorg.highwire.dtl.DTLVardef@99a292org.highwire.dtl.DTLVardef@80426dorg.highwire.dtl.DTLVardef@892436_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Anteromedial Thalamus Gates the Selection & Stabilization of Long-Term Memories

Memories initially formed in hippocampus gradually stabilize to cortex, over weeks-to-months, for long-term storage. The mechanistic details of this brain re-organization process remain poorly understood. In this study, we developed a virtual-reality based behavioral task and observed neural activity patterns associated with memory reorganization and stabilization over weeks-long timescales. Initial photometry recordings in circuits that link hippocampus and cortex revealed a unique and prominent neural correlate of memory in anterior thalamus that emerged in training and persisted for several weeks. Inhibition of the anteromedial thalamus-to-anterior cingulate cortex projections during training resulted in substantial memory consolidation deficits, and gain amplification more strikingly, was sufficient to enhance consolidation of otherwise unconsolidated memories. To provide mechanistic insights, we developed a new behavioral task where mice form two memories, of which only the more salient memory is consolidated, and also a technology for simultaneous and longitudinal cellular resolution imaging of hippocampus, thalamus, and cortex throughout the consolidation window. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus forms preferential tuning to salient memories, and establishes inter-regional correlations with cortex, that are critical for synchronizing and stabilizing cortical representations at remote time. Indeed, inhibition of this thalamo-cortical circuit while imaging in cortex reveals loss of contextual tuning and ensemble synchrony in anterior cingulate, together with behavioral deficits in remote memory retrieval. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer term cortical storage.

neuroscience↗

bioRxiv2022

Deletion induced splicing in RIC3 drives nicotinic acetylcholine receptor regulation with implications for endoplasmic reticulum stress in human astrocytes

Nicotinic acetylcholine receptor (nAChR) dysregulation in astrocytes is reported in neurodegenerative disorders. Modulation of nAChRs through agonists confers protection to astrocytes from stress but regulation of chaperones is unclear. Resistance to inhibitors of cholinesterase 3 (RIC3) is a potential chaperone of nAChRs but poorly studied in humans. We characterized RIC3 in astrocytes derived from an isogenic wild-type and a Cas9 edited del human iPSC line harboring a 25bp homozygous deletion in exon2. Altered RIC3 transcript ratio due to deletion induced splicing and an unexpected gain of 7nAChR expression were observed in del astrocytes. Transcriptome analysis showed higher expression of neurotransmitter/G-protein coupled receptors mediated by cAMP and calcium/calmodulin-dependent kinase signaling. Functional implications of these observations were examined using tunicamycin induced ER stress. Wild-type astrocyte stress model showed cell cycle arrest, RIC3 upregulation, reduction in 7nAChR surface levels but increased 4nAChR surface expression. Conversely, tunicamycin treated del astrocytes showed a comparatively higher 4nAChR surface expression and upsurged cAMP signaling. In addition, reduced expression of stress markers CHOP, phospho-PERK and lowered XBP1 splicing in western blot and qPCR, validated by proteome-based pathway analysis indicated lowered disease severity. These findings indicate i) a complex RNA regulatory mechanism via exonic deletion induced splicing; ii) RIC-3 as a disordered protein having contrasting effects on co-expressed nAChR subtypes under basal/stress conditions; and iii) RIC3 as a potential drug target against ER stress in astrocytes for nicotine related brain disorders. Furthermore, cellular rescue mechanism through deletion induced exon skipping possibly opens up ASO based therapies for tauopathies.

neuroscience↗

bioRxiv2021

Task-independent metrics of computational hardness predict performance of human problem-solving

The survival of human organisms depends on our ability to solve complex tasks in the face of limited cognitive resources. However, little is known about the factors that drive the complexity of those tasks. Here, building on insights from computational complexity theory, we quantify the computational hardness of cognitive tasks using a set of task-independent metrics related to the computational resource requirements of individual instances of a task. We then examine the relation between those metrics and human behavior and find that they predict both time spent on a task as well as accuracy in three canonical cognitive tasks. Our findings demonstrate that performance in cognitive tasks can be predicted based on generic metrics of their inherent computational hardness. TeaserThe ability of humans to solve cognitive tasks is affected by generic mathematical properties of problems related to their computational complexity.

animal behavior and cognition↗

bioRxiv2020

Molecular evidence indicates the existence of multiple lineages of Sperata species in Indian Rivers

Sperata seenghala (Giant river-catfish) and Sperata aor (Long-whiskered catfish) are commercially important freshwater catfishes of India, belongs to family Bagridae. Due to high nutritional significance and the low number of intramuscular bones, both fishes have considerable demand in South Asian countries. Both of the Sperata species are morphologically close and well adapted to the same habitat. In this study, we have assessed the level of genetic diversity and differentiation of S. seenghala and S. aor in the Ganga River based on the mitochondrial DNA (mtDNA) control region and compared with the other major Indian rivers. We found high haplotypes diversity for both the species in the Ganga. However, it was comparatively low for S. seenghala in Mahanadi and Brahmaputra populations. The phylogenetic and median-joining network strongly indicated the presence of two distinct maternal lineages of S. seenghala from the Ganga river. Interestingly, the genetic differentiation between S. seenghala of Ganga-Brahmaputra was much higher (~25.3%) than the S. seenghala and S. aor (~17%), whereas it was comparatively low between Ganges-Mahanadi (~8.0%). Our finding provided evidence that all the three rivers: Ganga, Mahanadi, and the Brahmaputra sustain a highly diverse and genetically distinct stock of giant river catfish; therefore, all populations should be considered as a different management unit for the protection of stocks. Our findings indicated that Brahmaputra lineages qualify the species level variations. This study can be further used as a reference database for proper lineage identification of S. seenghala and S. aor that could formulate the appropriate conservation and management plans.

genetics↗

bioRxiv2018

Where the really hard choices are: A general framework to quantify decision difficulty

Life presents us with decisions of varying degrees of difficulty. Many of them are NP-hard, that is, they are computationally intractable. Two important questions arise: which properties of decisions drive extreme computational hardness and what are the effects of these properties on human-decision making? Here, we postulate that we can study the effects of computational complexity on human decision-making by studying the mathematical properties of individual instances of NP-hard problems. We draw on prior work in computational complexity theory, which suggests that computational difficulty can be characterized based on the features of instances of a problem. This study is the first to apply this approach to human decision-making. We measured hardness, first, based on typical-case complexity (TCC), a measure of average complexity of a random ensemble of instances, and, second, based on instance complexity (IC), a measure that captures the hardness of a single instance of a problem, regardless of the ensemble it came from. We tested the relation between these measures and (i) decision quality as well as (ii) time expended in a decision, using two variants of the 0-1 knapsack problem, a canonical and ubiquitous computational problem. We show that participants expended more time on instances with higher complexity but that decision quality was lower in those instances. These results suggest that computational complexity is an inherent property of the instances of a problem, which affect human and other kinds of computers.

animal behavior and cognition↗

bioRxiv2018

CMT3 and SUVH4/KYP silence the exonic retroelement Evelknievel to allow for reconstitution of CMT1 mRNA

Highlights: O_LISilencing of the intragenic Evelknievel (EK) retroelement is maintained by CMT3-KYP/SUVH4 independently of DDM1 and the RdDM pathways.\nC_LIO_LIMethylation and silencing of EK is required for transcription through the EK retroelement.\nC_LIO_LISilencing of EK allows for splicing out of the entire EK and reconstitution of an intact CMT1 mRNA.\nC_LI\n\nBackgroundCHROMOMEHYLASE1 (CMT1) has long been considered a non-essential gene because, in certain Arabidopsis ecotypes, the CMT1 gene is disrupted by the retroelement Evelknievel (EK), inserted within exon 13, or contains frame-shift mutations resulting in a truncated, non-functional protein. Here, we wanted to explore the regulatory pathway responsible for EK silencing in the Ler ecotype and its effect on CMT1 transcription.\n\nResultsMethylome databases confirmed that EK retroelement is heavily methylated but methylation is extended toward CMT1 downstream region. Strong transcriptional activation of EK accompanied by significant reduction in non-CG methylation was found in cmt3 and kyp2, but not in ddm1 or RdDM mutants. EK activation in cmt3 and kyp2 did not interfere with upstream CMT1 expression but abolish transcription through the EK. We identified, in wild type Ler, three spliced variants in which the entire EK is spliced out; one variant (25% of splicing incidents) facilitates proper reconstitution of an intact CMT1 mRNA. We could recover very low amount of the full length CMT1 mRNA from WT Ler and Col but not from cmt3 mutant..\n\nConclusionsOur findings highlight CMT3-SUVH4/KYP as the major pathway silencing the intragenic EK via inducing non-CG methylation. Furthermore, retroelement insertion within exons (e.g., CMT1) may not lead to a complete abolishment of the gene product when the element is kept silent. Rather the element can be spliced out to bring about reconstruction of a very low level of an intact, functional mRNA and possibly to retrieval of an active protein.

plant biology↗