Biology subjects

Patnaik, S.

Publications and source records attributed to Patnaik, S..

14 recordsLinked to original sources

bioRxiv2026

Species climate-niche properties suggest that both physiological tolerance and stress dominance shape plant community assembly across a tropical dry ecosystem

Climate influences community assembly by constraining the conditions under which species can persist, but the consistency of macroecological processes across different ecosystems remains unclear. Interspecific variation in climatic niche properties that govern community assembly across climate gradients can be gleaned from species distributions. Species-climate associations, niche properties, and resulting assembly remains poorly understood for plants in tropical dry ecosystems, and among different life-forms. We examined how species-climate associations governed community assembly of four plant life-forms across 60,000 km2 of tropical dry ecosystem in peninsular India. In the 1750 km long Eastern Ghats mountain range, we surveyed vegetation in 2500 20 x 50 m plots. Across the north-south climatic gradient from cool, wet and seasonal sites to warm, dry and less-seasonal sites, from presence-absence data of 1601 species in four life forms (trees, shrubs, herbs, climbers), we performed Bayesian Hierarchical Modelling of Species Communities to predict conditions of occurrence for each species. From this, we derived species climatic niche optima and niche width, and examined the local-level prevalence of niche properties across the climate gradient to glean assembly. Most tree, shrub and climber species associated with warm-dry conditions had wider niches than species associated with cool-wet conditions, which also resulted in assemblages having wider niches at warmer sites. Herbaceous species, by contrast, had narrower niches when associated with warmer conditions, where narrow-niche species dominated the assemblage. In all life-forms, however, assemblages in both warm-dry and cool-humid conditions consisted of species primarily associated with and preferring (having their optima in) those conditions, suggestive of stress dominance. Further evidence for stress dominance in shrubs and climbers came from assemblages in the warmest and coolest sites having low richness and comprising mainly of species with wider niches. Tree richness increased at either end of the gradient, while herb richness increased in warm-dry conditions. Overall, our results suggest that plant life-forms differ in the processes driving assembly across broad climate gradients in a tropical dry ecosystem, but many herbs were specialized to warm-dry climates. To understand life-form-specific responses to environmental gradients in tropical dry ecosystems, future work should incorporate traits and evolutionary history.

ecology↗

bioRxiv2024

Discovery of Novel and Selective GPR17 Antagonists as Pharmacological Tools for Developing New Therapeutic Strategies in Diabetes and Obesity

G protein coupled receptors (GPCRs) are promising targets for diabetes and obesity therapy due to their roles in metabolism and excellent potential for pharmacological manipulation. We previously reported that Gpr17 ablation in the brain-gut axis leads to improved metabolic homeostasis, suggesting GPR17 antagonism could be developed for diabetes and obesity treatment. Here, we performed high throughput screening (HTS) and identified two new GPR17 antagonists (compound 978 and 527). Both compounds antagonized downstream Gi/o, Gq and {beta}-arrestin signaling with high selectivity for GPR17, but not the closely related purinergic and cysteinyl leukotriene receptors. The molecular mechanisms of antagonism were revealed through Schild analysis, structure-activity relationship (SAR) studies and homology modelling. Compound 978 and its analog (793) attenuated GPR17 signaling and promoted glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine cells. In summary, we identified selective GPR17 antagonists through HTS, which represent promising pharmacological tools for developing new therapeutic strategies in diabetes and obesity. SignificanceOur work highlights the therapeutic potential of GPR17 antagonism in the treatment of diabetes and obesity by leveraging its role in metabolic regulation. In previous studies, we have shown that Gpr17 ablation improves metabolic homeostasis, and here we expanded our research by identifying two novel small molecule antagonists of GPR17 through high-throughput screening. The compounds inhibited multiple downstream signaling pathways of GPR17 with high selectivity over other closely related receptors. Of particular significance, compound 978 and its analogs not only attenuated GPR17 signaling but also increased glucagon-like peptide-1 (GLP-1) secretion, a critical hormone for glucose homeostasis and appetite regulation. These findings shed new light into the molecular mechanisms of GPR17 antagonism and introduce valuable pharmacological tools for further exploration of therapeutic strategies in diabetes and obesity.

pharmacology and toxicology↗

bioRxiv2024

The BBS/CCT chaperonin complex ensures the localization of the adhesion G protein-coupled receptor ADGRV1 to primary cilia

Primary cilia are antenna-like sensory organelles present on almost all eukaryotic cells. Their sensory capacity relies on receptors, in particular G-protein-coupled receptors (GPCRs) which localize to the ciliary membrane. Here we show that ADGRV1, a member of the GPCR subfamily of adhesion GPCRs, is part of a large protein network, interacting with numerous proteins of a comprehensive ciliary proteome. ADGRV1 is localized to the base of prototypic primary cilia in cultured cells and the modified primary cilia of retinal photoreceptors, where it interacts with TRiC/CCT chaperonins and the Bardet Biedl syndrome (BBS) chaperonin-like proteins. Knockdown of ADGRV1, CCT2 and 3, and BBS6 result in common ciliogenesis phenotypes, namely reduced ciliated cells combined with shorter primary cilia. In addition, the localization of ADGRV1 to primary cilia depends on the activity of a co-complex of TRiC/CCT chaperonins and the BBS chaperonin-like proteins. In the absence of components of the TRiC/CCT-BBS chaperonin co-complex, ADGRV1 is depleted from the base of the primary cilium and degraded via the proteasome. Defects in the TRiC/CCT-BBS chaperonin may lead to an overload of proteasomal degradation processes and imbalanced proteostasis. Dysfunction or absence of ADGRV1 from primary cilia may underly the pathophysiology of human Usher syndrome type 2 and epilepsy caused by mutations in ADGRV1.

cell biology↗

bioRxiv2024

Predicting recoverability of collapsed food webs through perturbation and dimension reduction

Biodiversity collapse, driven by escalating environmental changes, poses significant threats to ecosystem stability and the provision of essential ecosystem services. Understanding the recoverability of collapsed food webs thus is crucial for devising effective conservation strategies. This study delves into the theoretical exploration of the recoverability of food webs from a collapsed state. Through simple tools like dimension reduction, propagation of species-specific perturbation, and dynamical simulations, we explore whether simple tri-trophic food webs can be recovered from a collapsed state. Our study examines in detail the topological features of predator-prey food webs that could either facilitate or impede their recovery. We demonstrate that the recoverability of complex food webs can be predicted by using a simple dimension-reduced model, with certain structural factors that could constrain the full recovery of collapsed food webs. Furthermore, dynamic simulations also highlighted the significance of topological features such as connectance and the number of predator links in determining recoverability. Our dimension-reduced modeling framework offers insights into the feasibility of restoring entire complex predator-prey networks through species-specific interventions. This study contributes to a deeper understanding of ecosystem resilience and aids in the development of targeted conservation strategies.

ecology↗

bioRxiv2023

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/beta-catenin to RTK/MAPK signaling

Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here we report for the first time that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulates the abundance of specific C4-methyl sterols lophenol and dihydro-TMAS. Highlighting its clinical relevance, FAXDC2 is repressed in Wnt/{beta}-catenin high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulates in the cancerous tissues and not in adjacent normal tissues. FAXDC2 links Wnts to RTK/MAPK signaling. Wnt inhibition drives increased recycling of RTKs and activation of the MAPK pathway, and this requires FAXDC2. Blocking Wnt signaling in Wnt-high cancers causes both differentiation and senescence; and this is prevented by knockout of FAXDC2. Our data shows the integration of three ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/571793v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@6608f2org.highwire.dtl.DTLVardef@d5566eorg.highwire.dtl.DTLVardef@1d889aorg.highwire.dtl.DTLVardef@f37411_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Planar Amorphous Silicon Carbide Microelectrode Arrays for Chronic Recording in Rat Motor Cortex

Chronic implantation of intracortical microelectrode arrays (MEAs) capable of recording from individual neurons can be used for the development of brain-machine interfaces. However, these devices show reduced recording capabilities under chronic conditions due, at least in part, to the brains foreign body response. This creates a need for MEAs that can minimize the foreign body response to enable long-term recording. A potential approach to reduce the foreign body response is the use of ultrathin MEAs. Here, we fabricated ultrathin (cross-sectional area: 160 {micro}m2) amorphous silicon carbide (a-SiC) MEAs with sixteen electrode channels and implanted them into the motor cortex of seven female Sprague-Dawley rats. A-SiC was chosen as the fabrication base for its high chemical stability, good electrical insulation properties, and amenability to thin film fabrication techniques. Electrochemical analysis and neural recordings were performed weekly for 4 months. MEAs were characterized in vitro pre-implantation and in vivo using electrochemical impedance spectroscopy and cyclic voltammetry at 50 mV/s and 50,000 mV/s. Neural recordings were analyzed for single unit activity. At the end of the study, animals were sacrificed for immunohistochemistry analysis. We observed statistically significant, but small, increases in 1 and 30 kHz impedance values and 50,000 mV/s charge storage capacity over the 16-week implantation period. Slow sweep 50 mV/s CV and 1 Hz impedance did not significantly change over time. Impedance values increased from 11.6 M{Omega} to 13.5 M{Omega} at 1 Hz, 1.2 M{Omega} to 2.9 M{Omega} at 1 kHz, and 0.11 M{Omega} to 0.13 M{Omega} at 30 kHz over 16 weeks. The median charge storage capacity of the implanted electrodes at 50 mV/s were 58.1 mC/cm2 on week 1 and 55.9 mC/cm2 on week 16, and at 50,000 mV/s were 4.27 mC/cm2 on week 1 and 5.93 mC/cm2 on week 16. Devices were able to record neural activity from 92% of all active channels at the beginning of the study, At the study endpoint, a-SiC devices were still recording single-unit activity on 51% of electrochemically active electrode channels. In addition, we observed that the signal-to-noise ratio experienced a small decline of only -0.19 per week. We also classified the units as fast and slow spiking based on the trough-to-peak time. Although the overall presence of single units declined, fast and slow spiking units declined at a similar rate. Furthermore, immunohistochemistry showed minimal foreign body response to the a-SiC devices, as highlighted by statistically insignificant differences in activated glial cells between implanted brains slices and contralateral sham slices, as evidenced by GFAP staining. NeuN staining revealed the presence of neural cell bodies close to the implantation site, again statistically not different from a contralateral sham slice. These results support the use of ultrathin a-SiC MEAs for long-term implantation and use in brain-machine interfaces.

bioengineering↗

bioRxiv2023

Isolation of the murine Glut1 deficient thalamocortical circuit: wavelet characterization and reverse glucose dependence of low and gamma frequency oscillations

Glucose represents the principal brain energy source. Thus, not unexpectedly, genetic glucose transporter 1 (Glut1) deficiency (G1D) manifests with encephalopathy. G1D seizures, which constitute a prominent disease manifestation, often prove refractory to medications but may respond to therapeutic diets. These seizures are associated with aberrant thalamocortical oscillations as inferred from human electroencephalography and functional imaging. Mouse electrophysiological recordings indicate that inhibitory neuron failure in thalamus and cortex underlies these abnormalities. This provides the motivation to develop a neural circuit testbed to characterize the mechanisms of thalamocortical synchronization and the effects of known or novel interventions. To this end, we used mouse thalamocortical slices on multielectrode arrays and characterized spontaneous low frequency oscillations and less frequent 30-50 Hz or gamma oscillations under near-physiological bath glucose concentration. Using the cortical recordings from layer IV, we quantified oscillation epochs via an automated wavelet-based algorithm. This method proved analytically superior to power spectral density, short-time Fourier transform or amplitude-threshold detection. As expected from human observations, increased bath glucose reduced the lower frequency oscillations while augmenting the gamma oscillations, likely reflecting strengthened inhibitory neuron activity. This approach provides an ex vivo method for the evaluation of mechanisms, fuels, and pharmacological agents in a crucial G1D epileptogenic circuit.

neuroscience↗

bioRxiv2023

Maintenance of pig brain function under extracorporeal pulsatile circulatory control (EPCC)

Selective vascular access to the brain is desirable in metabolic tracer, pharmacological and other studies aimed to characterize neural properties in isolation from somatic influences from chest, abdomen or limbs. However, current methods for artificial control of cerebral circulation can abolish pulsatility-dependent vascular signaling or neural network phenomena such as the electrocorticogram even when preserving individual neuronal activity. Thus, we set out to mechanically render cerebral hemodynamics fully regulable to replicate or modify native pig brain perfusion. To this end, blood flow to the head was surgically separated from the systemic circulation and full extracorporeal pulsatile circulatory control (EPCC) delivered via a modified aorta or brachiocephalic artery. This control relied on a computerized algorithm that maintained, for several hours, blood pressure, flow and pulsatility at near-native values individually measured before EPCC. Continuous electrocorticography and brain depth electrode recordings were used to evaluate brain activity relative to the standard offered by awake human electrocorticography. Under EPCC, this activity remained unaltered or minimally perturbed compared to the native circulation state, as did cerebral oxygenation, pressure, temperature and microscopic structure. Thus, our approach enables the study of neural activity and its circulatory manipulation in independence of most of the rest of the organism.

neuroscience↗

bioRxiv2022

Anti-tumour efficacy of Musa paradisiaca flower extracts on DMBA induced Mammary carcinogenesis in female Wistar rats.

BackgroundSeveral reports have shown the beneficial advantages of Musa paradisiaca in wound healing activities and other ailments. Previously, our in vitro studies validated the anti-cancer activities of Musa flower extracts and confirmed the potential. This thread has led to our current investigation to explore the anticancer potential in vivo. PurposeThis study focused on the efficacy of banana florets on DMBA induced breast cancer in female wistar rats. MethodsInduction of tumour using Dimethylbenzanthracene (DMBA) in female wistar rats. Hormonal, antioxidant and anticarcinogenic studies were performed in vivo. ResultsIn our current study, we investigated that tumour induction has an effect in disrupting the estrous cycle in mice which may result by hormonal fluctuation levels. Antioxidant and hormonal analysis in vivo revealed the imbalance in estrogen and progesterone levels in untreated group compared to the treated ones. Floral crude extract treatment in vivo has shrunken the tumour volume in flower extract treatment group as well as in standard drug compared to the control. Histopathological staining confirms the disruption of epithelial tissues in tumour induced groups compared to the treated ones. Moreover, Musa floral treatment has shown to revert the damaged tissue morphology in the treated groups compared to the saline treated one. In-vitro studies in MCF-7 and MDA-MB-231 breast cancer cell lines has shown the potent anti-tumorigenic activity using Musa floral extracts. ConclusionTaken together, our finding confirmed that banana flower extracts showcase anti-carcinogenic activity against breast cancer both in vitro and in vivo. Tumour induction in mice has an effect in showing the disruption of estrous cycles. HighlightsO_LIMusa paradisiaca crude ethanolic flower extracts have a potential in reducing the tumour growth. C_LIO_LIDMBA induced cancer has a deleterious effect on estrogen cycles in female wistar rats. C_LIO_LIDisruption of epithelial morphology was observed in tumour induced wistar rats. C_LIO_LITreatment with crude Musa flower extracts on cancer induced rats shows the reduced level of damage and oxidative stress compared to the no treatment group. C_LI

cancer biology↗

bioRxiv2022

In BRAFV600E-mutated colorectal cancer cells, fascin1 restructures adherens junctions to drive Wnt activation

Fascin1 expression in colorectal carcinomas (CRCs) is linked to a clinically aggressive disease with poor prognosis. Despite that fascin1s role in the etiology of CRCs has not been directly investigated. We show fascin1 expression in one-third of all CRCs underscoring the critical need to identify fascin1s function in colorectal carcinogenesis. Here, we identify for the first time, fascin1s role as a mechanosensor that modulates CRC cell adherens junction (AJ) plasticity to induce tumor growth and metastasis. We show that fascin1 expression drives protein sorting to transform AJ mechanotransduction and we reveal how these force-sensitive pathways activate oncogenic signaling in CRC cells. We made the novel finding that AJ remodeling by fascin1 also controls "collective plasticity" and bidirectional cell migration. Few studies have examined AJ plasticity in cancer cells, which remains poorly understood and has not been therapeutically targeted. Our findings could have widespread implications for understanding and treating metastatic carcinomas.

cancer biology↗

bioRxiv2022

Detailed investigation on the role of lipid metabolizing enzymes in the pathogenesis of retinopathy of prematurity among preterm infants.

PurposeExtremely preterm infants are at risk of developing retinopathy of prematurity (ROP), characterized by an initial insufficient vascular network development in the retina (due to hyperoxia) that progress to neovascularization and neuroinflammation (hypoxic phase) ultimately leading to partial or total vision loss. Lipid metabolism has been shown to be a significant pathway that is involved in the regulation of angiogenesis, inflammation, and apoptosis in oxygen induced retinopathy mouse model, however, it is not explored in human ROP patients. The present study aimed to explore the association of lipid metabolizing, angiogenic and apoptotic genes with altered lipid metabolites in the ROP patients with different severity. MethodsThe blood, vitreous humor (VH), and fibrovascular membrane (FVM) samples were collected from premature infants diagnosed with ROP and controls. Gene expression of lipid metabolizing enzymes, angiogenesis, and apoptotic genes were performed using semi-quantitative PCR in blood. Lipid metabolites were identified and quantified by LC-MS in VH and were correlated with gene expression. The expression of key lipid metabolizing enzymes in severe stages of ROP was assessed by measuring their expression in FVM by immunohistochemistry. ResultsGenes coding for the lipid metabolizing enzymes such as CYP1B1, CYP2C8, COX2, and ALOX15 were upregulated while EPHX2 responsible for the conversion of epoxide fatty acids into diol fatty acids was significantly downregulated in ROP cases. The increase in the metabolic intermediates generated from the lipid metabolism pathway further confirmed the role of these enzymes in ROP. except for EPHX2 which did not show any change in its activity. The glial cells in the FVM of ROP infants too showed a lack of EPHX2 expression. A significantly higher expression of genes involved in angiogenesis (VEGF165/189, NOTCH1, and APH1B) and apoptosis (CASP3/8) correlated with altered activity of lipid metabolizing enzymes (based on metabolites levels) among ROP cases. ConclusionsLipid metabolism may play a significant role in ROP development and progression. EPHX2 activity is a key step in the metabolic pathway of arachidonic acid that mediates and regulates inflammation and vascular pathology in preterm infants.

genomics↗

bioRxiv2020

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51 are dependent on Wnt/{beta}-catenin signaling in Wnt-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. This coherent regulation of DNA repair genes occurs via a Wnt/{beta}-catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt high APCmin mutant polyps. Our findings suggest a general paradigm that Wnt/{beta}-catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.

cancer biology↗

bioRxiv2019

Identification of activators of human fumarate hydratase by quantitative high-throughput screening

Fumarate hydratase (FH) is a metabolic enzyme that is part of the Krebs-cycle, and reversibly catalyzes the hydration of fumarate to malate. Mutations of the FH gene have been associated with fumarate hydratase deficiency (FHD), hereditary leiomyomatosis, renal cell cancer (HLRCC), and other diseases. Currently there are no high-quality small molecule probes for studying human fumarate hydratase. To address this, we developed a quantitative high throughput screening (qHTS) FH assay and screened a total of 57,037 compounds from in-house libraries in dose-response. While no inhibitors of FH were confirmed, a series of phenyl-pyrrolo-pyrimidine-diones were identified as activators of human fumarate hydratase. These compounds were not substrates of fumarate hydratase, were inactive in a malate dehydrogenase counter screen, and showed no detectable reduction-oxidation activity. The binding of two compounds from the series to human fumarate hydratase was confirmed by microscale thermophoresis. The low hit rate in this screening campaign confirmed that FH is a tough target to modulate, and the small molecule activators of human fumarate hydratase reported here may serve as a starting point for further optimization and development into cellular probes of human FH and potential drug candidates.

biochemistry↗

bioRxiv2018

The complete mitochondrial genome of Melon thrips, Thrips palmi (Thripinae) and comparative analysis: A vector for Tospoviruses

The melon thrips, Thrips palmi is a serious pest and vector for plant viruses on a wide range of economically important crops. DNA barcoding evidenced the presence of cryptic diversity in T. palmi and that warrants exhaustive molecular data. Our present study is on decoding the first complete mitochondrial genome of T. palmi (15,333 bp) through NGS technology. The mitogenome contains 37 genes, including 13 PCGs, two rRNAs, 22 tRNAs, and two control regions. The comparative analyses were conducted for gene arrangements, nucleotide composition, codon usage and phylogenetic relationship with other thrips mitogenomes. The nucleotide composition was 78.29% AT, and 21.72% GC with positive AT skewness (0.09) and negative GC skewness (-0.06). The ATN initiation codons were observed in 12 PCGs except cox1 with unique start codon (TTG). The RSCU analysis revealed Phe, Leu, Ile, Tyr, Asn, Lys and Met were the most frequently used amino acids in all PCGs. The codon CGG (Arg) was absent in T. palmi as compared to other thrips mitogenomes. The Ka/Ks ratio ranges from 0.078 in cox1 to 0.913 in atp8. We observed the typical cloverleaf secondary structure in most of the tRNA genes with a few exceptions; absence of DHU stem and loop in trnV and trnS, absence of DHU loop in trnE, lack of T-arm and loop in trnN. The position of trnS1 (between cox3 and CR2) is unique in T. palmi among all the studied thrips mitogenomes. The mitogenome contained 24 intergenic spacer regions and 12 overlapping regions. The CR2 is 63.77% similar to CR1, indicating a possible duplication and translocation in control region. Both the ML and BI phylogenetic trees revealed the close relationships of Thrips with Scirtothrips as compared to Frankliniella. Thus, more mitogenomes on the diverse thrips species is required to understand the in-depth phylogenetic and evolutionary relationships.

genomics↗