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Bhardwaj, M.

Publications and source records attributed to Bhardwaj, M..

5 recordsLinked to original sources

Trickle-down ecology: Vertical stratification of temperate forests drives asymmetric cross-layer effects on consumer communities

O_LIForests are vertically structured ecosystems where light attenuation, microclimatic buffering and resource availability occur along continuous gradients from the canopy to the understorey layers. Despite this complexity, studies rarely integrate trophic interactions across vertical layers, overlooking how vertical forest structure shapes consumer communities through abiotic and biotic pathways. C_LIO_LIIn this study, we combined layer-specific measurements of plant diversity, structure and microclimate with arthropod sampling in the canopy and understorey, as well as bird survey data, in a temperate forest. Applying Bayesian structural equation models with explicitly defined directional pathways, we modelled both consumer biomass and abundance across trophic levels and vertical layers. C_LIO_LIAbundance measures were predominantly filtered by local layer conditions, while biomass responded to conditions across layers, reflecting stand-level energy flow. This suggests that these two metrics capture fundamentally different ecological processes. Canopy conditions consistently predicted understorey arthropod abundance across trophic levels, while the reverse was not observed, suggesting a strong asymmetric downward propagation of canopy-driven effects. Furthermore, trophic interactions between arthropod primary and secondary consumers remained largely stratified within vertical layers, suggesting a vertical food web compartmentalisation rarely shown in structurally complex aboveground systems. C_LIO_LIPlant diversity, structure and microclimate shaped consumer communities mainly through the modulation of resource availability and plant apparency, with effects varying across vertical layers, trophic levels and taxonomic groups. Through complementary mechanisms, plant diversity likely determined the variability of resources available to consumers at different trophic levels. Structural properties, in contrast, potentially drove the spatial redistribution of these resources through light attenuation and microclimatic buffering, which in turn influenced the physiological capacity of consumers to access and exploit available resources. C_LIO_LIThese findings demonstrate that vertical stratification mediates trophic pathways in a highly directional manner, with canopy characteristics playing a disproportionate role in structuring the forest community across layers. Integrating layer-specific structural and trophic indicators into forest biodiversity assessments and management strategies is therefore essential to fully evaluate biodiversity dynamics and multifunctionality in structurally complex forest ecosystems. C_LI

ecology↗

Modulating p38MAPK recalibrates sensitivity of drug-resistant pancreatic adenoductal carcinoma cells toward chemotherapy and correlate with improved outcome in PDAC patients: Experimental and metadata evidence

Pancreatic cancer is one of the deadliest cancers and has very limited therapeutic options and a dismal prognosis. Among various signaling pathways which are activated during tumor development, hyperactivation of Mitogen-Activated Protein Kinase (MAPK) is responsible for high grade angiogenesis, polarization of Tumor Associated Macrophages, unfolded protein responses and exhaustion of T cells, which together contributes towards this therapeutic resistance. We therefore believe that MAPK targeting is expected to enhance sensitivity of highly resistant PDAC cells toward various cancer directed interventions. In this context, we investigated the impact of modulating p38MAPK on the sensitivity of pancreatic cancer cells towards gemcitabine. Supporting our hypothesis, our results convincely, demonstrated that indeed, p38 inhibition sensitizes both KRAS positive Panc-1 and MiaPaCa2 pancreatic carcinoma cells towards gemcitabine induced death. Interestingly p38MAPK targeting significantly reduced the cell viability, clonogenic potential of these cells and enhanced the early apoptosis. Our in-silico studies, supporting our in vitro data, potentially correlated that that high expression of p38 MAPK14 in PDAC patients is associated with poor prognosis and disease free survival. Deep miming of in silico data further demonstrated that MAPK14, in association with, hypoxia inducible factor-1 alpha and vascular endothelial growth factor signaling pathways promote angiogenic programming of PDAC which render these tumors refractory for cancer directed interventions. Based on our preliminary data, we believe that p38 MAPK based approach is potential approach for changing the faith of PDAC patients toward chemo and immunotherapy and believed to improve PDAC burden effectively in the host. HighlightsO_LIp38 MAPK inhibition enhances the sensitivity of KRAS+ pancreatic cancer cells for Gemcitabine C_LIO_LIP38MAPK knockdown cells are sensitive for Gemcitabine induced death C_LIO_LIMAPK14 (p38) is associated with angiogenesis and poor prognosis in pancreatic cancer C_LIO_LIMAPK14 Regulates Pro-Tumorigenic Pathways and immune infiltration in Pancreatic Cancer C_LI

cancer biology↗

Caloric restriction: A potential approach for mitigating neuronal damage: Lesson from cellular model of Alzheimer Disease

Alzheimers disease is a neurodegenerative disorder and characterized by amyloid beta accumulation, synaptic dysfunction, and oxidative stress, lacks effective therapies. Caloric restriction mimetics such as fisetin and chlorogenic acid, natural polyphenols with antioxidant and autophagy-inducing properties, show promise in mitigating age-related diseases. This study investigates their neuroprotective effects against amyloid beta induced toxicity in differentiated human neuroblastoma SHSY5Y cells. Amyloid beta exposure disrupted redox homeostasis, impaired autophagy, induced mitochondrial dysfunction, and exacerbating neuronal degeneration. Fisetin and chlorogenic acid treatments reversed these deleterious effects by restoring redox balance, suppressing reactive oxygen species and upregulating critical antioxidant enzymes like SOD1, GSR, and catalase. These compounds also attenuated amyloid beta induced mitophagy via reduced PINK1 expression and restored mitochondrial fusion by upregulating Mfn2. Autophagy-related pathways were significantly modulated, evidenced by increased AMPK and decreased mTOR mRNA levels, alongside elevated expression of ATG101, ATG13, ULK1, P62 and reduced ATG5 levels. Docking studies also revealed binding of fisetin and CGA within the binding pockets of AMPK and FKBP12 supporting their interaction. Furthermore, fisetin and CGA improved synaptic integrity by upregulating PSD95 and synaptophysin and reducing acetylcholinesterase expression. These findings highlight their potential in ameliorating amyloid beta induced neuronal toxicity through autophagy activation, synaptic preservation, and mitochondrial function enhancement. While this study demonstrates the transcriptional impact and binding affinities of these caloric restriction mimetics further translational and biophysical analyses are required to elucidate their mechanisms and confirm their therapeutic viability. This research underscores the potential of fisetin and CGA as neuroprotective agents, offering promising therapeutic avenues for combating related Alzheimers disease neuropathies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/628076v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1253dd0org.highwire.dtl.DTLVardef@1fd3ffforg.highwire.dtl.DTLVardef@1749d1dorg.highwire.dtl.DTLVardef@f71415_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Glucosylceramide depletion disrupts endolysosomal function in GBA-linked Parkinsons fibroblasts?

In Gaucher and Niemann-Pick C diseases, the glucosylceramide (GlcCer) depletion hypothesis states that depletion of non-lysosomal sphingolipid pools can lead to dysfunction in the secretory and lysosomal system. The hypothesis suggests: 1) lysosomal dysfunction can be separated from lysosomal storage, 2) Lysosomal/secretory dysfunction/vATPase activity is corrected by increasing non-lysosomal GlcCer pools, and 3) Changes in higher glycosphingolipid synthesis due to changes in Golgi pH and/or GlcCer non-vesicular transport. Evidence for this mechanism includes 1) Successful treatment of cells and animals by imino sugar inhibition of the non-lysosomal neutral pH GlcCer hydrolase GBA2, 2) Increasing ER/cytosol GlcCer increases in vATPase regulatory V0a1 subunit expression. Heterozygous mutations in GBA1, a lysosomal glucocerebrosidase (GCase), cause GCase misfolding and mislocalisation in the ER/cytoplasm which is linked to Parkinsons disease (GBA-PD). Unexpectedly, similar to previous results in storing fibroblasts, N370S and L444P fibroblasts revealed increased endolysosomal pH and size despite the absence of glucolipid storage. Induction of storage by reducing residual lysosomal GCase activity in the N370S/L444P fibroblasts by the addition conduritol B-epoxide had no further effect on lysosomal function. In contrast, the addition of a soluble GlcCer analogue (adaGlcCer) reverses increased endolysosomal pH and volume in N370S mutant fibroblasts. The results are consistent with ER/cytosolic glucolipid depletion in GBA-PD fibroblasts. We discuss the potential for toxic/ectopic GBA1 hydrolysis and disrupted vATPase activity may lead to defective dopamine packaging and synaptic vesicle endocytosis as a new hypothesis in GBA-PD.

cell biology↗

Genomic surveillance reveals circulation of multiple variants and lineages of SARS-CoV-2 during COVID-19 pandemic in Indian city of Bengaluru

Genomic surveillance in response to coronavirus disease (COVID-19) pandemic is crucial for tracking spread, identify variants of concern (VoCs) and understand the evolution of its etiological agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). India has experienced three waves of COVID-19 cases, which includes a deadly wave of COVID-19 that was driven by the Delta lineages (second/Delta wave) followed by another wave driven by the Omicron lineages (third/Omicron wave). These waves were particularly dramatic in the metropolitan cities due to high population density. We evaluated the prevalence, and mutational spectrum of SARS-CoV-2 variants/lineages in one such megapolis, Bengaluru city, across these three waves between October 2020 and June 2022. 15,134 SARS-CoV-2 samples were subjected to whole genome sequencing (WGS). Phylogenetic analysis revealed, SARS-CoV-2 variants in Bengaluru city belonged to 18 clades and 196 distinct lineages. As expected, the Delta lineages were the most dominant lineages during the second wave of COVID-19. The Omicron lineage BA.2 and its sublineages accounted for most of the COVID-19 cases in the third wave. Most number of amino acid changes were observed in spike protein. Among the 18 clades, majority of the mutations and least similarity at nucleotide sequence level with the reference genome were observed in Omicron clades.

genomics↗