Biology subjects

Kumar, R.

Publications and source records attributed to Kumar, R..

319 records · Page 18Linked to original sources

bioRxiv2018

sFlt-1 commutes unfolded protein response into endoplasmic reticulum stress in trophoblast cells in preeclamptic pregnancies

Preeclampsia (PE) and its subtypes (early and late onset) are serious concerns all across the globe affecting about 8% of total pregnancies and accounts for approximately 60,000 deaths annually with a predominance in developing under-developed and countries. The two-stage model in the progression of this disease, deficient spiral artery remodelling and an imbalance between angiogenic (VEGF) and anti-antigenic factor(s) (sFlt-1) are well established facts pertaining to this disease. The presence of increased sFlt-1, high oxidative stress and Endoplasmic reticulum stress (ER stress) have been proposed in preeclamptic pregnancies. Recently, the role of endoplasmic reticulum stress in the onset of the variant forms of PE highlighted a new window to explore further. In our previous studies, we demonstrated that sFlt-1 can induce apoptosis and oxidative stress in trophoblast cells. However the role of sFlt-1, in inducing ER stress is not known so far. In the present study, we for the first time demonstrated significant ER stress in the placental cells (BeWo Cells) (in vitro) when exposed to sera from preeclamptic pregnancies having increased concentration of sFlt-1. The expression of ER stress markers (GRP78, eIF2, XBP1, ATF6 and CHOP) at both transcript and protein levels were compared (between preeclamptic and normotensive non-proteinuric women) at three different time points (8h, 14h and 24hrs), analyzed and found to be significant (p<0.05).\n\nConclusionOur results suggested that sFlt-1, released from placental cells in preeclampsia may be one of the various factors having potential to induce endoplasmic reticulum stress in BeWo cells.

developmental biology↗

bioRxiv2018

Targeted Drug Delivery by Radiation-Induced Tumor Vascular Modulation

Effective drug delivery is severely restricted by the presence of complex pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, mature and hypopermeable tumor blood vessels limit the permeation and penetration of chemo or nanotherapeutics to cancer cells and substantially reduce the treatment efficacy. New, clinically-viable strategies are therefore sought to breach the neoplastic barriers that prevent optimal tumor-specific drug delivery. Here, we present an original idea to boost targeted drug delivery by selectively knocking down the tumor vascular barrier in a poorly permeable human pancreatic cancer model. For the first time, we demonstrate that clinical irradiation (10 Gy, 6 MV) can induce tumor vascular modulation when combined with tumor endothelial-targeting gold nanoparticles. Active disruption of tumor blood vessels by nanoparticle-combined radiotherapy led to increased vessel permeability and improved tumor uptake of two prototypical model nanodrugs: i) a short-circulating nanocarrier with MR-sensitive gadolinium (Gad-NC; 8 kDa; t1/2=1.5 h) and ii) a long-circulating nanocarrier with fluorescence-sensitive NIR dye (FL-NC; 30 kDa; t1/2=25 h). Functional changes in the altered tumor vessel dynamics, measured by relative changes in permeability (Ktrans), flux rate (Kep) and extracellular interstitial volume (Ve) were consistent with the concomitant increase in nanodrug delivery. This combination of radiation-induced antivascular and nanodrug-mediated anti-tumor treatment offers high therapeutic benefit for tumors with pathophysiology that restricts efficient drug delivery.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC=\"FIGDIR/small/268714_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (84K):\norg.highwire.dtl.DTLVardef@a6df8borg.highwire.dtl.DTLVardef@19e3179org.highwire.dtl.DTLVardef@c223aaorg.highwire.dtl.DTLVardef@1b3a08d_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT\n\nC_FIG

bioengineering↗

bioRxiv2018

Effects of different load on physiological, hematological, biochemical, cytokines indices of Zanskar ponies at high altitude

High altitude people required high endurance pack animals for load carrying and riding at prevalent mountainous terrains and rugged region. So far no studies have been taken to evaluate effect of loads on physiology of ponies in high altitude region. So, in this view we evaluated variation in physiological, hematological, biochemical, and cytokines indices of Zanskar ponies during load carrying at high altitude. Total twelve (12) numbers of Zanskar ponies, mare, age 4-6 years, were divided into three groups; group-A (without load), group-B (60 kg), and group-C (80 kg) of back pack loads. Track was very narrow and slippery with gravel, uneven with rocky surface and has a steep gradient of 4 km uphill at altitude 3291 to 3500 m. When we evaluate these parameters, it is understood that the heart rate, pulse rate and respiration rate was significantly (p<0.05) increased in 80 kg group among the three groups. The hematology parameters viz. hemoglobin, PCV, lymphocytes, monocytes%, ESR and eosinophil% significantly (p<0.05) changed in 80 kg group after load carrying among the three groups which was followed by control and 60 kg group. In biochemical parameters viz. LA, LDH, TP, HK, CORT, T3, CRT, AST, CK-MB, GPx, FRAP and IL-6 significantly (p<0.05) changed in 80 kg group after load carrying among the three groups which was followed by control and 60 kg group. The ALT, ALB, GLB, UR and UA significantly (p<0.05) changed in 80 kg group before and after load carrying among the three groups which was followed by control and 60 kg group. It has been concluded that, this result has revealed strong correlation of change in biomarkers level with performance in ponies during load carry. Hence, these parameters might be use for performance of endurance of Zanskar ponies in high mountain region.

physiology↗

bioRxiv2017

sFlt-1 (sVEGFR1) induces placental endoplasmic reticulum stress in trophoblast cell: implications for the complications in preeclampsia - an in vitro study

BackgroundThe concentration of sFlt-1, a major anti-angiogenic protein in maternal circulation has been seen to be raised in preeclamptic pregnancies. Endoplasmic reticulum (ER) stress represents one of the three (immunological, oxidative and ER stress) major stresses which placenta undergoes during pregnancies. The present study is designed to investigate the role of sFlt-1 in induction of ER stress in trophoblast cells.\n\nMaterials and MethodsMaternal serum levels of anti-angiogenic protein sFlt-1 and central regulator of unfolded protein response GRP78 was measured using sandwich ELISA. The expression of various ER stress markers (GRP78, eIF2, XBP1, ATF6 and apoptotic protein CHOP) were analyzed depending on various treatments given to the trophoblast cells using Immunofluorescence, western blot and q-RT PCR.\n\nResultsIncreased expression of ER stress markers (GRP78, eIF2, XBP1 ATF6 and apoptotic protein CHOP) was detected in the placental trophoblast cells treated with raised concentration of sFlt-1.\n\nConclusionSignificant upregulated expression of ER stress markers in trophoblast cells exposed with increased concentration of sFlt-1 suggested that it may be one of the anti-angiogenic factors present in maternal sera which not only contributes to oxidative stress but also may cause endoplasmic reticulum stress.

developmental biology↗

bioRxiv2017

The prognostic effects of somatic mutations in ER-positive breast cancer

More than 50 genes are recurrently affected by somatic mutation in estrogen receptor positive (ER+) breast cancer but prognostic effects have not been definitively established. Primary tumor DNA was therefore subjected to targeted sequencing from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients. Independent validation of prognostic interactions was achieved using independent data from the METABRIC study. Associations between MAP3K1 and PIK3CA with luminal A status and TP53 mutations with Luminal B/non-luminal tumors were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutation was validated as a poor outcome driver. For MA12, poor outcome associated with PIK3R1 mutation was similarly validated. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false-discovery correction (q=0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typify ER+ breast cancer.

genomics↗

bioRxiv2017

HumCFS: A database of fragile sites in human chromosomes

Genomic instability is the hallmark of cancer and several other pathologies, such as mental retardation; preferentially occur at specific loci in genome known as chromosomal fragile sites. HumCFS (http://webs.iiitd.edu.in/raghava/humcfs/) is a manually curated database provides comprehensive information on 118 experimentally characterized fragile sites present in human chromosomes. HumCFS comprises of 19068 entries with wide range of information such as nucleotide sequence of fragile sites, their length, coordinates on the chromosome, cytoband, their inducers and possibility of fragile site occurrence i.e. either rare or common etc. Each fragile region gene is further annotated to disease database DisGenNET, to understand its disease association. Protein coding genes are identified by annotating each fragile site to UCSC genome browser (GRCh38/hg38). To know the extent of miRNA lying in fragile site region, miRNA from miRBase has been mapped. Comprehensively, HumCFS encompasses mapping of 5010 genes with 19068 transcripts, 1104 miRNA and 3737 disease-associated genes on fragile sites. In order to facilitate users, we integrate standard web-based tools for easy data retrieval and analysis.

bioinformatics↗

bioRxiv2017

Regulation of thickness of actomyosin cortex in well-spread cells by contractility and spread area

The contractile cortical actomyosin cytoskeleton (or cortex) in interphase cells confers rigidity to cells, but also lead to shape dynamics. Regulation of its thickness, although well studied in rounded cells, is less explored in well-spread cells. In this paper, we quantify the variations in thickness and study the contribution of actin polymerization, myosin II activity and spread area of cells. We report an increase in cortex thickness and its variations on disrupting actin network by actin depolymerizing agents or reducing contractility by inhibiting motor activity of myosin II. On spread area reduction by substrate micropatterning, we find reduced cell volume and increased mean & variability of thickness. To validate, we follow cells through de-adhesion with EDTA. The thickness of cortex increases (and oscillates) while the volume of cells reduces with 5-15 mins timescales. Moreover, total internal reflection fluorescence (TIRF) imaging reveals stress fibre dissolution and events of their buckling along with a growing population of micron-sized mobile filaments. We believe that the cytoskeleton responds to the loss of adhesion by contracting and fragmenting, hence leading to cortex thickening. Limiting volume reduction does not suppress cortex thickening on de-adhesion, suggesting that decreased traction stress may be primarily responsible for the cortex thickening.

biophysics↗

bioRxiv2017

NAC-NOR mutations in tomato Penjar accessions attenuate multiple metabolic processes and prolong the fruit shelf life

Several Penjar accessions of tomato (Solanum lycopersicum), widely grown in the Mediterranean region, exhibit prolonged shelf life, and harbor alcobaca mutation with valine-106-aspartic acid substitution in the NAC-NOR protein. To uncover the metabolic basis underlying the prolonged shelf life, we compared four Penjar accessions to Ailsa Craig (AC). Three accessions bore alcobaca mutation, whereas fourth was a novel NAC-NOR allele with only six amino acids in the encoded protein. The cuticle composition among Penjars varied widely during the progression of fruit ripening. All Penjars exhibited delayed ripening, prolonged on-vine and off-vine shelf life, low ethylene emission and carotenoid levels albeit with accession-specific differences. Metabolic profiling revealed shifts in Krebs cycle intermediates, amino acids, and {beta}-aminobutyric acid levels indicating the attenuation of respiration in Penjars during post-harvest storage. The prolonged shelf life of Penjar fruits was associated with a concerted downregulation of a number of cell-wall modifying genes and cell-wall-related metabolites. The accumulation of higher ABA and sucrose levels at the onset of senescence in Penjar fruits likely contribute to reduced water loss. Our analyses reveal that in addition to specialized cuticle composition, the attenuation of various metabolic processes by NAC-NOR mutation likely prolongs the shelf life of Penjar fruits.\n\nHighlightThe prolonged shelf life of tomato Penjar accessions bearing mutations in NAC-NOR transcription factor appears to be regulated by a combined effect of attenuation of respiration, altered cuticle composition, enhanced ABA and sucrose levels in fruits and downregulation of cell wall modification

plant biology↗

bioRxiv2017

Neotrygon indica sp. nov., the Indian-Ocean blue-spotted maskray (Myliobatoidei, Dasyatidae)

The blue-spotted maskray, previously N kuhlii, consists of up to eleven lineages representing separate species. Nine of these species (N australiae, N. bobwardi, N. caeruleopunctata, N. malaccensis, N moluccensis, N orientale, N. vali, N varidens, N westpapuensis) have already been formally described and two (Indian-Ocean maskray and Ryukyu maskray) remain undescribed. Here the Indian-Ocean maskray is described as a new species, Neotrygon indica sp. nov.

zoology↗

bioRxiv2017

FIGL1 and its novel partner FLIP form a conserved complex that regulates homologous recombination.

Homologous recombination is central to repair DNA double-strand breaks (DSB), either accidently arising in mitotic cells or in a programed manner at meiosis. Crossovers resulting from the repair of meiotic breaks are essential for proper chromosome segregation and increase genetic diversity of the progeny. However, mechanisms regulating CO formation remain elusive. Here, we identified through protein-protein interaction and genetic screens FIDGETIN-LIKE-1 INTERACTING PROTEIN (FLIP) as a new partner of the previously characterized anti-crossover factor FIDGETIN-LIKE-1 (FIGL1) in Arabidopsis thaliana. We showed that FLIP limits meiotic crossover together with FIGL1. Further, FLIP and FIGL1 form a protein complex conserved from Arabidopsis to Human. FIGL1 interacts with the recombinases RAD51 and DMC1, the enzymes that catalyze the DNA stand exchange step of homologous recombination. Arabidopsis flip mutants recapitulates the figl1 phenotype, with enhanced meiotic recombination associated with change in DMC1 dynamics. Our data thus suggest that FLIP and FIGL1 form a conserved complex that regulates the crucial step of strand invasion in homologous recombination.

genetics↗

bioRxiv2017

A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma

BackgroundShort-acting B2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S 1, 2. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma3\n\nObjectiveTo identify genetic variants that may contribute to differences in BDR in African Americans with asthma.\n\nMethodsWe performed a genome-wide association study of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase 3 genotypes. We used linear regression models adjusting for age, sex, body mass index and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. Two additional populations of 416 Latinos and 1,325 African Americans were used to replicate significant associations.\n\nResultsWe identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69 x 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p[≤]5 x 10-8).\n\nConclusionsOur findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.\n\nKey messagesO_LIA GWAS for BDR in African American children with asthma identified an intergenic population specific variant at 9q21 to be associated with increased bronchodilator drug response (BDR).\nC_LIO_LIA meta-analysis of GWAS across African Americans and Latinos identified shared genetic variants at 10q21 in the intron of PRKG1 to be associated with differences in BDR.\nC_LIO_LIFurther genetic studies need to be performed in diverse populations to identify the full set of genetic variants that contribute to BDR.\nC_LI

genomics↗

bioRxiv2017

Feature Engineering Coupled Machine Learning Algorithms For Epileptic Seizure Forecasting From Intracranial EEGs

Epilepsy is one of the major neurological disorders affecting nearly 1 percentage of the global population. The major blunt is born by under developed and developing countries due to expensive treatment of epileptic conditions. Further, the lack of proper forecasting methods for an occurrence of epileptic seizures in epileptic-drug resistant patients or patients not amenable for surgery affects their psychological behaviour and restricts their daily activities. The forecasting is usually performed by human experts that leave a wide gap for human-bias and human error. Therefore, in the current work, we have evaluated the efficiency of several machine learning algorithms to automatically identify the preictal patterns corresponding to epileptic seizures from intracranial EEG signals. The robustness of the machine learning algorithms were tested after the data set was pre-processed using carefully chosen feature engineering strategies viz. denoised Fourier transforms as well as cross-correlation across electrodes in time and frequency domain. Extensive experimentations were carried out to determine the best combination of feature engineering techniques and machine learning algorithms. The best combination of feature engineering techniques and machine learning algorithm resulted in 0.7685 AUC (Area under the Receiver Operating Characteristic curve) on the random test samples. The suggested approach was fairly good at prediction of epilepsy in random samples and therefore, it can be used in epileptic seizure forecasting in patients where medication/surgery is ineffective. Eventually, our strategy reveals a robust method for brain disorders forecasting from EEGs.

bioengineering↗

bioRxiv2017

Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci

BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.\n\nMETHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.\n\nRESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 x 10-9 and 2.97 x 10-8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the \"atopic march\" and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 x10-6 [≤] p [≤] 3.06 x10-6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.\n\nCONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

bioinformatics↗