Biology subjects

Mohan, A.

Publications and source records attributed to Mohan, A..

27 records · Page 2Linked to original sources

bioRxiv2022

Chronic hyperglycemia drives alterations in macrophage effector function in pulmonary tuberculosis

BackgroundThe rising prevalence of Diabetes mellitus (DM) in high TB endemic countries has the potential to adversely affect sustainability of TB control since DM can lead to alterations in both innate and adaptive immune response constituting as a risk factor for development of active tuberculosis (TB). The impact of hyperglycemia on TB specific innate immune response in terms of macrophage functions remains poorly addressed. Material and methodsMacrophage effector functions in diabetic and non-diabetic individuals with and without PTB infection as well as non-diabetic-uninfected controls (fifty individuals in each group) were assessed. Phagocytic capacity against BCG and surface expression of PRRs (CD11b, CD14, CD206, MARCO and TLR2) were measured via flow cytometry. Effector molecules (ROS and NO) were assessed via DCFDA and Griess reaction respectively. ResultsA systematic dysregulation in phagocytic capacity with concurrent alterations in expression pattern of key PRRs (CD11b, MARCO and CD206) and effector molecules (ROS and NO) was observed in diabetic individuals with PTB. These altered macrophage functions were positively correlated with increase in disease severity in diabetic individuals. ConclusionOur results highlight several key patterns of immune dysregulation against M.Tb under hyperglycemic conditions. A significant reduction in macrophage effector functions in infected diabetic individuals which further correlated with increase in disease severity reveals a negative impact of hyperglycemia with aetiology and pathological progression of TB.

immunology↗

bioRxiv2021

Interaction of hypoxia and nicotine acetylcholine receptor signaling network reveals a novel mechanism for lung adenocarcinoma progression in never-smokers

High incident of lung cancer among never smokers and their disease pathogenesis is an unexplained phenomenon. We have analyzed 1727 lung cancer patient data to understand the impact of smoking on overall survival of lung cancer patients and have observed a difference of only 47 days between smokers and never smokers in adenocarcinoma patients suggesting that the disease is equally fatal in never-smokers irrespective of gender. In this study, we have investigated the possible collaboration between the nAChR and hypoxia signaling pathway to elucidate a mechanism of disease progression in never-smokers. We report a previously unidentified increase in both acetylcholine and nAChR-7 levels in non small cell lung cancer cells in hypoxia. Similar increase in ubiquitously expressed nAChR-7 transcripts was also observed in other cancer lines. A direct binding of HIF-1 with the hypoxia response element (HRE) present at -48 position preceding the transcriptional start site in nAChR-7 promoter region was established. Significantly, the increased acetylcholine levels in hypoxia drove a feedback loop via modulation of PI3K/AKT pathway to stabilize HIF-1 in hypoxia. Further, Bungarotoxin, an antagonist of nAChR-7 significantly reversed hypoxia mediated metastasis and induction of HIF-1 in these cells. Our study gives a plausible explanation for the equally worse prognosis of lung adenocarcinoma in never-smokers wherein the nAChR signaling is enhanced in hypoxia by acetylcholine, in the absence of nicotine.

cancer biology↗

bioRxiv2020

Whole Genome Sequences of Aedes aegypti (Linn.) Field Isolates from Southern India

Aedes spp. mosquitoes are a major health concern as they transmit several viral pathogens resulting in millions of deaths annually around the world. This is compounded by the emergence of insecticide-resistant strains and global warming, which could expose more than half of the world's population to Aedes-borne diseases in the future. Therefore, a comprehensive understanding of vector biology and the genomic basis of phenotypes such as insecticide resistance in natural populations are of paramount importance. Here, we sequenced the genome of Aedes aegypti mosquitos sampled from dengue-endemic areas and investigated the genetic variations between the previously reported laboratory-reared strain and our field isolates. The mosquito genomic DNA was used for paired-end sequencing using the Illumina platform. The reads were used for template-based assembly and mapped to the Aedes aegypti reference genome. Stringent parameters and multiple variant calling methods were used to identify unique single nucleotide variants (SNVs) and insertions-deletions (indels) and mapped to the Aedes chromosomes to create a draft consensus genome. Gene Ontology analyses was performed on the variant-enriched genes while two gene families involved in insecticide resistance were used for comparative sequence and phylogenetic analyses. Comparative sequence variant analyses showed that the majority of the high-quality variants in our samples mapped to non-coding regions of the genome, while gene ontology analyses of genic variants revealed enrichment of terms relevant to drug binding and insecticide resistance. Importantly, one mutation implicated in pyrethroid resistance was found in one Aedes sample. This is the first report of genome sequences of A. aegypti field isolates from India which reveals variants specific to the wild population. This is a useful resource which will facilitate development of robust integrated vector control strategies for management of Aedes-borne diseases through genetic manipulation of local mosquito populations.

genomics↗

bioRxiv2020

MicroRNA-574 Regulates FAM210A Expression and Influences Pathological Cardiac Remodeling

Aberrant synthesis of mitochondrial proteins impairs cardiac function and causes heart disease. However, the mechanism of regulation of mitochondria encoded protein expression during cardiac disease remains underexplored. Here, we have shown that multiple pathogenic cardiac stressors induce the expression of miR-574 guide and passenger strands (miR-574-5p/3p) in both humans and mice. miR-574 knockout mice exhibit severe cardiac disorder under heart disease-triggering stresses. miR-574-5p/3p mimics that are delivered systematically using nanoparticles reduce cardiac pathogenesis under disease insults. Transcriptome analysis of miR-574-null hearts uncovers FAM210A as a common target mRNA for both strands of miR-574. The interactome capture and translational state analyses suggest that FAM210A interacts with mitochondrial translation factors and regulates the protein expression of mitochondrial encoded electron transport chain genes. Using a human cardiomyocyte cell culture system, we discover that miR-574 regulates FAM210A expression and modulates mitochondrial encoded protein expression, which influences cardiac remodeling in heart failure.

pathology↗

bioRxiv2019

Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

Parkinsons disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding alpha-synuclein protein (aSyn), either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent pre-formed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the non-human primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that by inhibiting production of aSyn it may be possible to reverse established pathology and thus supports the development of SNCA ASOs as a potentially disease modifying therapy for PD and related synucleinopathies.\n\nSummaryAntisense oligonucleotides designed against SNCA, which are progressing to the clinic, have the potential to be a disease modifying therapeutic for Parkinsons disease patients.

neuroscience↗

bioRxiv2019

A Sex-Specific Switch in Platelet Receptor Signaling Following Myocardial Infarction

BACKGROUNDA Sex-specific, personalized approach to anti-platelet therapy may be important in patients with myocardial infarction (MI).\n\nOBJECTIVESOur goal was to determine whether platelets activate differently in healthy men and women compared to following MI.\n\nMETHODSBlood was obtained from healthy subjects or patients presenting acutely with ST-segment Elevation Myocardial Infarction (STEMI) and non-ST Segment Elevation Myocardial Infarction (NSTEMI). Platelet function through surface receptor activation was examined in healthy subjects, in patients with MI, and in age- and strain-matched mice before and after MI. Multivariate regression analyses revealed clinical variables associated with platelet receptor sensitivity at the time of MI.\n\nRESULTSPlatelets from healthy women are dose-dependently more active compared to men, particularly through the platelet thromboxane signaling pathway (7.8-fold increase in women vs. 3.0-fold in men, P=0.02). At the time of MI, platelet activation through surface protease-activated receptor 1 (PAR1) was less in women than men (3.5-fold vs. 8.5-fold, respectively, P=0.0001). Multivariate regression analyses revealed male sex (P=0.04) and NSTEMI (P=0.003) as independent predictors of enhanced platelet PAR1 signaling at the time of MI. Similar to humans, healthy female mice showed preferential thrombin-mediated platelet activation compared to male mice (8.7-fold vs. 4.8-fold, respectively; P<0.001). In the immediate post-MI environment, male mice showed preferential thrombin-mediated platelet activation compared to female mice (12.4-fold vs. 5.5-fold, respectively; P<0.001).\n\nCONCLUSIONSThese results outline a previously unrecognized sex-dependent platelet phenotype where inhibition of thrombin signaling in the peri-MI environment--particularly in males--may be an important consideration.\n\nCONDENSED ABSTRACTPreclinical studies evaluating anti-platelet drugs are generally conducted in platelets isolated from healthy individuals. Growing evidence suggests changes in platelet signaling properties in certain disease conditions compared to healthy platelets may alter the response to anti-platelet medications. This investigation revealed that platelets from men and women who are healthy and following MI signal differently, particularly through thromboxane and PAR1 receptors. This effect was especially noted in patients with NSTEMI compared to STEMI. These observations raise the possibility of considering a sex-specific anti-platelet regimen for males and females in atheroembolic vascular diseases such as NSTEMI.

molecular biology↗

bioRxiv2018

Optic disc centered imaging versus quadrant imaging in retinal oximetry

We aimed to compare intra eye quadrant variation in retinal vessel oxygen saturation in optic disc centered versus quadrant imaging. Forty two consecutive healthy subjects were included in the study. Fifty degree optic disc centered images and images of 4 quadrants (supero-temporal - ST, supero-nasal - SN, infero-nasal - IN and infero-temporal - IT) were taken. The thickest arteriole and venule were chosen in each quadrant in the optic disc centered images. For quadrant images averaged values of 3 segments of thickest arterioles and venules, each above 100{micro}m were chosen. The intra-eye variation between quadrants for arteriolar and venous saturation (%) was compared between optic disc centered and quadrant images. Smaller vessels (70 - 100 {micro}m) in the quadrant images were selected to study the effect of vessel calibre on oxygen saturation. Optic disc centered images gave average arteriolar saturation (%) of 90, 94, 93 and 89 and venous saturation of 58, 60, 60 and 52 in the ST, SN, IN and IT respectively. For quadrant images the average arteriolar saturation was 94, 95, 94 and 91 and the venous saturation was 62, 60, 61 and 60 in the ST, SN, IN and IT respectively. Temporally, the saturation values were significantly different (p<0.001) between optic disc centered and quadrant images. We found no differences nasally. The average intra eye range for arterioles was 11.9 in optic disc centered versus 7.1 in quadrant images (p<0.001) and for venules was 11.6 in optic disc centered versus 7.5 in quadrant images (p<0.001). We found a positive correlation of r=0.18 between saturation and vessel calibre for arteries (p=0.001) and a negative correlation of r=-0.52 for venes (p<0.001). Quadrant imaging significantly reduced intra eye variation between quadrant measurements indicating that maybe the larger variation observed in optic disc centered images are artefactual. Differences in saturation between optic disc centered and quadrant imaging were only seen temporally. We also see physiologically reducing saturation from large arterioles to small arterioles to small venules to large venules.

physiology↗

bioRxiv2017

An elective course for medical students on innovation and entrepreneurship

Here we describe \"Innovation and Entrepreneurship in Medicine\" (IEMed), a short elective course that exposed medical students to innovation and entrepreneurship. We assess students self-rated familiarity with various learning objectives after the course and report survey outcomes. Students were most interested in further educational offerings focused on startups and innovation. However, students self-reported relatively lower levels of understanding in regulatory, reimbursement, and legal aspects of health tech. Most participants reported a desire to collaborate with or consult for industry partners, rather than to found or work at a startup. We conclude with a broader discussion of the need to expose medical students to opportunities in the technology industry.

scientific communication and education↗

bioRxiv2017

Efficacy of the β-lactam\β-lactamase inhibitor combination is linked to WhiB4 mediated changes in redox physiology of Mycobacterium tuberculosis

AimsInhibition of {beta}-lactamase by clavulanate (Clav) sensitizes multi-and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains towards {beta}-lactams such as amoxicillin (Amox). However, the underlying mechanism of how Mtb responds to Amox-Clav combination (Augmentin; AG) is not characterized.\n\nResultsWe integrated global expression profiling with the protein-protein interaction landscape and generated a genome-scale network of Mtb in response to AG. In addition to specific targets (e.g., peptidoglycan biosynthesis and {beta}-lactamase), the response to AG was also centered on redox-balance, central carbon metabolism (CCM), and respiration in Mtb. We discovered that AG modulates superoxide levels, NADH/NAD+ balance and mycothiol redox potential (EMSH) of Mtb. Higher intra-mycobacterial EMSH potentiates mycobactericidal efficacy of AG, whereas lower EMSH induces tolerance. Further, Mtb responds to AG via a redox-sensitive transcription factor, WhiB4. Mtb{Delta}whiB4 displayed higher expression of genes involved in {beta}-lactam resistance along with those mediating respiration, CCM and redox balance. Moreimportantly, WhiB4 binds to the promoter regions and represses transcription of genes involved in {beta}-lactamase expression in a redox-dependent manner. Lastly, while Mtb{Delta}whiB4 maintained internal EMSH, exhibited greater {beta}-lactamase activity and displayed AG-tolerance, overexpression of WhiB4 induced oxidative shift in EMSH and repressed {beta}-lactamase activity to aggravate AG-mediated killing of drug-sensitive and -resistant strains of Mtb.\n\nInnovation and ConclusionsThis work demonstrate that efficacy of {beta}-lactam\\{beta}-lactamase inhibitor combination can be attenuated by elevating mycobacterial antioxidant capabilities and potentiated by impairing redox buffering capacity of Mtb. The functional linkage between {beta}-lactams, redox balance, and WhiB4 can be exploited to potentiate AG action against drug-resistant Mtb.

microbiology↗