Biology subjects

Chakraborty, S.

Publications and source records attributed to Chakraborty, S..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

H2 consumption by acetogenic bacteria follows first-order kinetics

Acetogenic bacteria play an important role in various biotechnological processes, because of their chemolithoautotrophic metabolism converting carbon dioxide with molecular hydrogen (H2) as electron donor into acetate. As the main factor limiting acetogenesis is often H2, insights into the H2 consumption kinetics of acetogens is required to assess their potential in biotechnological processes. In this study, initial H2 consumption rates at a range of different initial H2 concentrations were measured for three different acetogens. Interestingly, for all three strains, H2 consumption was found to follow first-order kinetics, i.e. the H2 consumption rate increased linearly with the dissolved H2 concentration, up to almost saturated H2 levels (600 {micro}M). This is in contrast with Monod kinetics and low half-saturation concentrations, which have commonly been assumed for acetogens. The obtained biomass specific first-order rate coefficients (k1X) were further validated by comparison with values obtained by fitting first-order kinetics on previous time-course experimental results. The latter method was also used to determine the k1X value of five additional acetogens strains. Biomass specific first-order rate coefficients were found to vary up to six-fold, with the highest k1X for Acetobacterium wieringae and the lowest for Sporomusa sphaeroides. Overall, our results demonstrate the importance of the dissolved H2 concentration to understand the rate of acetogenesis in biotechnological systems.

microbiology↗

bioRxiv2024

Bi-directional allosteric pathway in NMDA receptor activation and modulation

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilized single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane segments inversely correlate with those observed at the amino-terminal domain, confirming direct allosteric communication between these domains. Additionally, binding of a positive allosteric modulator at the transmembrane domain shifts the conformational profile of the amino-terminal domain towards the active state, revealing a bidirectional allosteric pathway between extracellular and transmembrane domains.

biophysics↗

bioRxiv2024

Evidence for intrinsic DNA dynamics and deformability in damage sensing by the Rad4/XPC nucleotide excision repair complex

Altered DNA dynamics at lesion sites are implicated in how DNA repair proteins sense damage within genomic DNA. We examined DNA dynamics related to damage recognition by Rad4 (yeast ortholog of XPC), which recognizes diverse lesions from environmental mutagens and initiates nucleotide excision repair. Using laser temperature-jump (T-jump), we measured the dynamics of DNA containing 3 base-pair mismatches recognized specifically by Rad4 in vitro. The T-jump kinetics traces measured using a cytosine-analog FRET pair, together with rigorous comparison with equilibrium measurements, enabled conformational dynamics to be revealed beyond the T-jump observation window of [~]20 {micro}s - 50 ms. AT-rich nonspecific sites (matched or mismatched) exhibited dynamics primarily within the T-jump window, albeit with some amplitude in "missing" fast (< 20 {micro}s) kinetics. The fast-kinetics amplitudes increased dramatically for specific sites, which were further distinguished by additional missing amplitude in slow (> 50 ms) kinetics at elevated temperatures. We posit that the rapid ({micro}s-ms) fluctuations help stall a diffusing protein at AT-rich/damaged sites and that the >50-ms kinetics reflect a propensity for specific DNA to adopt unwound/bent conformations that may resemble Rad4-bound structures. These studies provide compelling evidence for unusual DNA dynamics and deformability that likely govern how Rad4 senses DNA damage.

biophysics↗

bioRxiv2024

Thermal tolerance of mosquito eggs is associated with urban adaptation and human interactions

Climate change is expected to profoundly affect mosquito distributions and their ability to serve as vectors for disease, specifically with the anticipated increase in heat waves. The rising temperature and frequent heat waves can accelerate mosquito life cycles, facilitating higher disease transmission. Conversely, higher temperatures could increase mosquito mortality as a negative consequence. Warmer temperatures are associated with increased human density, suggesting a need for anthropophilic mosquitoes to adapt to be more hardy to heat stress. Mosquito eggs provide an opportunity to study the biological impact of climate warming as this stage is stationary and must tolerate temperatures at the site of female oviposition. As such, egg thermotolerance is critical for survival in a specific habitat. In nature, Aedes mosquitoes exhibit different behavioral phenotypes, where specific populations prefer depositing eggs in tree holes and prefer feeding non-human vertebrates. In contrast, others, particularly human-biting specialists, favor laying eggs in artificial containers near human dwellings. This study examined the thermotolerance of eggs, along with adult stages, for Aedes aegypti and Ae. albopictus lineages associated with known ancestry and shifts in their relationship with humans. Mosquitoes collected from areas with higher human population density, displaying increased human preference, and having a human-associated ancestry profile have increased egg viability following high-temperature stress. Unlike eggs, thermal tolerance among adults showed no significant correlation based on the area of collection or human-associated ancestry. This study highlights that the egg stage is likely critical to mosquito survival when associated with humans and needs to be accounted when predicting future mosquito distribution.

ecology↗

bioRxiv2024

Intra-species quantification reveals differences in activity and sleep levels in the yellow fever mosquito, Aedes aegypti

Aedes aegypti is an important mosquito vector of human disease with a wide distribution across the globe. Climatic conditions and ecological pressure drive differences in the biology of several populations of this mosquito, including blood-feeding behavior and vector competence. However, no study has compared activity and/or sleep among different populations/lineages of Ae. aegypti. Having recently established sleep-like states in three mosquito species with observable differences in timing and amount of sleep among species, we investigated differences in activity and sleep levels among 17 Ae. aegypti lines drawn from both its native range in Africa and its invasive range across the global tropics. Activity monitoring indicates that all the lines show consistent diurnal activity, but significant differences in activity level, sleep amount, number of sleep bouts, and bout duration were observed among the lines. Variations in specific activity and sleep parameters were explained by differences in host preference, ancestry, and human population density for the lineages collected in Africa. This study provides evidence that the diurnal sleep and activity profiles for Ae. aegypti are consistent, but there are significant population differences for Ae. aegypti sleep and activity levels and interactions with humans may significantly impact mosquito activity and sleep.

physiology↗

bioRxiv2024

Post-GWAS functional analyses of CNTNAP5 suggests its role in glaucomatous neurodegeneration

Primary angle closure glaucoma (PACG) affects more than 20 million people worldwide, with an increased prevalence in south-east Asia. In a prior haplotype-based GWAS, we identified a novel CNTNAP5 genic region, significantly associated with PACG. In the current study, we have extended our perception of CNTNAP5 involvement in glaucomatous neurodegeneration in a zebrafish model, through investigating phenotypic consequences pertinent to retinal degeneration upon knockdown of cntnap5 by translation-blocking morpholinos. While cntnap5 knockdown was successfully validated using an antibody, immunofluorescence followed by western blot analyses in cntnap5-morphant (MO) zebrafish revealed increased expression of acetylated tubulin indicative of perturbed cytoarchitecture of retinal layers. Moreover, significant loss of Nissl substance is observed in the neuro-retinal layers of cntnap5-MO zebrafish eye, indicating neurodegeneration. Additionally, in spontaneous movement behavioural analysis, cntnap5-MO zebrafish have a significantly lower average distance traversed in light phase compared to mismatch-controls, whereas no significant difference was observed in the dark phase, corroborating with vision loss in the cntnap5-MO zebrafish. This study provides the first direct functional evidence of a putative role of CNTNAP5 in visual neurodegeneration.

genetics↗

bioRxiv2024

Aedes albopictus colonies from different geographic origins differ in their sleep and activity levels but not in the time of peak activity

Mosquitoes occupy a wide range of habitats where they experience various environmental conditions. The ability of some species, such as the tiger mosquito, Aedes albopictus, to adapt to local conditions certainly contributes to their invasive success. Among traits that remain to be examined, mosquitoes ability to time their activity with that of the local host population has been suggested to be of significant epidemiological importance. However, whether different populations display heritable differences in their chronotype has not been examined. Here, we compared laboratory strains originating from 8 populations from 3 continents, monitored their spontaneous locomotor activity patterns, and analyzed their sleep-like states. Overall, all strains showed conserved diurnal activity concentrated in the hours preceding the crepuscule. Similarly, they all showed increased sleep levels during the morning and night hours. However, we observed strain-specific differences in the activity levels at each phase of the day. We also observed differences in the fraction of time that each strain spends in a sleep-like state, explained by variations in the sleep architecture across strains. Human population density and the latitude of the site of geographic origin of the tested strain showed significant effects on sleep and activity patterns. Altogether, these results suggest that Ae. albopictus mosquitoes adapt to local environmental conditions via heritable adaptations of their chronotype.

animal behavior and cognition↗

bioRxiv2024

O6-Alkylguanine-DNA Alkyltransferase Maintains Genomic Integrity During Peroxynitrite-Mediated DNA Damage by Forming DNA-Protein Crosslinks

Inflammation is an early immune response against invading pathogens and damaged tissue. Although beneficial, uncontrolled inflammation leads to various diseases and may be fatal. Peroxynitrite (PN) is a major reactive nitrogen species (RNS) generated during inflammation. It produces various DNA lesions including labile 8-nitroguanine which spontaneously converts into abasic sites resulting in DNA strand breakage. Here, we report the discovery of a previously unrecognized function of the human repair protein O6-alkylguanine-DNA alkyltransferase (hAGT or MGMT). We showed that hAGT through its active site nucleophilic Cys145 thiolate can spontaneously react with 8-nitroguanine in DNA to form a stable DNA-protein crosslink (DPC). Interestingly, the process of DPC formation provides protection from PN-mediated genome instability. The Cys145-mutant of hAGT failed to form DPC and provide protection against inflammation-associated, PN-mediated cytotoxicity. Gel shift, dot blot and UV-Vis assays showed formation of a covalent linkage between PN-damaged DNA and hAGT through its active site Cys145. Finally, expression of hAGT was found to be significantly increased by induced macrophages and PN. The data presented here clearly demonstrated hAGT as a dual function protein that along with DNA repair is capable of maintaining genomic integrity and providing protection from the toxicity caused by PN-mediated DNA damage. Although DPCs may seem detrimental, there are multiple systems in place in normal cells for their repair.

pharmacology and toxicology↗

bioRxiv2024

RomX, a novel prokaryotic regulator, links the response receiver domain of RomR with GTP-bound MglA for establishing Myxococcus xanthus polarity

Cell polarity specification and reversals are distinctive features of motility of the soil bacterium Myxococcus xanthus. The bacterial small Ras-like GTPase, MglA, serves as a key player orchestrating these polarity oscillations. RomR, a response regulator, along with its partner RomX, has been identified to function as a guanine nucleotide exchange factor (GEF) for MglA, crucial for its polar recruitment. In this study, we determine the crystal structure of RomX, a protein of a hitherto unknown fold. RomX consists of a three-helix bundle, identified to be the same fold as the stalk domain of atlastin, a member of the dynamin family of GTPases. From our structure-based sequence analysis for proteins of a similar fold, we observe the co-occurrence of the RomX fold with response receiver domains in several bacterial response regulators. Based on mutational analysis and affinity measurements, we conclude that the helix-1 of RomX mediates the interaction with MglA-GTP, while helix-3 of RomX interacts with the RomR N-terminal receiver (REC) domain. We demonstrate that the binding between MglA and RomX is exclusively in the presence of GTP. The absence of additional stimulation of RomX GEF activity in the presence of RomR-REC supports the mutually exclusive interface on RomX for RomR and MglA interaction. Collectively, our findings validate the positioning of RomX between MglA and RomR-REC, providing insights into the concerted action of the RomR/RomX complex at both poles in driving MglA localization within polarized cells.

biochemistry↗

bioRxiv2024

S-nitrosylation of EZH2 at C329 and C700 interplay with PRC2 complex assembly, methyltransferase activity, and EZH2 stability to regulate endothelial functions

Nitric oxide (NO), a versatile bio-active molecule modulates cellular function through diverse mechanisms including S-nitrosylation of proteins. However, the role of this post-translational modification in regulating epigenetic pathways was very limitedly explored. Herein, we report that NO causes S-nitrosylation of selected cysteine residues of EZH2 in endothelial cells (EC) resulting in SUZ12 dissociation from EZH2 bound PRC2 complex, reduced methyltransferase activity, and diminished nuclear localization eventually hampering its stability. We detected a significant reduction in H3K27me3 upon exposure to NO as contributed by the early dissociation of SUZ12 from the PRC2 complex. Longer exposure to NO donors caused EZH2 cytosolic translocation, its ubiquitination, and further degradation primarily through the autophagosome-lysosome pathway. Through in silico S-nitrosylation prediction analysis and site-directed mutagenesis assay, we identified three cysteine residues namely at locations 260, 329, and 700 in EZH2 and further determined that S-nitrosylation of cysteine 329 induced EZH2 instability while S-nitrosylation of cysteine 700 abrogated EZH2s catalytic activity. A double mutant of EZH2 containing mutations at Cysteine 329 and 700 remained undeterred to NO exposure. Furthermore, reinforcing H3K27me3 in NO exposed EC through the use of an inhibitor of H3K27me3 demethylase, we confirmed a significant contribution of the EZH2-H3K27me3 axis in defining NO-mediated regulation of endothelial gene expression and migration. Molecular dynamics simulation study revealed SUZ12s inability in efficiently binding to the SAL domain of EZH2 upon S-nitrosylation of C329 and C700. Taken together, our study for the first-time reports that S-nitrosylation dependent regulation of EZH2 and its associated PRC2 complex influences endothelial homeostasis.

cell biology↗

bioRxiv2024

ALTering cancer by triggering telomere replication stress through the stabilization of promoter G-quadruplex in SMARCAL1

Most of the human cancers are dependent on telomerase to extend the telomeres. But [~]10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to poor prognosis, the ALT status is not being considered yet in the diagnosis of cancer. No such specific treatment is available till date for ALT cancers. ALT positive cancers are dependent on replication stress to deploy DNA repair pathways to the telomeres to execute homology recombination mediated telomere extension. SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is associated with the ALT telomeres to resolve replication stress thus providing telomere stability. Thus, the dependency on replication stress regulatory factors like SMARCAL1 made it a suitable therapeutic target for the treatment of ALT positive cancers. In this study, we found a significant downregulation of SMARCAL1 expression by stabilizing the G-quadruplex (G4) motif found in the promoter of SMARCAL1 by potent G4 stabilizers, like TMPyP4 and BRACO-19. SMARCAL1 downregulation led towards the increased localization of PML (promyelocytic leukaemia) bodies in ALT telomeres and triggered the formation of APBs (ALT-associated promyelocytic leukaemia bodies) in ALT positive cell lines, thus increasing telomere replication stress and DNA damage at genomic level. Induction of replication stress and hyper recombinogenic phenotype in ALT cells mediated by G4 stabilizing molecules already highlighted their possible application as a new therapeutic window to target ALT-positive tumors. In accordance with this, our study will also provide a valuable insight towards the development of G4 based ALT-therapeutics targeting SMARCAL1.

biochemistry↗

bioRxiv2024

Curtailed CaSR expression in peripheral blood mononuclear cells is associated with hypertension

The calcium-sensing receptor (CaSR) is a GPCR family member. CaSR is abundantly expressed in the parathyroid gland and controls calcium homeostasis. There are no particular discoveries involving CaSR expression in hypertensive peripheral blood mononuclear cells. We investigated lower CaSR expression in hypertensive human and animal models. Nitric oxide (NO) has an important role in vascular function. Impaired NO production disrupts CaSR-mediated fine adjustment of the intra- and extracellular [Ca2+] gradients. According to the law Ca2+ transportation through Ca channels maintains its connection from the circulatory micro-vascular bed to interstitial space, influenced by capillary and interstitial fluid hydrostatic pressure, as well as oncotic pressure. In that situation, the alterations in Ca2+ microenvironment and dynamics remain unknown. CaSR on circulatory mononuclear cells may detect changes in the Ca2+ microenvironment in the ISF of endothelial cells-VSMC and endothelium lining in hypertension. In this experiment, the decreased expression of CaSR revealed a molecular sensor in the presence of elevated blood pressure.

biochemistry↗

bioRxiv2023

Fermented polyherbal formulation restored ricinoleic acid-induced diarrhea in Sprague Dawley rats and exhibited in vitro antibacterial effect on multiple antibiotics resistant gastric pathogens

The involvement of multiple antibiotics resistant gastric pathogens in diarrhea aggravates the disease condition uncontrollably. Current study was aimed at finding and developing a suitable formulation utilizing multiple natural components from known plant sources to augment current therapeutic outcomes. Hydro-ethanolic extraction method was applied through boiling and fermentation, on ancient observation based efficacious plant parts for developing antidiarrheal polyherbal formulation AP-01. Animal study model of diarrhea was used to evaluate safety and efficacy of the formulation. The formulation was tested in vitro on four different multiple antibiotics resistant gastric pathogens collected from national repository. The formulation depicted no cytotoxicity on normal gut cells and was efficacious at 10 ml/Kg single dose in relieving symptoms of diarrhea by 79.71%, in comparison with standard drug showing reduction of symptoms by 83.01%. AP-01 exhibited delaying the gastric motility. Symptoms of diarrhea ceased to occur within 321 minutes with AP-01, where the standard drug took 308 minutes. AP-01 was found successful at a viable dosage regimen of 75 to 100 microliter per ml, in inhibiting growth of different pathogens from Enterobacteriaceae family possessing resistance against several classes of antibiotics, in culture media. Chemical analysis revealed different alkaloids, flavonoids and polyphenols those probably work in unison through multiplex modes of action to arrest diarrhea and inhibit pathogens at the same time. These promising results shown by AP-01 should definitely evoke an effort to dive deep into research and development for better therapeutic formulations for infectious diarrhea by harvesting the arsenal of nature.

microbiology↗

bioRxiv2023

Fermented polyherbal formulation ameliorates the severity of acute multiple - antibiotics - resistant Pseudomonas aeruginosa infected burn wound in rat burn model

Pseudomonas aeruginosa, a Gram-negative opportunistic bacterium has emerged as a cause of life-threatening infections in topical burn wounds. Current therapeutic approaches thru wound dressings and systemic medicines are far from satisfactory; multiple-antibiotic-resistance shown by pathogens contribute to failures of therapy causing mortality. This animal study was conducted to check efficacy of one Ayurveda based fermented polyherbal preparation (AP 01) against multiple antibiotic resistant Pseudomonas aeruginosa HW01 infected rat burn wounds. AP-01 was applied on artificially inflected burn wound on rat model infected with Multiple Antibiotics Resistant Pseudomonas aeruginosa to register the healing effects in terms of reduction in residual wound area percentage, presence of C-reactive protein in blood, presence of viable bacteria colony while keeping conventional antibiotics as positive control. The polyherbal preparation had reduced the infected residual burn wound area at 40.63% {+/-} 0.69 from the initial burn wound area within two weeks after a single intervention; whereas residual burn wound area remained much higher in case of animals left untreated and in case of the animals treated with control drug. Restoration to normalcy of serum C-reactive protein level were also achieved earlier in case of polyherbal AP-01 treated groups than other groups. Fermented formulation using components of AP-01 singly or in different combinations were never been tested earlier for topical application in infected burn-wound. The formulation AP-01 was found superior in terms of rate of healing and control of infection by multiple-antibiotic-resistant P. aeruginosa strains in burn wounds in rat model.

microbiology↗

bioRxiv2023

SUMO protease and proteasome recruitment at the nuclear periphery differently affect replication dynamics at arrested forks.

Nuclear pores complexes (NPCs) are genome organizers, defining a particular nuclear compartment enriched for SUMO protease and proteasome activities, and acting as docking sites for DNA repair. In fission yeast, the anchorage of perturbed replication forks to NPCs is an integral part of the recombination-dependent replication restart mechanism (RDR) that resumes DNA synthesis at terminally dysfunctional forks. By mapping DNA polymerase usage, we report that SUMO protease Ulp1-associated NPCs ensure efficient initiation of restarted DNA synthesis, whereas proteasome-associated NPCs sustain the progression of restarted DNA polymerase. In contrast to Ulp1-dependent events, this last function occurs independently of SUMO chains formation. By analyzing the role of the nuclear basket, the nucleoplasmic extension of the NPC, we reveal that the activities of Ulp1 and the proteasome cannot compensate for each other and affect RDR dynamics in distinct ways. Our work probes the mechanisms by which the NPC environment ensures optimal RDR. Highlights[bullet] Ulp1-associated NPCs ensure efficient initiation of restarted DNA synthesis, in a SUMO chain-dependent manner [bullet]Proteasome-associated NPCs foster the progression of restarted DNA synthesis, in a SUMO chain-independent manner [bullet]The nucleoporin Nup60 promotes the spatial sequestration of Ulp1 at the nuclear periphery [bullet]Ulp1 and proteasome activities are differently required for optimal recombination-mediated fork restart.

molecular biology↗

bioRxiv2023

Identification of new markers of angiogenic sprouting using transcriptomics: New role for RND3

BackgroundNew blood vessel formation requires endothelial cells to transition from a quiescent to an invasive phenotype. Transcriptional changes are vital for this switch, but a comprehensive genome-wide approach focused exclusively on endothelial cell sprout initiation has not been reported. Approach and ResultsUsing a model of human endothelial cell sprout initiation, we developed a protocol to physically separate cells that initiate the process of new blood vessel formation (invading cells) from non-invading cells. We used this model to perform multiple transcriptomics analyses from multiple donors to monitor endothelial gene expression changes. Single-cell Population Analyses, single-cell Cluster Analyses, and bulk RNA sequencing were used to delineate transcriptomic changes in invading cells. The results revealed a 39 gene signature that was consistent with activation of signal transduction, morphogenesis, and immune responses. Many of the genes were previously shown to regulate angiogenesis, and include multiple tip cell markers. Upregulation of SNAI1, PTGS2, and JUNB protein expression was confirmed in invading cells, and silencing JunB and SNAI1 significantly reduced invasion responses. Separate studies investigated Rounding 3 (RND3), also known as RhoE, which has not yet been implicated in angiogenesis. Silencing RND3 reduced endothelial invasion distance as well as filopodia length, fitting with a pathfinding role for RND3 via regulation of filopodial extensions. Analysis of in vivo retinal angiogenesis in Rnd3 heterozygous mice confirmed a decrease in filopodial length compared to wild type littermates. ConclusionValidation of multiple genes, including RND3, revealed a functional role for this gene signature early in the angiogenic process. This study expands the list of genes that are associated with the acquisition of a tip cell phenotype during endothelial cell sprout initiation. HIGHLIGHTSO_LITranscriptomic analyses identified 39 candidate genes that were upregulated at the onset of endothelial sprouting C_LIO_LIThe gene signature includes signal transduction, morphogenesis, and immune responses C_LIO_LINewly-identified RND3 is associated with filopodial extension and pathfinding C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/563021v1_ufig1.gif" ALT="Figure 1"> View larger version (92K): org.highwire.dtl.DTLVardef@1045439org.highwire.dtl.DTLVardef@1357703org.highwire.dtl.DTLVardef@1189cf2org.highwire.dtl.DTLVardef@e7d574_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Focal acetylcholinergic modulation of the human midcingulo-insular network during attention: Meta-analytic neuroimaging and behavioral evidence

The basal forebrain cholinergic neurons provide acetylcholine to the cortex via large projections. Recent molecular imaging work in humans indicates that the cortical cholinergic innervation is not uniformly distributed, but rather may disproportionately innervate cortical areas relevant to supervisory attention. In this study, we therefore reexamined the spatial relationship between acetylcholinergic modulation and attention in the human cortex using meta-analytic strategies targeting both pharmacological and nonpharmacological neuroimaging studies. We found that pharmaco-modulation of acetylcholine evoked both increased activity in the anterior cingulate and decreased activity in the opercular and insular cortex. In large independent meta-analyses of non-pharmacological neuroimaging research, we demonstrate that during attentional engagement these cortical areas exhibit (1) task-related co-activation with the basal forebrain, (2) task-related co-activation with one another, and (3) spatial overlap with dense cholinergic innervations originating from the BF, as estimated by multimodal PET and MR imaging. Finally, we provide meta-analytic evidence that pharmaco-modulation of acetylcholine also induces a speeding of responses to targets with no apparent tradeoff in accuracy. In sum, we demonstrate in humans that acetylcholinergic modulation of midcingulo-insular hubs of the ventral attention/salience network via basal forebrain afferents may coordinate selection of task relevant information, thereby facilitating cognition and behavior.

neuroscience↗

bioRxiv2023

COVID-19 ORF3a Viroporin Influenced Common and Unique Cellular Signalling Cascades in Lung, Heart and Brain Choroid Plexus Organoids with Additional Enriched MicroRNA Network Analyses for Lung and Brain Tissues

Tissue specific implications of SARS-CoV-2 encoded accessory proteins are not fully understood. SARS-CoV-2 infection can severely affect three major organs - the heart, lung, and brain. We analysed SARS-CoV-2 ORF3a interacting host proteins in these three major organs. Further we identified common and unique interacting host proteins, their targeting miRNAs (lung and brain), and delineated associated biological processes reanalysing RNA-seq data from the brain (COVID-19 infected/uninfected Choroid Plexus Organoids study), lung tissue from COVID-19 patients/healthy subjects, and cardiomyocyte cells based transcriptomics analyses. Our in silico studies showed ORF3a interacting proteins could vary depending upon tissues. Number of unique ORF3a interacting proteins in brain, lung and heart were 10, 7 and 1 respectively. Though common pathways influenced by SARS-CoV-2 infection were more, unique 21 brain and 7 heart pathways were found. One unique pathway for heart was negative regulation of calcium ion transport. Reported observations of COVID-19 patients with the history of hypertension taking calcium channel blockers (CCBs) or dihydorpyridine CCBs had elevated rate of intubation or increased rate of intubation/death respectively. Also likelihood of hospitalization of chronic CCB users with COVID-19 was more in comparison to long term Angiotensin Converting Enzyme inhibitors/Angiotensin Receptor Blockers users. Further studies are necessary to confirm this. miRNA analysis of ORF3a interacting proteins in brain and lung revealed, 2 of 37 brain miRNAs and 1 of 25 lung miRNAs with high degree and betweenness indicating their significance as hubs in the interaction network. Our study could help in identifying potential tissue specific COVID-19 drug/drug repurposing targets.

bioinformatics↗