Biology subjects

Sen, P.

Publications and source records attributed to Sen, P..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

A hyper-quiescent chromatin state formed during aging is reversed by regeneration

Epigenetic alterations are a key hallmark of aging but have been limitedly explored in tissues. Here, using naturally aged murine liver as a model and extending to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach, and the first direct visualization of aged chromatin we find that globally, old cells show H3K27me3-driven broad heterochromatinization and transcription suppression. At the local level, site-specific loss of H3K27me3 over promoters of genes encoding developmental transcription factors leads to expression of otherwise non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver.

genomics↗

bioRxiv2023

Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging

DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.

genomics↗

bioRxiv2022

Codon degeneracy as well as pretermination codons influence transition to transversion ratio in coding sequences

Transition (ti) and transversion (tv) are the major causes for genome variation. The accurate estimation of ti to tv ratio [Formula] in genomes is crucial for understanding of mutational and selection processes in organisms as it is influenced by both codon degeneracy and pretermination codons (PTC). Therefore, we developed a method (accessible at https://github.com/CBBILAB/CBBI.git) to estimate [Formula] ratio by accounting codon degeneracy as well as PTC in protein coding sequences. Our findings revealed a distinct impact of codon degeneracy and PTC on the [Formula] ratio in the Escherichia coli genome. We observed a decreasing order among the frequencies of different base substitutions such as synonymous transition (Sti) > synonymous transversion (Stv) > non-synonymous transition (Nti) > non-synonymous transversion (Ntv) in E. coli genome. The correlation was strong between Sti and Stv values (Pearson r value 0.795) whereas the correlation was weak between Sti and Nti (Pearson r value 0.192). Coding sequences with similar Sti values exhibited a wide range of Nti values. This indicated the varying strength of purifying selection acting on the coding sequences. In concordance with the assumption, the genes having higher Nti values were observed with lower codon adaptation index (CAI) values than that of the genes having lower Nti values. Our approach is convenient to visualize the frequency of base substitution variation as well as selection in protein coding sequences. The proposed method is useful to estimate different [Formula] ratios accurately in coding sequences and is insightful from an evolutionary perspective. Article SummaryGenetic diversity is pivotal in evolution, with base substitution as a key driver. Transition (ti) frequency surpasses transversion (tv) frequency in genomes, making [Formula] ratios a valuable metric for studying mutation bias. Our improved estimator for [Formula] calculation accounts for codon degeneracy and nonsense substitutions in pretermination codons. Additionally, we unveil insights into the frequency of different substitutions such as Sti, Stv, Nti, and Ntv and demonstrate the impact of selection on protein coding sequences.

evolutionary biology↗

bioRxiv2022

Identification of potential antifibrinolytic compounds against kringle-1 and serine protease domain of plasminogen and kringle-2 domain of tissue-type plasminogen activator using combined virtual screening, molecular docking, and molecular dynamics simulation approaches.

The zymogen protease Plasminogen (Plg) and its active form plasmin (Plm) carry out important functions in the blood clot disintegration (breakdown of fibrin fibres) process. Inhibition of plasmin effectively reduces fibrinolysis to circumvent heavy bleeding. Currently, available Plm inhibitor tranexamic acid (TXA) that is used to treat severe hemorrhages is associated with an increased incidence of seizures which in turn were traced to gamma-aminobutyric acid antagonistic activity (GABAa) in addition to having multiple side effects. Fibrinolysis can be suppressed by targeting the three important protein domains: kringle-1 and serine protease domain of plasminogen and kringle-2 domain of tissue plasminogen activator. In the present study, combined approaches of structure-based virtual screening and molecular docking using Schrodinger Glide, AutoDock Vina, and ParDock/BAPPL+ were employed to identify potential hits from the ZINC database. Thereafter, the drug-likeness properties of the top three leads for each protein target were evaluated using Discovery Studio. Subsequently, a molecular dynamics simulation of 200ns for each protein-ligand complex was performed in GROMACS. The identified ligands are found to impart higher rigidity and stability to the protein-ligand complexes. Furthermore, the results were validated by performing the principal component analysis (PCA), and calculation of binding free energy using the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approach. The identified ligands occupy smaller phase space, form stable clusters and exhibit stronger non-bonded interactions. Thus, our findings can be useful for the development of promising anti-fibrinolytic agents. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/512028v2_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@b762fforg.highwire.dtl.DTLVardef@1c47591org.highwire.dtl.DTLVardef@1028dc1org.highwire.dtl.DTLVardef@a884ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

The transcribed intergenic regions exhibit lower frequency of nucleotide polymorphism than the untranscribed intergenic regions in the genomes of Escherichia coli and Salmonella enterica

The temporary exposure of single-stranded regions in the genome during the process of replication and transcription makes the region vulnerable to cytosine deamination resulting higher rate of C[->]T transitions. Intra-operon intergenic regions undergo transcription along with adjacent co-transcribed genes in an operon, whereas inter-operon intergenic regions only undergo replication. Hence these two types of intergenic regions (IGRs) can be compared to find out the contribution of replication-associated mutations (RAM) and transcription-associated mutations (TrAM) towards bringing variation in genomes. In our work, we performed a polymorphism spectra comparison between intra-operon IGRs and inter-operon IGRs in genomes of two well-known closely related bacteria such as Escherichia coli and Salmonella enterica. In general, the size of intra-operon IGRs was smaller than that of inter-operon IGRs in these bacteria. Interestingly, the polymorphism frequency at intra-operon IGRs was 2.5-fold lesser than that in the inter-operon IGRs in E. coli genome. Similarly, the polymorphism frequency at intra-operon IGRs was 2.8-fold lesser than that in the inter-operon IGRs in S. enterica genome. Therefore, the intra-operon IGRs were often observed to be more conserved. In the case of inter-operon IGRs, the T[->]C transition frequency was a minimum of two times more than T[->]A transversion frequency whereas in the case of intra-operon IGRs, T[->]C transition frequency was similar to that of T[->]A transversion frequency. The polymorphism was purine biased and keto biased more in intra-operon IGRs than the inter-operon IGRs. In E. coli, the Ti/Tv ratio was observed as 1.639 and 1.338 in inter-operon and in intra-operon IGRs, respectively. In S. enterica, the Ti/Tv ratio was observed as 2.134 and 2.780 in inter-operon and in intra-operon IGRs, respectively. The observation in this study indicates that transcribed IGRs might not always have higher polymorphism frequency than the untranscribed IGRs. The lower polymorphism frequency at intra-operon IGRs might be attributed to different events such as the transcription-coupled DNA repair, sequences facilitating translation initiation and avoidance of rho-dependent transcription termination.

evolutionary biology↗

bioRxiv2022

Synonymous polymorphism difference relating to codon degeneracy between co-transcribed genes in the genome of Escherichia coli

The previous findings suggest that replication and transcription are two major reasons behind the different substitution patterns of mutations in genomic DNA. In the current work, we have compared the adjacent co-transcribed gene pairs regarding synonymous polymorphism in five different operons in Escherichia coli. It is interesting that the co-transcribed genes were different from each other regarding the polymorphism spectra. The transition to transversion ratio between gene pairs were different due to their compositional differences regarding two-fold degenerate codon and four-fold degenerate codons. Further, the polymorphism spectra difference between the gene pairs was more prominent in four-fold and six-fold degenerate codons than in the two-fold degenerate codons. In case of rpoB and rpoC, the major difference was found at UCC, GUA, CCG, GCU, GGC and CGC codons. Similarly, in case of the other four pairs of co-transcribed genes, the difference was more prominent in the higher degenerate codons than the two-fold degenerate codons. It may be that the restriction of two-fold degenerate codons to transition substitutions only regarding synonymous polymorphism is making these codons different from the higher degeneracy codons in this study.

evolutionary biology↗

bioRxiv2022

Spurious intragenic transcription is a hallmark of mammalian cellular senescence and tissue aging

Mammalian aging is characterized by the progressive loss of tissue integrity and function manifesting in ill health and increased risk for developing multiple chronic conditions. Accumulation of senescent cells in aging tissues partly contributes to this decline and targeted depletion of senescent cells in vivo ameliorates many age-related phenotypes. However, the fundamental molecular mechanisms responsible for the decline of cellular health and fitness during senescence and aging are largely unknown. In this study, we investigated whether chromatin-mediated loss of transcriptional fidelity, known to contribute to fitness and survival in yeast and worms, also occurs during human cellular senescence and mouse aging. Our findings reveal that aberrant transcription initiation inside genes is widespread in senescence and aging. It co-occurs with changes in the chromatin landscape and formation of non-canonical transcription start sites. Interventions that alter spurious transcripts have dramatic consequences on cellular health primarily affecting intracellular signal transduction pathways. We propose that spurious transcription is a conserved hallmark of aging that promotes a noisy transcriptome and degradation of coherent transcriptional networks.

genomics↗

bioRxiv2022

An in vivo and in silico evaluation of the magical hepatoprotective potentialities of Gynura procumbens: a promising agent for combating hepatotoxicity

IntroductionLiver being the most important metabolic organ of the body performs a wide variety of vital functions. Hepatic cell injury occurs by the activation of reactive oxygen species (ROS) by CCl4, xenobiotics and other toxic substances generated through cytochrome P450 dependent step resulting from covalent bond formation with lipoproteins and nucleic acids. Observing the alarming state of hepatotoxic patients worldwide, different medicinal plants and their properties can be explored to combat against such free radical degermation of liver. This paper evaluates the antioxidant property of Gynura procumbens in both in silico and in an in vivo assay, and its hepatoprotective activity in CCl4 induced hepatotoxicity. Materials and MethodsGynura procumbens leaves were collected and extracted using 50% ethanol. Required chemicals (CCl4), standard drug (Silymarin) and blood serum analyzing kits were stocked. The in vivo tests were performed in 140 healthy Wister albino male rats under well controlled parameters dividing into 14 groups, strictly maintaining IEAC protocols. In silico molecular docking and ADMET studies were performed and the results were analyzed statistically. Results and discussionThe body weight increased significantly in CCl4 induced, G. procumbens administered hepatotoxic rats. The increase in SGPT, SGOT, ALP, creatinine, LFH, triglycerides, LDL, SOD, MDA, total cholesterol, DNA fragmentation ranges, {gamma}GT levels of CCl4 treated group was decreased by both standard drug Silymarin and G. procumbens leaf extract. On the other hand, G. procumbens increased HDL levels and displayed contrasting results in CAT level tests. Some results contradicted with the negative controlled group displaying varying efficacy between leaf extract and Silymarin. In the molecular docking analysis, G. procumbens phytoconstituents performed poorly against TGF-{beta}1 compared to the control drug Galunisertib while 26 phytoconstituents scored better than the control, bezafibrate against PPAR-. Flavonoids and phenolic compounds performed better than other constituents in providing hepatoprotective activity.

bioinformatics↗

bioRxiv2022

In Silico transcriptional analysis of asymptomatic and severe COVID-19 patients reveals the susceptibility of severe patients to other comorbidities and non-viral pathological conditions

COVID-19 is a severe respiratory disease caused by SARS-CoV-2, a novel human coronavirus. The host response to SARS-CoV-2 infection is not clearly understood. Patients infected with SARS-CoV-2 exhibit heterogeneous intensity of symptoms, i.e., asymptomatic, mild, and severe. Moreover, effects on organs also vary from person to person. These heterogeneous responses pose pragmatic hurdles for implementing appropriate therapy and management of COVID-19 patients. Post-COVID complications pose another major challenge in managing the health of these patients. Thus, understanding the impact of disease severity at the molecular level is vital to delineate the precise host response and management. In the current study, we performed a comprehensive transcriptomics analysis of publicly available seven asymptomatic and eight severe COVID-19 patients. Exploratory data analysis using Principal Component Analysis (PCA) showed the distinct clusters of asymptomatic and severe patients. Subsequently, the differential gene expression analysis using DESeq2 identified 1,224 significantly upregulated genes (logFC>= 1.5, p-adjusted value <0.05) and 268 significantly downregulated genes (logFC<= -1.5, p-adjusted value <0.05) in severe samples in comparison to asymptomatic samples. Eventually, Gene Set Enrichment Analysis (GSEA) of upregulated genes revealed significant enrichment of terms, i.e., anti-viral and anti-inflammatory pathways, secondary infections, Iron homeostasis, anemia, cardiac-related, etc. Gene set enrichment analysis of downregulated genes indicates lipid metabolism, adaptive immune response, translation, recurrent respiratory infections, heme-biosynthetic pathways, etc. In summary, severe COVID-19 patients are more susceptible to other health issues/concerns, non-viral pathogenic infections, atherosclerosis, autoinflammatory diseases, anemia, male infertility, etc. And eventually, these findings provide insight into the precise therapeutic management of severe COVID-19 patients and efficient disease management.

bioinformatics↗

bioRxiv2022

Single-cell analysis of skeletal muscle macrophages reveals age- associated functional subpopulations

Tissue-resident macrophages represent a group of highly responsive innate immune cells that acquire diverse functions by polarizing towards distinct subgroups. The subgroups of macrophages that reside in skeletal muscle (SKM) and their changes during aging are poorly characterized. By single-cell transcriptomic analysis, we found that mouse SKM macrophages primarily comprise two large populations, "healing" LYVE1+ and "proinflammatory" LYVE1-macrophages. SKM macrophages were further classified into four functional subgroups based on the expression levels of another cell-surface marker, MHCII: LYVE1+/MHCII-lo (similar to alternatively activated M2), LYVE1-/MHCII-hi (similar to classically activated M1), and two new subgroups, LYVE1+/MHCII-hi and LYVE1-/MHCII-lo. Notably, the new subgroup LYVE1+/MHCII-hi had traits of both M2 and M1 macrophages, while the other new subgroup, LYVE1-/MHCII-lo, expressed high levels of mRNAs encoding cytotoxicity proteins. Flow cytometric analysis validated the presence of the four macrophage subgroups in SKM. In old SKM, LYVE1-macrophages were more abundant than LYVE1+ macrophages. Furthermore, complementary unsupervised classification revealed the emergence of specific macrophage subclusters expressing abundant proinflammatory markers, including S100a8 and S100a9 in aged SKM. In sum, our study has identified dynamically polarized mouse SKM macrophages and further uncovered the contribution of specific macrophage subpopulations to the proinflammatory status in old SKM.

cell biology↗

bioRxiv2022

Matrix-driven jamming dynamics mediates transition of ovarian cancer spheroids to stable morphologies

Cancer metastasis through a confining peritoneal fluid microenvironment is mediated by spheroids: clusters of disseminated transformed cells. Ovarian cancer spheroids are frequently cavitated and their blastuloid morphology is correlated with an extracellular matrix (ECM) coat. Here, we investigate the effects of such morphology on the mechanical integrity of confined cancer spheroids. Atomic force microscopy showed higher elastic modulus for blastuloid spheroids relative to their prefiguring non-lumen moruloid counterparts. Subsequently, spheroids were flowed through microfluidic conditions mimicking peritoneal confinement. Traversing moruloids exhibited asymmetric cell flows during entry, often deformed and disintegrated through travel, and showed an incomplete- and slow shape recovery upon exit. In contrast, blastuloids traveled faster, exhibited rapid and efficient shape recovery upon exit, symmetric vector flows, and lesser disintegration. A multiscale computational model predicted higher intercellular adhesion and a dynamical lumen make blastuloids resilient. Although, E-cadherin overexpression in moruloids did not affect their resilience, blastuloid ECM-debridement decreased E-cadherin membrane localization, obliterated the lumen, and reversed the rheological properties of blastuloids to those typifying moruloids. The ECM-induced lumen therefore drives spheroidal transition from a labile viscoplastic to a resilient elastic state allowing them to survive spatially-constrained peritoneal flows.

biophysics↗

bioRxiv2022

Modified dN/dS for accounting transition and transversion frequency difference and non-sense substitution in genomes

The dN/dS value is estimated in homologous protein coding gene sequences between two closely related organisms for studying selection on the genes. In the usual method of calculation of synonymous (S) and non-synonymous (NS) sites in codons, the transition and transversion rates are considered same as well as no difference of pretermination codons from the other codons regarding NS substitutions is considered. In this study we are proposing a modification in the method by estimating the S and the NS sites in codons by considering difference between the transition and transversion rates and the NS substitutions leading to non-sense codons in pretermination codons. So, the dN/dS value calculated by our approach was higher than that calculated by the earlier method. The modified method was applied in estimating dN/dS in 29 homologous gene sequences of Escherichia coli and Salmonella enterica. Impact of codon degeneracy and pretermination codons on the dN/dS values estimated by our method were observed clearly. Our method of estimation that considers the above features is a realistic representation of dN/dS values in coding sequences.

evolutionary biology↗

bioRxiv2021

Polymorphism at four-fold degenerate site, but not at the intergenic regions, explains nucleotide compositional strand asymmetry in bacteria

We investigated single nucleotide polymorphism in intergenic regions (IRs) and four-fold degenerate sites (FFS) in genomes of three {gamma}-Proteobacteria and two Firmicutes to understand the mechanism of nucleotide compositional asymmetry between the leading and the lagging strands. Pattern of the polymorphism spectra were alike regarding transitions but variable regarding transversions in the IRs of these bacteria. Contrasting trends of complementary polymorphisms such as C[->]T vs G[->]A as well as A[->]G vs T[->]C in the IRs vindicated similar replication-associated strand asymmetry regarding cytosine and adenine deamination, respectively, across these bacteria. Surprisingly, the polymorphism pattern at FFS was different from that of the IRs and its frequency was always more than the IRs in these bacteria. Further, the polymorphism patterns within a bacterium were inconsistent across the five amino acids, which neither the replication nor the transcription-associated mutations could explain. However, the polymorphism at FFS coincided with amino acid specific codon usage bias in the five bacteria. Further, strand asymmetry in nucleotide composition could be explained by the polymorphism at FFS, not at the IRs. Therefore, polymorphisms at FFS might not be treated as nearly neutral unlike that in IRs in these bacteria.

molecular biology↗

bioRxiv2021

Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define colitis associated with immune checkpoint inhibitors

Therapeutic blockade of co-inhibitory immune receptors PD-1 and CTLA-4 has revolutionized oncology, but treatments are limited by immune-related adverse events (IRAEs). IRAE Colitis (irColitis) is the most common, severe IRAE affecting up to 25% of patients on dual PD-1 and CTLA-4 inhibition. Here, we present a systems biology approach to define the cell populations and transcriptional programs driving irColitis. We collected paired colon mucosal biopsy and blood specimens from 13 patients with irColitis, 8 healthy individuals, and 8 controls on immune checkpoint inhibitors (ICIs), and analyzed them with single-cell/nuclei RNA sequencing with paired TCR and BCR sequencing, multispectral fluorescence microscopy, and secreted factor analysis (Luminex). We profiled 299,407 cells from tissue and blood and identified 105 cell subsets that revealed significant tissue remodeling in active disease. Colon mucosal immune populations were dominated by tissue-resident memory (TRM) ITGAE-expressing CD8 T cells representing a phenotypic spectrum defined by gene programs associated with T cell activation, cytotoxicity, cycling, and exhaustion. CD8 TRM and effector CD4 T cells upregulated type 17 immune programs (IL17A, IL26) and Tfh-like programs (CXCL13, PDCD1). We also identified for the first time an increased abundance of two KLRG1 and ITGB2-expressing CD8 T cell populations with circulatory cell markers, including a GZMK TRM-like population and a CX3CR1 population that is predicted to be intravascular. These two populations were more abundant in irColitis patients treated with dual PD-1/CTLA-4 inhibition than those receiving anti-PD-1 monotherapy. They also had significant TCR sharing with PBMCs, suggesting a circulatory origin. In irColitis we observed significant epithelial turnover marked by fewer LGR5-expressing stem cells, more transit amplifying cells, and upregulation of apoptotic and DNA-sensing programs such as the cGAS-STING pathway. Mature epithelial cells with top crypt genes upregulated interferon-stimulated pathways, CD274 (PD-L1), anti-microbial genes, and MHC-class II genes, and downregulated aquaporin and solute-carrier gene families, likely contributing to epithelial cell damage and absorptive dysfunction. Mesenchymal remodeling was defined by increased endothelial cells, both in irColitis patients and specifically in patients on dual PD-1/CTLA-4 blockade. Cell-cell communication analysis identified putative receptor-ligand pairs that recruit CD8 T cells from blood to inflamed endothelium and positive feedback loops such as the CXCR3 chemokine system that retain cells in tissue. This study highlights the cellular and molecular drivers underlying irColitis and provides new insights into the role of CTLA-4 and PD-1 signaling in maintaining CD8 TRM homeostasis, regulating CD8 T recruitment from blood, and promoting epithelial-immune crosstalk critical to gastrointestinal immune tolerance and intestinal barrier function.

immunology↗

bioRxiv2021

Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60.

Nuclear DNA damage is intricately linked to cellular metabolism. However, the underlying mechanisms and full range of metabolic alterations that occur in response to persistent DNA damage are not well understood. Here, we use a DNA repair-deficient model of ERCC1-XPF in Caenorhabditis elegans (C. elegans), that accumulates physiologically relevant, endogenous DNA damage, to gain molecular insights on how persistent genotoxic stress drives biological aging. Using an integrated multi-omic approach, we discover that persistent genotoxic stress rewires lipid metabolism. In particular, nuclear DNA damage promotes mitochondrial {beta}-oxidation and leads to a global loss of fat depots. This metabolic shift to {beta}-oxidation generates acetyl-CoA and drives histone hyperacetylation. Concomitantly, we observe an associated change in gene expression of immune-effector and cytochrome (CYP) genes. We identify MYS-1, the ortholog of mammalian histone acetyltransferase TIP60, as a critical regulator of this metabolic-epigenetic axis. Moreover, we show that in response to persistent DNA damage, polyunsaturated fatty acids (PUFAs), especially arachidonic acid (AA) and AA-related lipid mediators are elevated. This elevation of PUFA species requires mys-1/Tip60. Together, these findings reveal that persistent nuclear DNA damage alters the metabolic-epigenetic axis to drive an immune-like response that can promote age-associated decline.

cell biology↗

bioRxiv2021

Bacterial hopanoids: a newly identified potent inducer of monocyte to macrophage differentiation

Monocyte to macrophage differentiation is an extremely essential cellular and immunological process aimed to combat the assault of foreign pathogens as well as this process has immense importance in the maintenance of physiological homeostasis. Differentiated macrophage, serving as specialized phagocytes is an indispensable component of innate immunity. Besides this, being a well-documented antigen-presenting cell (APC) macrophages also function as a key regulator of both humoral and cell-mediated immunity: the two integral components of adaptive immunity. Bacterial hopanoids are a primitive analogous of eukaryotic sterols that are established as a prominent immunomodulator. In this study, we have demonstrated the isolation protocol of neutral lipid fractions from different Gram-negative bacteria, and adopting several analytical approaches we proposed that the extracted lipid fractions may contain hopanoid as an active component. We have delved deeper into the biological effect of these probable hopanoids like compounds. Here, by considering the several structural and functional attributes like altered phenotype, expression of macrophage-specific markers, increased intracellular organelles, acquirement of enhanced phagocytic and inflammatory property, induction of autophagy, etc we have established hopanoids as a potential inducer of monocyte to macrophage differentiation. Thus, our study has unraveled a new immunomodulator present in Gram-negative bacteria and would undoubtedly help to understand the intricacies of host-pathogen interaction in a better and conclusive manner.

cell biology↗

bioRxiv2021

Delineating the complex mechanistic interplay between autophagy and monocyte to macrophage differentiation: a functional perspective

Autophagy is an extremely essential cellular process aimed to clear redundant and damaged materials. In this study, we demonstrated that mTOR dependent classical autophagy is ubiquitously triggered in differentiating monocytes. Moreover, autophagy plays a decisive role in sustaining the process of monocyte to macrophage differentiation. We have delved deeper into understanding the underlying mechanistic complexities that trigger autophagy during differentiation. We have also shown that autophagy directs monocyte differentiation via protein degradation. Further, we delineated the complex cross-talk between autophagy and cell-cycle arrest in differentiating monocytes. This study also inspects the contribution of adhesion on various steps of autophagy and its ultimate impact on monocyte differentiation. Our study reveals new mechanistic insights into the process of autophagy associated with monocyte differentiation and would undoubtedly help to understand the intricacies of the process better for the effective design of therapeutics as autophagy and autophagy-related processes have enormous importance in human patho-physiology. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

cell biology↗

bioRxiv2021

A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2

The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63+ intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profiles in situ and distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies.

genomics↗