An endophytic Schizophyllum commune possessing antioxidant activity exhibits genoprotective and organprotective effects in fresh water fish Channa punctatus exposed to bisphenol A.

BACKGROUND: Oxidative stress is responsible for the onset of several chronic and degenerative diseases. Exogenous supply of antioxidants is reported to neutralize the effects of oxidative stress. Several synthetic antioxidants suffer from various side effects which necessitates the exploration of antioxidant compounds from natural sources. Endophytic fungi residing in the plants are gaining the attention of researchers as a source of novel antioxidants. Majority of the research conducted so far on endophytic fungi has been restricted to the members of phylum ascomycota. Basidiomycota, inspite of their immense bioactive potential remain relatively unexploited. This study aimed to assess the ameliorative effects of an endophytic Schizophyllum commune (basidiomycetous fungus) against oxidative stress associated altered antioxidant levels, genotoxicity and cellular damage to different organs in bisphenol A exposed fresh water fish Channa punctatus. RESULTS: Good antioxidant and genoprotective potential was exhibited by S. commune extract in in vitro studies conducted using different antioxidant, DNA damage protection, and cytokinesis blocked micronuclei assays. In vivo studies were performed in fresh water fish Channa punctatus exposed to bisphenol A. A significant decrease in the considered parameters for DNA damage (% micronuclei and comet assay) were recorded in fish treated with S. commune extract on comparison with untreated bisphenol A exposed group. The S. commune extract treated fish also exhibited an increase in the level of antioxidant enzymes viz. catalase, superoxide dismutase and glutathione reductase as well as histoprotective effect on various organs. GC-MS analysis revealed the presence of 3-n-propyl-2,4-pentanedione, n-heptadecanol-1, trans-geranylgeraniol, 3-ethyl-2-pentadecanone, 1-heneicosanol and squalene as some of the compounds in S. commune extract. CONCLUSION: The study highlights the significance of an endophytic basidiomycetous fungus S. commune as a source of antioxidant compounds with possible therapeutic potential.

COVID-19-associated Pulmonary Aspergillosis: A Case Series.

Background: With the development of coronavirus disease-2019 (COVID-19) pandemic, there is also increased risk of multiple secondary infections either disease- or drug-related. It includes many bacterial as well as invasive fungal infections. Patients and methods: There was suspicion of invasive pulmonary aspergillosis (IPA) infection in COVID-19 patients who were critically ill and had acute respiratory distress syndrome (ARDS). We did radiological evaluation and galactomannan assay in these patients. Result: We have diagnosed COVID-19-associated pulmonary aspergillosis (CAPA) in these patients and started antifungal treatment with voriconazole in all of these COVID-19 patients. Conclusion: It is very important to report such cases, so that healthcare professionals and authorities related to healthcare will be aware of and may also prepare for the increasing burden of this complication. We describe a case series of CAPA infection. How to cite this article: Sharma K, Kujur R, Sharma S, Kumar N, Ray MK. COVID-19-associated Pulmonary Aspergillosis: A Case Series. Indian J Crit Care Med 2022;26(9):1039-1041.

Molecular Imaging of Mesothelin-Expressing Ovarian Cancer with a Human and Mouse Cross-Reactive Nanobody.

Mesothelin is an epithelial marker highly expressed at the cell surface of cancer cells from diverse origins, including ovarian and pancreatic adenocarcinomas and mesotheliomas. Previously, we identified and characterized an antimesothelin nanobody (NbG3a) for in vitro diagnostic applications. The main goal of this research was to establish the potential of NbG3a as a molecular imaging agent. Site-specific biotinylated NbG3a (bNbG3a) was bound to streptavidin-conjugated reagents for in vitro and in vivo assays. Initially, we performed microscale thermophoresis to determine the binding affinity between bNbG3a and human ( Kd = 46 ± 8 nM) or mouse ( Kd = 4.8 ± 0.4 nM) mesothelin protein. The human and mouse cross-reactivity was confirmed by in vivo optical imaging using bNbG3a bound to fluorescent streptavidin. We also localized the binding site of nNbG3a on human mesothelin using overlapping peptide scan. NbG3a recognized an epitope within residues 21-65 of the mature membrane bound form of human mesothelin, which is part of the N-terminal region of mesothelin that is important for interactions between mesothelin on peritoneal cells and CA125 on tumor cells. Next, the bNbG3a in vivo half-life after intravenous injection in healthy mice was estimated by ELISA assay to be 5.3 ± 1.3 min. In tumor-bearing animals, fluorescent bNbG3a accumulated in a subcutaneous ovarian xenograft (A1847) and in two syngeneic, orthotopic ovarian tumors (intraovary and intraperitoneal ID8) within an hour of intravenous injection that peaked by 4 h and persisted up to 48 h. MRI analysis of bNbG3a-targeted streptavidin-labeled iron oxides showed that the MRI signal intensity decreased 1 h after injection for a subcutaneous xenograft model of ovarian cancer for bNbG3a-labeled iron oxides compared to unlabeled iron oxides. The signal intensity differences continued up to the final time point at 24 h post injection. Finally, in vivo immunofluorescence 24 or 48 h after bNbG3a intravenous injection showed bNbG3a diffuse distribution of both xenograft and syngeneic ovarian tumors, with local areas of high concentration throughout A1847 human tumor. The data support the use of NbG3a for continued preclinical development and translation to human applications for cancers that overexpress mesothelin.

A comparative study of clonidine and dexmedetomidine as an adjunct to bupivacaine in supraclavicular brachial plexus block.

BACKGROUND AND AIMS: Various additives are mixed with local anesthetic agents to increase the quality of block in regional anesthesia. We compared clonidine and dexmedetomidine as an adjunct to bupivacaine in supraclavicular brachial plexus block with respect to the onset and duration of sensory and motor block and duration of analgesia. MATERIAL AND METHODS: Sixty American Society of Anesthesiologists Grades I and II patients scheduled for various orthopedic surgeries of the upper limb under supraclavicular brachial plexus block were divided into two equal groups in a randomized, double-blind manner. Patients were assigned randomly to one of the two groups. In Group C (n = 30), 39 ml of 0.25% bupivacaine plus 1 ml (1 µg/kg) clonidine and in Group D (n = 30), 39 ml of 0.25% bupivacaine plus 1 ml (1 µg/kg) dexmedetomidine were given. The onset and duration of sensory and motor block, duration of analgesia, and quality of anesthesia were studied in both the groups. RESULTS: There was no statistically significant difference in the onset of sensory and motor block in both the groups. The durations of sensory and motor block were 316.67 ± 45.21 and 372.67 ± 44.48 min, respectively, in Group C, whereas they were 502.67 ± 43.78 and 557.67 ± 38.83 min, respectively, in Group D. The duration of analgesia was 349.33 ± 42.91 min, significantly less in Group C compared to 525.33 ± 42.89 min in Group D (P < 0.001). The quality of anesthesia was significantly better in dexmedetomidine group compared to clonidine group (P < 0.001). CONCLUSION: The addition of dexmedetomidine prolongs the durations of sensory and motor block and duration of analgesia and improves the quality of anesthesia as compared with clonidine when injected with bupivacaine in supraclavicular brachial plexus block.

Yet another function of p53--the switch that determines whether radiation-induced autophagy will be cytoprotective or nonprotective: implications for autophagy inhibition as a therapeutic strategy.

The influence of autophagy inhibition on radiation sensitivity was studied in human breast, head and neck, and non-small cell lung cancer cell lines, in cell lines that were either wild type or mutant/null in p53, and in cells where p53 was inducible or silenced. Whereas ionizing radiation promoted autophagy in all tumor cell lines studied, pharmacological inhibition of autophagy and/or genetic silencing of autophagy genes failed to influence sensitivity to radiation in p53 mutant Hs578t breast tumor cells, HN6 head and neck tumor cells, and H358 non-small cell lung cancer cells. The requirement for functional p53 in the promotion of cytoprotective autophagy by radiation was confirmed by the observation that radiation-induced autophagy was nonprotective in p53 null H1299 cells but was converted to the cytoprotective form with induction of p53. Conversely, whereas p53 wild-type HN30 head and neck cancer cells did show sensitization to radiation upon autophagy inhibition, HN30 cells in which p53 was knocked down using small hairpin RNA failed to be sensitized by pharmacological autophagy inhibition. Taken together, these findings indicate that radiation-induced autophagy can be either cytoprotective or nonprotective, a functional difference related to the presence or absence of function p53. Alternatively, these findings could be interpreted to suggest that whereas radiation can induce autophagy independent of p53 status, inhibition of autophagy promotes enhanced radiation sensitivity through a mechanism that requires functional p53. These observations are likely to have direct implications with respect to clinical efforts to modulate the response of malignancies to radiation through autophagy inhibition.

Role of Interleukin-1 in Radiation-Induced Cardiomyopathy.

Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardiomyopathy. The aim of this study was to determine the role of interleukin (IL)-1 in response to XRT injury to the heart and on the cardiomyopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. Wild-type (wt) or IL-1R1 KO mice were treated with a single session of XRT (20 or 14 gray [Gy]). Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis and pericardial thickening. After 20 Gy, the contractile reserve was impaired in wt mice at d 3, and the LV ejection fraction (EF) was reduced after 4 months when compared with sham-XRT. IL-1R1 KO mice had preserved contractile reserve at 3 d and 4 months and LVEF at 4 months after XRT. Anakinra treatment for 1 d before and 7 d after XRT prevented the impairment in contractile reserve. A significant increase in LV end-diastolic pressure, associated with increased myocardial interstitial fibrosis and pericardial thickening, was observed in wt mice, as well as in IL-1R1 KO-or anakinra-treated mice. In conclusion, induction of IL-1 by XRT mediates the development of some, such as the contractile impairment, but not all aspects of the XRT-induced cardiomyopathy, such as myocardial fibrosis or pericardial thickening.

Cytotoxic autophagy in cancer therapy.

Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles, and misfolded or damaged proteins to eliminate these components that might otherwise be deleterious to cellular survival. Consequently, autophagy has generally been considered a prosurvival response. Many, if not most chemotherapeutic drugs and radiation also promote autophagy, which is generally considered a cytoprotective response, in that its inhibition frequently promotes apoptotic cells death. Furthermore, it has been shown that conventional chemotherapeutic drugs and radiation alone rarely induce a form of autophagy that leads to cell death. However, there are multiple examples in the literature where newer chemotherapeutic agents, drug combinations or drugs in combination with radiation promote autophagic cell death. This review will describe autophagic cell death induced in breast tumor cells, lung cancer cells as well as glioblastoma, demonstrating that it cannot be concluded that stress induced autophagy is, of necessity, cytoprotective in function.

Impact of untreated and microbially treated equalization tank effluent of textile industry on freshwater fish Channa punctata using haematological, biochemical, histopathological and ultrastructural analysis.

The unregulated expulsion of untreated or partially treated industrial effluents poses serious threat to the aquatic ecosystem. Therefore, in the present study fish Channa punctata were exposed to untreated and microbially treated equalization tank effluent of textile industry and toxicity studies were carried out for 45 days. The study was planned to analyze the toxicity proffered by textile effluents through haematological, biochemical, histopathological and ultrastructural analysis in blood, liver and gill tissues of fish. While comparing untreated and microbially treated effluent exposed groups haematological parameters were significantly (P ≤ 0.05) less in the untreated effluent exposed group whereas White blood cell count was highly escalated. However, in the microbially treated groups, the alterations were less severe. Increased malondialdehyde content indicating oxidative stress, reduced Catalase (CAT) and Superoxide dismutase (SOD) activity showing a weakened antioxidant defence system and increased glutathione activity was also perceived in untreated effluent exposed groups in comparison to microbially treated groups. Histopathological alterations in gill (telangiectasia, lamellae fusion, breakage, vacuolization and bending of lamellae) and liver (sinusoid dilations, fusion, necrosis and congestion) were more pronounced and severe in the untreated effluent exposed group as compared to microbially treated group. The results observed in histopathology were further reaffirmed by scanning electron microscopy. The study clearly highlights less alterations and deformities in microbially treated effluent groups in comparison to untreated effluent groups. These findings, therefore, necessitate the search for more effective microbial inocula for the better treatment of effluents in order to protect the aquatic life as well as human beings. Highlights: Channa punctata exposed for 15, 30 and 45 days to untreated and microbially treated equalization tank effluent of textile industry.Untreated and microbially treated effluent exposed fish elicited alterations in blood, liver and gill tissuesHaematology, biochemical, histopathology and ultrastructural analysis resulted in massive pathologies in groups subjected to untreated effluent inducing maximum damage after 45 days of exposure.Less pronounced toxicity in fish C. punctata was observed in fish exposed to microbially treated effluent indicating its efficacy in toxicity reduction.

Distribution, toxicity load and risk assessment of heavy metals in the groundwater of Dhemaji, Assam, India.

Metal contamination in drinking water has drawn attention since it gravely jeopardizes human health. This study was conducted in pre- and post-monsoon season in 2021 at Dhemaji, Assam, India. It characterized metal pollutants in groundwater, their distribution, possible sources, and evaluated the potential toxicity and associated health risk assessment. The seasonal mean concentration of Fe in both seasons is observed highest followed by Mn, Zn, Cu, As, and Ni. Furthermore, the metal concentrations during pre-monsoon are comparatively higher. The geogenic processes and agricultural practices are the major sources of groundwater metal contamination as evident from the statistical analysis. The different pollution indices viz. Heavy-metal Pollution Index (HPI), Heavy-metal Evaluation Index (HEI) and Degree of Contamination (Cd) suggested that groundwater is not suitable for drinking uses. The Heavy Metal Toxicity Load (HMTL) suggesting As, Co, Mn and Hg should be removed from the groundwater to ensure safety. Water pollution indices (WPI) suggest that Fe, Mn, As and Ni are the main pollution-causing metals in the study area which may be restored under the BIS and WHO limit by diluting the water. The human health risk has been calculated by carcinogenic and non-carcinogenic risk assessment. The non-carcinogenic risk for adults and children is within the threshold limit. The carcinogenic risk shows that continuous exposure of As and Ni may give rise to cancer among adults and children in the region. Therefore, comprehensive groundwater quality monitoring with well-planned treatment should be needed to provide safe and clean drinking water in the studied area.

Potential inhibitors of VEGFR1, VEGFR2, and VEGFR3 developed through Deep Learning for the treatment of Cervical Cancer.

Cervical cancer stands as a prevalent gynaecologic malignancy affecting women globally, often linked to persistent human papillomavirus infection. Biomarkers associated with cervical cancer, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E, show upregulation and are linked to angiogenesis and lymphangiogenesis. This research aims to employ in-silico methods to target tyrosine kinase receptor proteins-VEGFR-1, VEGFR-2, and VEGFR-3, and identify novel inhibitors for Vascular Endothelial Growth Factors receptors (VEGFRs). A comprehensive literary study was conducted which identified 26 established inhibitors for VEGFR-1, VEGFR-2, and VEGFR-3 receptor proteins. Compounds with high-affinity scores, including PubChem ID-25102847, 369976, and 208908 were chosen from pre-existing compounds for creating Deep Learning-based models. RD-Kit, a Deep learning algorithm, was used to generate 43 million compounds for VEGFR-1, VEGFR-2, and VEGFR-3 targets. Molecular docking studies were conducted on the top 10 molecules for each target to validate the receptor-ligand binding affinity. The results of Molecular Docking indicated that PubChem IDs-71465,645 and 11152946 exhibited strong affinity, designating them as the most efficient molecules. To further investigate their potential, a Molecular Dynamics Simulation was performed to assess conformational stability, and a pharmacophore analysis was also conducted for indoctrinating interactions.

Epigenetic dysregulation in cancers by isocitrate dehydrogenase 2 (IDH2).

Recent advances in genome-wide studies have revealed numerous epigenetic regulations brought about by genes involved in cellular metabolism. Isocitrate dehydrogenase (IDH), an essential enzyme, that converts isocitrate into -ketoglutarate (KG) predominantly in the tricarboxylic acid (TCA) cycle, has gained particular importance due to its cardinal role in the metabolic pathway in cells. IDH1, IDH2, and IDH3 are the three isomeric IDH enzymes that have been shown to regulate cellular metabolism. Of particular importance, IDH2 genes are associated with several cancers, including gliomas, oligodendroglioma, and astrocytomas. These mutations lead to the production of oncometabolite D-2-hydroxyglutarate (D-2-HG), which accumulates in cells promoting tumor growth. The enhanced levels of D-2-HG competitively inhibit α-KG dependent enzymes, inhibiting cell TCA cycle, upregulating the cell growth and survival relevant HIF-1α pathway, promoting DNA hypermethylation related epigenetic activity, all of which synergistically contribute to carcinogenesis. The present review discusses epigenetic mechanisms inIDH2 regulation in cells and further its clinical implications.

Decoding post-translational modifications of mammalian septins.

Septins are cytoskeletal GTPases that form nonpolar filaments and higher-ordered structures and they take part in a wide range of cellular processes. Septins are conserved from yeast to mammals but absent from higher plants. The number of septin genes vary between organisms and they usually form complex heteropolymeric networks. Most septins are known to be capable of GTP hydrolysis which may regulate septin dynamics. Knowledge on regulation of septin function by post-translational modifications is still in its infancy. In this review article, we highlight the post-translational modifications reported for the 13 human septins and discuss their implications on septin functions. In addition to the functionally investigated modifications, we also try to make sense of the complex septin post-translational modification code revealed from large-scale phospho-proteomic datasets. Future studies may determine how these isoform-specific and homology group specific modifications affect septin structure and function.

Assessment of textile industry effluent (untreated and microbially treated) induced genotoxic, haematological, biochemical, histopathological and ultrastructural alterations in fresh water fish Channa punctata.

The unregulated expulsion of untreated textile water into water bodies is a major hazard to aquatic ecosystems. The present investigation was contrived to estimate the impact of textile dye bath effluent (untreated and microbially treated) on fish Channa punctata. Untreated effluent-exposed fish showed extremely altered behaviour (air gulping, erratic and speedy movements, increased opercular activity) and morphology (deposition of dyes on skin and scales, high pigmentation, mucus exudation). Significantly increased micronuclei (1.61-, 1.28-, 1.38-fold) and aberrant cell frequency (1.37-, 1.45-, 1.28-fold) was observed in untreated group as compared to treated group after 15, 30, and 45 days of exposure. Tail length, % tail intensity, tail moment and olive tail moment were also enhanced in all the exposed tissues. However, maximum damage was noticed in gill tissues showing 1.19-, 1.37-, 1.34- and 1.50-fold increased TL, %TI, TM and OTM in untreated group as compared to treated group after 45 days of exposure. On comparing untreated and treated groups, increased blood parameters and significantly reduced white blood cell count (WBC) were noticed in treated group. Significantly enhanced alterations in biochemical parameters were also analysed in untreated group. Reduced alterations in enzymological levels of fishes exposed to treated effluent indicate lesser toxic nature of the degraded metabolites of dye. Histological analysis in fishes exposed to untreated effluent showed several deformities in liver (necrosis, congestion, fusion of cells and melanomacrophage infiltration) and gill tissues (necrosis, bending of lamellae and severe aneurysm). Scanning electron microscopy (SEM) analysis further reaffirmed the pathologies observed in histological analysis. Fewer structural alterations were noticed in treated effluent fishes. The results concluded that untreated effluent inflicted toxicity potential on morphology as well as physiological defects in fish, and the severity increased with increasing duration of exposure, whereas reduction in toxicity in microbially treated groups can be analysed for aquacultural purposes owing to their lesser toxic nature.

Development and operation of immobilized cell plug flow bioreactor (PFR) for treatment of textile industry effluent and evaluation of its working efficiency.

The release of untreated/partially treated effluent and solid waste from textile dyeing industries, having un-reacted dyes, their hydrolysed products and high total dissolved solids (TDS) over the period of time had led to the deterioration of ecological niches. In an endeavour to develop a sustainable and effective alternative to conventional approaches, a plug flow reactor (PFR) having immobilized cells of consortium of three indigenous bacterial isolates was developed. The reactor was fed with effluent collected from the equalization tank of a textile processing unit located near city of Amritsar, Punjab (India). The PFR over a period of 3 months achieved 97.98 %, 82.22 %, 87.36%, 77.71% and 68.75% lowering of colour, chemical oxygen demand (COD), biological oxygen demand (BOD), total dissolved solids (TDS) and total suspended solids (TSS) respectively. The comparison of the phytotoxicity and genotoxicity of untreated and PFR-treated output samples using plant and animal models indicated significant lowering of respective toxicity potential. This is a first report, as per best of our knowledge, regarding direct treatment of textile industry effluent without any pre-treatment and with minimal nutritional inputs, which can be easily integrated into already existing treatment plant. The successful implementation of this system will lower the cost of coagulants/flocculants and also lowering the sludge generation.

Role of rare-earth oxides, conjugated with [Formula: see text], in the enhancement of power conversion efficiency of dye sensitized solar cells (DSSCs).

Different rare-earth (RE) metal-oxides nano-particles (NPs) viz. Samarium (III) oxide (Sm2O3), Neodymium (III) oxide (Nd2O3), and Gadolinium (III) oxide (Gd2O3) were synthesized using co-precipitation route, and investigated by structural, optical, and morphological studies. Findings and supporting studies were presented to understand the role of RE-metal-oxides NPs as photo-anode material for dye sensitized solar cells (DSSCs) applications. Structural analysis of prepared RE-metaloxides, by X-ray diffraction (XRD), reveals the crystalline nature of the particles ranging from 24 to 37 nm. Morphological study by field emission scanning electron microscopy (FESEM) supports the crystalline nature in the nano range of the prepared RE-metal oxides particles. The observed d values of each sample support the growth of Gd2O3, Nd2O3, and Sm2O3 material. The band-gap of prepared material was estimated from the UV-VIS absorption data and Tauc relation. The observed band gap values are 3.55 eV, 3.31 eV, and 3.52 eV for Gd2O3, Nd2O3, and Sm2O3 respectively. These values are reasonably high compare to the bulk values, indicates the nanostructure formation. Optimized RE-metal oxides NPs employed in the form of TiO2 photo anode for the fabrication of DSSCs. FESEM confirms that the Gd2O3-based photo-anode shows more uniform and decent coverage with more porosity on the TiO2. The EIS measurements of prepared DSSCs also supported the improvement in the photovoltaic output for the modified photo-anode devices as cells with modified photo-anode exhibited less charge recombination at the photo-anode/dye/electrolyte interface with increased electron lifetime leading to improved device performance as compared to the unmodified-based DSSCs. The highest efficiency 5.51% was demonstrated by [Formula: see text]/[Formula: see text] photo-anode-based DSSCs compare to Sm2O3, and Nd2O3 activated photo-anode.

Mapping of long stretches of highly conserved sequences in over 6 million SARS-CoV-2 genomes.

We identified 11 conserved stretches in over 6.3 million SARS-CoV-2 genomes including all the major variants of concerns. Each conserved stretch is ≥100 nucleotides in length with ≥99.9% conservation at each nucleotide position. Interestingly, six of the eight conserved stretches in ORF1ab overlapped significantly with well-folded experimentally verified RNA secondary structures. Furthermore, two of the conserved stretches were mapped to regions within the S2-subunit that undergo dynamic structural rearrangements during viral fusion. In addition, the conserved stretches were significantly depleted for zinc-finger antiviral protein (ZAP) binding sites, which facilitated the recognition and degradation of viral RNA. These highly conserved stretches in the SARS-CoV-2 genome were poorly conserved at the nucleotide level among closely related ß-coronaviruses, thus representing ideal targets for highly specific and discriminatory diagnostic assays. Our findings highlight the role of structural constraints at both RNA and protein levels that contribute to the sequence conservation of specific genomic regions in SARS-CoV-2.

Characterization of Polycyclic Aromatic Hydrocarbons (PAHs) associated with fine aerosols in ambient atmosphere of high-altitude urban environment in Sikkim Himalaya.

Polycyclic Aromatic Hydrocarbons (PAHs) compounds are ubiquitous in ambient air due to their persistence, carcinogenicity, and mutagenicity. Gangtok being one of the cleanest cities in India located in Eastern Himalayan region, witnesses high developmental activities with enhanced urbanization affecting the ambient air quality. The present study aims to measure PM2.5 and PAHs in the ambient atmosphere of the Sikkim Himalaya to understand the influence of natural and anthropogenic activities on aerosol loading and their chemical characteristics. The PM2.5 samples were collected and analysed for the duration from Jan 2020 to Feb 2021.The seasonal mean concentrations of PM2.5 and PAHs were observed to be high during autumn and low during summer season. Overall, the annual mean concentration of PM2.5 was found higher than the prescribed limit of World Health Organization and National Ambient Air Quality Standards. The concentration of the 16 individual PAHs were found to be highest during autumn season (55.26 ± 37.15 ng/m3). Among the different PAHs, the annual mean concentration of fluorene (3.29 ± 4.07 ng/m3) and naphthalene (1.15 ± 3.76 ng/m3) were found to be the highest and lowest, respectively. The Molecular Diagnostic Ratio (MDR) test reveals higher contribution from heavy traffic activities throughout the winter and autumn seasons. The other possible sources identified over the region are fossil fuel combustion, and biomass burning. The multivariate statistical analysis (Multifactor Principal Component Analysis) also indicates a strong association between PM2.5 /PAHs and meteorological variables across the region in different seasons. The precipitation and wind pattern during the study period suggests that major contribution of the PM2.5 and PAHs were from local sources, with minimal contribution from long-range transport. The findings are important for comprehending the trends of PAH accumulation over a high-altitude urban area, and for developing sustainable air quality control methods in the Himalayan region.

Obesity impairs cardiolipin-dependent mitophagy and therapeutic intercellular mitochondrial transfer ability of mesenchymal stem cells.

Mesenchymal stem cell (MSC) transplantation alleviates metabolic defects in diseased recipient cells by intercellular mitochondrial transport (IMT). However, the effect of host metabolic conditions on IMT and thereby on the therapeutic efficacy of MSCs has largely remained unexplored. Here we found impaired mitophagy, and reduced IMT in MSCs derived from high-fat diet (HFD)-induced obese mouse (MSC-Ob). MSC-Ob failed to sequester their damaged mitochondria into LC3-dependent autophagosomes due to decrease in mitochondrial cardiolipin content, which we propose as a putative mitophagy receptor for LC3 in MSCs. Functionally, MSC-Ob exhibited diminished potential to rescue mitochondrial dysfunction and cell death in stress-induced airway epithelial cells. Pharmacological modulation of MSCs enhanced cardiolipin-dependent mitophagy and restored their IMT ability to airway epithelial cells. Therapeutically, these modulated MSCs attenuated features of allergic airway inflammation (AAI) in two independent mouse models by restoring healthy IMT. However, unmodulated MSC-Ob failed to do so. Notably, in human (h)MSCs, induced metabolic stress associated impaired cardiolipin-dependent mitophagy was restored upon pharmacological modulation. In summary, we have provided the first comprehensive molecular understanding of impaired mitophagy in obese-derived MSCs and highlight the importance of pharmacological modulation of these cells for therapeutic intervention. A MSCs obtained from (HFD)-induced obese mice (MSC-Ob) show underlying mitochondrial dysfunction with a concomitant decrease in cardiolipin content. These changes prevent LC3-cardiolipin interaction, thereby reducing dysfunctional mitochondria sequestration into LC3-autophagosomes and thus impaired mitophagy. The impaired mitophagy is associated with reduced intercellular mitochondrial transport (IMT) via tunneling nanotubes (TNTs) between MSC-Ob and epithelial cells in co-culture or in vivo. B Pyrroloquinoline quinone (PQQ) modulation in MSC-Ob restores mitochondrial health, cardiolipin content, and thereby sequestration of depolarized mitochondria into the autophagosomes to alleviate impaired mitophagy. Concomitantly, MSC-Ob shows restoration of mitochondrial health upon PQQ treatment (MSC-ObPQQ). During co-culture with epithelial cells or transplantation in vivo into the mice lungs, MSC-ObPQQ restores IMT and prevents epithelial cell death. C Upon transplantation in two independent allergic airway inflammatory mouse models, MSC-Ob failed to rescue the airway inflammation, hyperactivity, metabolic changes in epithelial cells. D PQQ modulated MSCs restored these metabolic defects and restored lung physiology and airway remodeling parameters.

Promoter-motif extraction from co-regulated genes and their relevance to co-expression using E. coli as a model.

Gene expression varies due to the intrinsic stochasticity of transcription or as a reaction to external perturbations that generate cellular mutations. Co-regulation, co-expression and functional similarity of substances have been employed for indoctrinating the process of the transcriptional paradigm. The difficult process of analysing complicated proteomes and biological switches has been made easier by technical improvements, and microarray technology has flourished as a viable platform. Therefore, this research enables Microarray to cluster genes that are co-expressed and co-regulated into specific segments. Copious search algorithms have been employed to ascertain diacritic motifs or a combination of motifs that are performing regular expression, and their relevant information corresponding to the gene patterns is also documented. The associated genes co-expression and relevant cis-elements are further explored by engaging Escherichia coli as a model organism. Various clustering algorithms have also been used to generate classes of genes with similar expression profiles. A promoter database 'EcoPromDB' has been developed by referring RegulonDB database; this promoter database is freely available at www.ecopromdb.eminentbio.com and is divided into two sub-groups, depending upon the results of co-expression and co-regulation analyses.

Unveiling the ESR1 Conformational Stability and Screening Potent Inhibitors for Breast Cancer Treatment

BACKGROUND: The current study recognizes the significance of estrogen receptor alpha (ERα) as a member of the nuclear receptor protein family, which holds a central role in the pathophysiology of breast cancer. ERα serves as a valuable prognostic marker, with its established relevance in predicting disease outcomes and treatment responses. METHOD: In this study, computational methods are utilized to search for suitable drug-like compounds that demonstrate analogous ligand binding kinetics to ERα. RESULTS: Docking-based simulation screened out the top 5 compounds - ZINC13377936, NCI35753, ZINC35465238, ZINC14726791, and NCI663569 against the targeted protein. Further, their dynamics studies reveal that the compounds ZINC13377936 and NCI35753 exhibit the highest binding stability and affinity. CONCLUSION: Anticipating the competitive inhibition of ERα protein expression in breast cancer, we envision that both ZINC13377936 and NCI35753 compounds hold substantial promise as potential therapeutic agents. These candidates warrant thorough consideration for rigorous In vitro and In vivo evaluations within the context of clinical trials. The findings from this current investigation carry significant implications for the advancement of future diagnostic and therapeutic approaches for breast cancer.