Using 1 year of aerosol optical thickness (AOT) retrievals from the MODerate resolution Imaging Spectro-radiometer (MODIS) on board NASA's Terra and Aqua satellite along with ground measurements of ...PM
2.5 mass concentration, we assess particulate matter air quality over different locations across the global urban areas spread over 26 locations in Sydney, Delhi, Hong Kong, New York City and Switzerland. An empirical relationship between AOT and PM
2.5 mass is obtained and results show that there is an excellent correlation between the bin-averaged daily mean satellite and ground-based values with a linear correlation coefficient of 0.96. Using meteorological and other ancillary datasets, we assess the effects of wind speed, cloud cover, and mixing height (MH) on particulate matter (PM) air quality and conclude that these data are necessary to further apply satellite data for air quality research. Our study clearly demonstrates that satellite-derived AOT is a good surrogate for monitoring PM air quality over the earth. However, our analysis shows that the PM
2.5–AOT relationship strongly depends on aerosol concentrations, ambient relative humidity (RH), fractional cloud cover and height of the mixing layer. Highest correlation between MODIS AOT and PM
2.5 mass is found under clear sky conditions with less than 40–50% RH and when atmospheric MH ranges from 100 to 200
m. Future remote sensing sensors such as Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) that have the capability to provide vertical distribution of aerosols will further enhance our ability to monitor and forecast air pollution. This study is among the first to examine the relationship between satellite and ground measurements over several
global locations.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The enzymes decaprenylphosphoryl-β-D-ribose oxidase (DprE1) and decaprenylphosphoryl-β-D-ribose-2-epimerase (DprE2) catalyze epimerization of decaprenylphosporyl ribose (DPR) todecaprenylphosporyl ...arabinose (DPA) and are critical for the survival of Mtb. Crystal structures of DprE1 so far reported display significant disordered regions and no structural information is known for DprE2. We used homology modeling, protein threading, molecular docking and dynamics studies to investigate the structural and dynamic features of Mtb DprE1 and DprE2 and DprE1-DprE2 complex. A three-dimensional model for DprE2 was generated using the threading approach coupled with ab initio modeling. A 50 ns simulation of DprE1 and DprE2 revealed the overall stability of the structures. Principal Component Analysis (PCA) demonstrated the convergence of sampling in both DprE1 and DprE2. In DprE1, residues in the 269-330 area showed considerable fluctuation in agreement with the regions of disorder observed in the reported crystal structures. In DprE2, large fluctuations were detected in residues 95-113, 146-157, and 197-226. The study combined docking and MD simulation studies to map and characterize the key residues involved in DprE1-DprE2 interaction. A 60 ns MD simulation for DprE1-DprE2 complex was also performed. Analysis of data revealed that the docked complex is stabilized by H-bonding, hydrophobic and ionic interactions. The key residues of DprE1 involved in DprE1-DprE2 interactions belong to the disordered region. We also examined the docked complex of DprE1-BTZ043 to investigate the binding pocket of DprE1 and its interactions with the inhibitor BTZ043. In summary, we hypothesize that DprE1-DprE2 interaction is crucial for the synthesis of DPA and DprE1-DprE2 complex may be a new therapeutic target amenable to pharmacological validation. The findings have important implications in tuberculosis (TB) drug discovery and will facilitate drug development efforts against TB.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Main protease (Mpro) is important validated target in SARS-CoV-2 for drug design and discovery.•The multiple computational tools (with two molecular dynamics simulations programs gromacs and ...Desmond) were found the consistent results for novel scaffolds ZINC000073548482, ZINC000036121206, and ZINC000064468475, in term of RMSD, RMSF, Rg, H-bonding and binding free energy.•These findings could be useful for further optimization and design of novel inhibitors against Mpro.
Pfizer in the USA has pioneered an orally active drug called Nirmatrelvir (PF-07321332) targeting the main protease (Mpro) protein of SARS-CoV-2. However, the current scenario demands additional scaffolds with greater potency and binding affinity.
Various computational techniques were employed to detect the new scaffold in comparison to Mpro. These techniques included shape-based screening, molecular docking, molecular dynamic simulation (MDS), and ADMET studies. The query molecule for the shape-based screening in the ZINC database was PF-07321332. In docking investigations, every screened molecule was assessed for binding mode analysis. The binding strength of the top 10 screened compounds was further examined using the Prime/MMGBSA, Glimpse, and KDeep tools. Only best four of the screened molecules were chosen for stability assessments within Mpro's active site using Gromacs for MDS studies. To validate the Gromacs MDS results, all of these screened molecules were subsequently processed in Desmond software for triplicate MDS investigations (per complex).
Through analysis involving RMSD, RMSF, H-bonding, and the radius of gyration, it was observed that during both MDS studies, the molecules ZINC000073548482, ZINC000036121206, and ZINC000064468475 displayed minimal fluctuations while exhibiting higher binding free energy against Mpro. This suggests that these molecules showcased exceptional stability within Mpro's active site throughout both MDS processes when compared to the reference (6W63). Consequently, these chemically varied screened molecules (ZINC000073548482, ZINC000036121206, and ZINC000064468475) could potentially serve as novel, diverse shape similar scaffolds against Mpro, previously unreported against SARS-CoV-2. However, these claims require experimental validation. The multiple screening methods with both MDS tools found valuable to find the novel scaffolds against Mpro. These scaffolds hold promise for furthering the development of innovative and refined therapeutics targeting Mpro in SARS-CoV-2.
The step-wise computational screening were identified the novel scaffolds against main protease of SARS-CoV-2 and exhibited high binding affinity in two MDS programs with good AMDET profile as compared to reference (6W63), but close to marketed drug (PF-07,321,332).
Display omitted
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The nuclear receptor (NR) superfamily of transcription factors regulates various key aspects of physiological processes; however, their role(s) in immune cells’ function are just beginning to ...unravel. Although few NRs have been shown to be critical for dendritic cell (DC) function, a lack of knowledge about their complete representation in DCs has limited the ability to harness their full potential. Here, we performed a comprehensive NR expression profiling and identified the key members of NR superfamily being expressed in immature, immunogenic, and tolerogenic DCs. Comparative analysis revealed discrete changes in the expression of various NRs among the studied DC subtypes, indicating a likely role in the modulation of DC functionality. Next, we characterized Nr4a2, a member of orphan NR family, and found that it suppresses the activation of bone marrow derived dendritic cells triggered by LPS. Overexpression and knockdown of Nr4a2 demonstrated that Nr4a2 orchestrates the expression of immunoregulatory genes, hence inducing a tolerogenic phenotype in bone marrow derived dendritic cells. Furthermore, we also found that Nr4a2 provides protection from EAE by promoting an increase in Treg cells, while limiting effector T cells. Our findings suggest a previously unidentified role for Nr4a2 as a regulator of DC tolerogenicity and demonstrate its potential as therapeutic target in DC‐associated pathophysiologies.
This study identifies 39 nuclear receptors being expressed in bone marrow derived dendritic cells. Of these, Nr4a2 limits the immunogenicity while endowing DCs with tolerogenic potential (I). In vivo administration of such bone marrow derived dendritic cells, which have ectopically expressing Nr4a2, attenuates EAE (II).
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Vascular endothelial growth factor-A (VEGF-A) and chemokne ligand-2 (CCL2) levels have been examined in Amyotrophic Lateral Sclerosis (ALS) patients in Western countries. We measured these values in ...North Indian ALS patients, since these patients display considerably enhanced survival duration.
Sporadic ALS patients were included on the basis of El Escorial criteria. VEGF-A and CCL2 levels were analyzed in serum and cerebrospinal fluid (CSF) of 50 ALS patients using enzyme linked immunosorbent assay (ELISA) and compared with normal controls. Their levels were adjusted for possible confounders like cigarette smoking, alcohol and meat consumption.
Contrary to previous studies, VEGF-A was found to be elevated significantly in serum and CSF in ALS patient population studied. We also found an increase in CCL2 levels in CSF of these ALS patients. Serum and CSF from definite ALS revealed higher VEGF-A as compared to probable and possible ALS. CCL2 was unaltered between definite, probable and possible ALS. Univariate and multivariate analysis revealed a lack of association of smoking, alcohol and meat consumption with VEGF-A and CCL2 levels.
VEGF-A upregulation may indicate an activation of compensatory responses in ALS which may reflect or in fact account for increased survival of North Indian ALS patients after disease onset. The intrathecal synthesis of CCL2 suggests the involvement of adult neural stem cells and microglial activation in ALS pathogenesis which needs further investigation.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The incidence of myocardial inflammation in patients with unexplained cardiomyopathy referred for ventricular arrhythmias (VAs) is unknown.
The purpose of this study was to report fasting positron ...emission tomographic (PET) scan findings in consecutive patients referred with unexplained cardiomyopathy and VA.
Fluorine-18 fluoro-2-deoxyglucose (18-FDG) PET/computed tomographic (CT) scans with a >16-hour fasting protocol were prospectively ordered for patients referred for VA and unexplained cardiomyopathy (ejection fraction <55%). Patients with focal myocardial FDG uptake were labeled as arrhythmogenic inflammatory cardiomyopathy (AIC) and classified into 4 groups based on the presence of lymph node uptake (AIC+) and perfusion abnormalities (early vs late stage).
Over a 3-year period, 103 PET scans were performed, with 49% (AIC+ 17, AIC 33) exhibiting focal FDG uptake. Mean patient age was 52 ± 12 years (ejection fraction 36% ± 16%). Patients with AIC were more likely to have a history of pacemaker (32% vs 6%, P = .002) compared to those with normal PET. When biopsy was performed, histologic diagnosis revealed nongranulomatous inflammation in 6 patients and sarcoidosis in 18 patients. Ninety percent of patients with AIC/AIC+ were prescribed immunosuppressive therapy, and 58% underwent ablation. Correlation between low voltage regions on electroanatomic mapping and FDG uptake was observed in 74%. Magnetic resonance imaging findings matched abnormal PET regions in only 40%.
Nearly 50% of patients referred with unexplained cardiomyopathy and VA demonstrate ongoing focal myocardial inflammation on FDG PET. These data suggest that a significant proportion of patients labeled "idiopathic" may have occult AIC, which may benefit from early detection and immunosuppressive medical therapy.
We have earlier shown that protein levels of vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) were elevated in Indian amyotrophic lateral sclerosis (ALS) patients. Here, we ...report the mRNA levels of VEGF-A and CCL2 in Indian ALS patients since they display extended survival after disease onset.
VEGF-A and CCL2 mRNA levels were measured in peripheral blood mononuclear cells (PBMCs) of 50 sporadic Indian ALS patients using Real Time Polymerase Chain Reaction (PCR) and compared with normal controls (n = 50). Their levels were adjusted for possible confounders like cigarette smoking, alcohol and meat consumption.
VEGF-A and CCL2 mRNA levels were found to be significantly elevated in PBMCs in ALS patients as compared to controls. PBMCs from definite ALS revealed higher VEGF-A mRNA expression as compared to probable and possible ALS. CCL2 mRNA levels were found to be unaltered when definite, probable and possible ALS were compared. PBMCs from patients with respiratory dysfunction showed much higher VEGF-A and CCL2 elevation when compared to patients without respiratory dysfunction. No association of smoking, alcohol and meat consumption with VEGF-A and CCL2 was observed after analyzing the data with univariate and multivariate analysis.
VEGF-A and CCL2 mRNA upregulation in PBMCs may have a clinico-pathological/etiological/epidemiological association with ALS pathogenesis. The cross-cultural and cross-ethnic investigations of these molecules could determine if they have any role in enhancing the mean survival time unique to Indian ALS patients.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Osteoarthritis (OA) is a common and debilitating chronic degenerative disease of the joints. Currently, cell-based therapy is being explored to address the repair of damaged articular cartilage in ...the knee joint.
The in vitro differentiation potential of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®) was determined by differentiating the cells toward the chondrogenic lineage and quantifying sulfated glycosaminoglycan (sGAG). The mono-iodoacetate (MIA)-induced preclinical model of OA has been used to demonstrate pain reduction and cartilage formation. In the clinical study, 60 OA patients were randomized to receive different doses of cells (25, 50, 75, or 150 million cells) or placebo. Stempeucel® was administered by intra-articular (IA) injection into the knee joint, followed by 2 ml hyaluronic acid (20 mg). Subjective evaluations-visual analog scale (VAS) for pain, intermittent and constant osteoarthritis pain (ICOAP), and Western Ontario and McMaster Universities Osteoarthritis (WOMAC-OA) index-were performed at baseline and at 1, 3, 6, and 12 months of follow-up. Magnetic resonance imaging of the knee was performed at baseline, and at 6 and 12 months follow-up for cartilage evaluation.
Stempeucel® differentiated into the chondrogenic lineage in vitro with downregulation of Sox9 and upregulation of Col2A genes. Furthermore, Stempeucel® differentiated into chondrocytes and synthesized a significant amount of sGAG (30 ± 1.8 μg/μg GAG/DNA). In the preclinical model of OA, Stempeucel® reduced pain significantly and also repaired damaged articular cartilage in rats. In the clinical study, IA administration of Stempeucel® was safe, and a trend towards improvement was seen in the 25-million-cell dose group in all subjective parameters (VAS, ICOAP, andWOMAC-OA scores), although this was not statistically significant when compared to placebo. Adverse events were predominant in the higher dose groups (50, 75, and 150 million cells). Knee pain and swelling were the most common adverse events. The whole-organ magnetic resonance imaging score of the knee did not reveal any difference from baseline and the placebo group.
Intra-articular administration of Stempeucel® is safe. A twenty-five-million-cell dose may be the most effective among the doses tested for pain reduction. Clinical studies with a larger patient population are required to demonstrate a robust therapeutic efficacy of Stempeucel® in OA.
Clinicaltrials.gov NCT01453738 . Registered 13 October 2011.
Abstract The inhibition of tumor necrosis factor (TNF)-α trimer formation renders it inactive for binding to its receptors, thus mitigating the vicious cycle of inflammation. We designed a peptide ...(PIYLGGVFQ) that simulates a sequence strand of human TNFα monomer using a series of in silico methods, such as active site finding (Acsite), protein–protein interaction (PPI), docking studies (GOLD and Flex-X) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNFα. Fluorescence-activated cell sorting and fluorescence microscopy revealed that the peptide effectively inhibited the binding of TNF to the cell surface receptors. The cell culture assays showed that the peptide significantly inhibited the TNFα-mediated cell death. In addition, the nuclear translocation of the nuclear factor kappa B (NFκB) was significantly suppressed in the peptide-treated A549 cells, as observed in immunofluorescence and gel mobility-shift assays. Furthermore, the peptide protected against joint damage in the collagen-induced arthritis (CIA) mouse model, as revealed in the micro focal-CT scans. In conclusion, this TNFα antagonist would be helpful for the prevention and repair of inflammatory bone destruction and subsequent loss in the mouse model of CIA as well as human rheumatoid arthritis (RA) patients. This calls upon further clinical investigation to utilize its potential effect as an antiarthritic drug.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PDF
