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Metal-dependent histone deacetylases (HDACs) are essential epigenetic regulators; their molecular and pharmacological roles in medically critical diseases such as neuropsychiatric disorders, neurodegeneration, and cancer are being studied globally. HDAC2’s differential expression in the central nervous system makes it an appealing therapeutic target for chronic neurological diseases like autism spectrum disorder. In this study, we identified H3R inhibitor molecules that are computationally effective at binding to the HDAC2 metal-coordinated binding site. The study highlights the importance of pitolisant in screening the potential H3R inhibitors by using a hybrid workflow of ligand and receptor-based drug discovery. The screened lead compounds with PubChem SIDs 103179850, 103185945, and 103362074 show viable binding with HDAC2 in silico . The importance of ligand contacts with the Zn 2+ ion in the HDAC2 catalytic site is also discussed and investigated for a significant role in enzyme inhibition. The proposed H3R inhibitors 103179850, 103185945, and 103362074 are estimated as dual-active molecules to block the HDAC2-mediated deacetylation of the EAAT2 gene (SLC1A2) and H3R-mediated synaptic transmission irregularity and are, therefore, open for experimental validation.

The present study provides the structural identification of the viable binding residues of the SARS-CoV-2 S2 fusion peptide region, which holds prime importance in the virus’s host cell fusion and entry mechanism. The classical molecular mechanics simulations were set on values that mimic physiological standards for a good approximation of the dynamic behavior of selected drugs in biological systems. The drug molecules screened and analyzed here have relevant antiviral properties, which are reported here and which might hint toward their utilization in the coronavirus disease 2019 (COVID-19) pandemic owing to their attributes of binding to the fusion protein binding region shown in this study. The membrane-anchored spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a pivotal role in directing the fusion of the virus particle mediated by the host cell receptor angiotensin-converting enzyme 2 (ACE-2). The fusion peptide region of the S protein S2 domain provides SARS-CoV-2 with the biological machinery needed for direct fusion to the host lipid membrane. In our present study, computer-aided drug design strategies were used for the identification of FDA-approved small molecules using the optimal structure of the S2 domain, which exhibits optimal interaction ratios, structural features, and energy variables, which were evaluated based on their performances in molecular docking, molecular dynamics simulations, molecular mechanics/generalized Born model and solvent accessibility binding free energy calculations of molecular dynamics trajectories, and statistical inferences. Among the 2,625 FDA-approved small molecules, chloramphenicol succinate, imipenem, and imidurea turned out to be the molecules that bound the best at the fusion peptide hydrophobic pocket. The principal interactions of the selected molecules suggest that the potential binding site at the fusion peptide region is centralized amid the Lys790, Thr791, Lys795, Asp808, and Gln872 residues. IMPORTANCE The present study provides the structural identification of the viable binding residues of the SARS-CoV-2 S2 fusion peptide region, which holds prime importance in the virus’s host cell fusion and entry mechanism. The classical molecular mechanics simulations were set on values that mimic physiological standards for a good approximation of the dynamic behavior of selected drugs in biological systems. The drug molecules screened and analyzed here have relevant antiviral properties, which are reported here and which might hint toward their utilization in the coronavirus disease 2019 (COVID-19) pandemic owing to their attributes of binding to the fusion protein binding region shown in this study.

Metal-dependent histone deacetylases (HDACs) are essential epigenetic regulators; their molecular and pharmacological roles in medically critical diseases such as neuropsychiatric disorders, neurodegeneration, and cancer are being studied globally. HDAC2's differential expression in the central nervous system makes it an appealing therapeutic target for chronic neurological diseases like autism spectrum disorder. In this study, we identified H3R inhibitor molecules that are computationally effective at binding to the HDAC2 metal-coordinated binding site. The study highlights the importance of pitolisant in screening the potential H3R inhibitors by using a hybrid workflow of ligand and receptor-based drug discovery. The screened lead compounds with PubChem SIDs 103179850, 103185945, and 103362074 show viable binding with HDAC2 in silico. The importance of ligand contacts with the Zn2+ ion in the HDAC2 catalytic site is also discussed and investigated for a significant role in enzyme inhibition. The proposed H3R inhibitors 103179850, 103185945, and 103362074 are estimated as dual-active molecules to block the HDAC2-mediated deacetylation of the EAAT2 gene (SLC1A2) and H3R-mediated synaptic transmission irregularity and are, therefore, open for experimental validation.

INTRODUCTION: Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing infectivity. In the current study, we tend to repurpose Food and Drug Administration-approved drugs as binder to the LA binding pocket in wild and double mutant spike protein. MATERIALS AND METHODS: Approved drugs from DrugBank database (n = 2456) were prepared using Ligprep module of Schrodinger. Crystal structure of LA bound to spike trimer was retrieved (PDB: 6ZB4) and prepared using protein preparation wizard and grid was generated. A virtual screening was performed. With the help of molecular dynamics (MD) studies interaction profile of screened drugs were further evaluated. The selected hits were further evaluated for binding to the double mutant form of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). RESULTS AND DISCUSSION: Following virtual screening, a total of 26 molecules were shortlisted, which were further evaluated using 1ns MD simulation study. Four ligands showing better root mean square deviation (RMSD), RMSD to LA with interaction profile similar to LA were further evaluated using 100 ns MD simulation studies. A total of 2 hits were identified, which performed better than LA (selexipag and pralatrexate). Both these ligands were also found to bind to LA binding site of the double mutant form (E484Q and L452R); however, the binding affinity of pralatrexate was found to be better. CONCLUSION: We have identified 2 ligands (selexipag and pralatrexate) as possible stable binders to the LA binding site in spike trimer (wild and mutant form). Among them, pralatrexate has shown in vitro activity against SARS-CoV-2, validating our study results.

ABSTRACT The membrane-anchored spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a pivotal role in directing the fusion of the virus particle mediated by the host cell receptor angiotensin-converting enzyme 2 (ACE-2). The fusion peptide region of the S protein S2 domain provides SARS-CoV-2 with the biological machinery needed for direct fusion to the host lipid membrane. In our present study, computer-aided drug design strategies were used for the identification of FDA-approved small molecules using the optimal structure of the S2 domain, which exhibits optimal interaction ratios, structural features, and energy variables, which were evaluated based on their performances in molecular docking, molecular dynamics simulations, molecular mechanics/generalized Born model and solvent accessibility binding free energy calculations of molecular dynamics trajectories, and statistical inferences. Among the 2,625 FDA-approved small molecules, chloramphenicol succinate, imipenem, and imidurea turned out to be the molecules that bound the best at the fusion peptide hydrophobic pocket. The principal interactions of the selected molecules suggest that the potential binding site at the fusion peptide region is centralized amid the Lys790, Thr791, Lys795, Asp808, and Gln872 residues. IMPORTANCE The present study provides the structural identification of the viable binding residues of the SARS-CoV-2 S2 fusion peptide region, which holds prime importance in the virus’s host cell fusion and entry mechanism. The classical molecular mechanics simulations were set on values that mimic physiological standards for a good approximation of the dynamic behavior of selected drugs in biological systems. The drug molecules screened and analyzed here have relevant antiviral properties, which are reported here and which might hint toward their utilization in the coronavirus disease 2019 (COVID-19) pandemic owing to their attributes of binding to the fusion protein binding region shown in this study.

PurposeThere is increasing evidence of an association between Modic changes (MC) and subclinical infection. However, the association of MC with postoperative surgical site infection (SSI) has not been adequately probed. This study primarily aimed to investigate a probable association between preoperative MC, total endplate damage score (TEPS), and SSI.MethodsA retrospective analysis of 1124 patients who underwent surgery in a single institution (2016–2018) was performed, using both univariate and multiple logistic regression analyses to identify independent risk factors for SSI.ResultsThe prevalence of SSI was 4% (44/1124 patients), with no association with age or sex. The prevalence of MC in the SSI group was significantly higher—79.54% (35/44) compared to 58.79% (635/1080) (p value = 0.006) in the control group with no specific relation to type or location of MC. A higher TEPS was associated with SSI (p value = 0.009). A receiver operating characteristic (ROC) curve for TEPS values to assess predictiveness of SSI showed TEPS ≥ 5.5 to have a better sensitivity of 84% than 72% for a TEPS ≥ 6.5. Univariate analysis showed TEPS > 6 (odds ratio 3.887) to have a stronger association with SSI than the presence of MC (odds ratio 2.725). Among various types of surgeries, discectomy had a higher association with SSI (p value = 0.03) when compared to fusion (p value = 0.071). However, multiple logistic regression analysis revealed only TEPS > 6, presence of MC and hypothyroidism as independent risk factors for SSI.ConclusionOur data suggest that preoperative MC and TEPS > 6 are independent risk factors for developing surgical site infections. MC could be foci of chronic subclinical infection and not mere markers of degeneration, as initially described.

YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction.

Autism Spectrum Disorder (ASD) is a developmental disorder whose symptoms become noticeable in early years of the age though it can be present in any age group. ASD is a mental disorder which affects the communicational, social and non-verbal behaviors. It cannot be cured completely but can be reduced if detected early. An early diagnosis is hampered by the variation and severity of ASD symptoms as well as having symptoms commonly seen in other mental disorders as well. Nowadays, with the emergence of deep learning approaches in various fields, medical experts can be assisted in early diagnosis of ASD. It is very difficult for a practitioner to identify and concentrate on the major feature's leading to the accurate prediction of the ASD and this arises the need for having an automated approach. Also, presence of different symptoms of ASD traits amongst toddlers directs to the creation of a large feature dataset. In this study, we propose a hybrid approach comprising of both, deep learning and Explainable Artificial Intelligence (XAI) to find the most contributing features for the early and precise prediction of ASD. The proposed framework gives more accurate prediction along with the recommendations of predicted results which will be a vital aid clinically for better and early prediction of ASD traits amongst toddlers.

In this article, we study the interaction of delta shock waves for the one-dimensional strictly hyperbolic system of conservation laws with split delta function. We prove that Riemann solutions are stable under local small perturbations of the Riemann initial data. The global structure and large time asymptotic behaviour of the perturbed Riemann solutions are constructed and analyzed case by case.

Fluoroscopy is considered to be the gold standard and an essential requirement for catheter insertion. However, there is a paucity of data regarding the outcomes in ultrasound (USG)-guided insertion with and without fluoroscopy. We compared the complications of USG-guided tunneled dialysis catheter (TDC) insertion with and without fluoroscopy assistance. This was a single-center randomized controlled trial (RCT) done in a tertiary hospital in North India. After screening 153 patients, 149 were enrolled: 87 were randomized into USG-guided insertion without fluoroscopy (group A) and 62 were randomized into USG-guided insertion with fluoroscopy (group B). All insertions were done in a dedicated procedure room by trained nephrologists. Outcomes were analyzed at baseline and at 1-month follow-up. Mechanical complications as well as infective and thrombotic complications were compared between both the groups. TDC insertion was successful (100%) in all the study participants ( = 149). One hundred twenty-nine catheters (86.5%) were inserted in the first attempt, 19 (12.5%) in the second attempt, and one catheter insertion required three attempts for insertion. The mean age of study participants was 43 years (±16.5), and males constituted 63% of the study cohort. Baseline laboratory characteristics of the two groups were comparable. The mean time of catheter insertion was 41.26 min (standard deviation [SD] 11.8) in group A and 47.74 min (SD 17.2) in group B ( = 0.007). The mean score of ease of catheter insertion, exit site bleed, infective and mechanical complications were not different between the two groups. Our study concluded that fluoroscopy has no additional advantage in reducing mechanical, infective, or thrombotic complications. In experienced hands, USG-guided TDC insertion without fluoroscopy assistance is as good as the insertion done with fluoroscopy assistance, with a shorter procedure time.