Search

Proteins function close to native and near-native conformations. These states are evolutionarily selected to ensure the effect of mutations is minimized. The structural organization of a protein is hierarchical and modular, which reduces the dimensionality of the configurational space of the native states. Thus, finding appropriate descriptors that define the native state among all possible states of a protein is a problem of immense interest. The present study explores the correlation between solvent accessible surface areas (SASAs) and different intraprotein as well as protein-water hydrogen bonds of 55 single-chain globular proteins from four different structural classes (all α, all β, α+β, and α/β), 16 multichain proteins, and 4 macromolecular complexes. A systematic analysis of the solvent accessible surface area and intraprotein and protein-water hydrogen bonds suggests a linear relationship between SASAs and hydrogen bonds. The number of protein-water hydrogen bonds per unit SASA ranges from 3 to 4 for all the different structural protein classes. In contrast, the number of intramolecular hydrogen bonds per unit SASA, including the mainchain-mainchain, mainchain-sidechain, and sidechain-sidechain, varies between 0.75 to 2. The solvation free energy of a protein linearly decreases with SASA. Our study also shows that the solvation free energy/SASA varies from -75 to -105 kJ mol

The molecular mechanism behind the ice growth inhibition by antifreeze proteins (AFPs) is yet to be understood completely. Also, what physical parameters differentiate between the AFP and non-AFP are largely unknown. Thus, to get an atomistic overview of the differential antifreeze activities of different classes of AFPs, we have studied ice growth from different ice surfaces in the presence of a moderately active globular type III AFP and a hyperactive spruce budworm (sbw) AFP. Results are compared with the observations of ice growth simulations in the presence of topologically similar non-AFPs using all-atom molecular dynamics simulations. Simulation data suggest that the ice surface coverage is a critical factor in ice growth inhibition. Due to the presence of an ice binding surface (IBS), AFPs form a high affinity complex with ice, accompanied by a transition of hydration water around the IBS from clathrate-like to ice-like. Several residues around the periphery of the IBS anchor the AFP to the curved ice surface mediated by multiple strong hydrogen bonds, stabilizing the complex immensely. In the high surface coverage regime, the slow unbinding kinetics dominates over the ice growth kinetics and thus facilitates the ice growth inhibition. Due to the non-availability of a proper IBS, non-AFPs form a low-affinity complex with the growing ice surface. As a result, the non-AFPs are continuously repelled by the surface. If the concentration of AFPs is low, then the effective surface coverage is reduced significantly. In this low surface coverage regime, AFPs can also behave like impurities and are engulfed by the growing ice crystal.

The length of hospital stay after transcatheter aortic valve implantation (TAVI) has decreased over the years, and next-day discharge is being increasingly adopted in clinical practice. Whether further expediting discharge after TAVI by allowing same-day discharge (SDD) in selected patients is safe or derives additional benefits remains unanswered. Using the United States Nationwide Readmission Database 2015 to 2019, we identified 196,618 patients who received TAVI (mean age 79.5 8.4 years, 45.0% female). Of these, 245 patients (0.12%) were discharged on the same day they received TAVI (SDD group), and the remaining 196,373 were discharged on a different day (different-day discharge [DDD] group). A propensity score-matched analysis was done. The rate of unplanned readmission within 30 days of discharge was not significantly different between the SDD and DDD groups (11.0% vs 10.6%, hazard ratio 1.03, 95% confidence interval 0.56 to 1.90, p = 0.921). Hospitalization costs were significantly lower in the SDD group than the DDD group ($37,811 ± 18,029 vs $49,130 ± 27,007, p 0.001). In conclusion, the 30-day readmission rate was similar for patients discharged on the same day after TAVI and for patients discharged at a later time point.

Abstract: Flavonoids are vital candidates to fight against a wide range of pathogenic microbial infections. Due to their therapeutic potential, many flavonoids from the herbs of traditional medicine systems are now being evaluated as lead compounds to develop potential antimicrobial hits. The emergence of SARS-CoV-2 caused one of the deadliest pandemics that has ever been known to mankind. To date, more than 600 million confirmed cases of SARS-CoV2 infection have been reported worldwide. Situations are worse due to the unavailability of therapeutics to combat the viral disease. Thus, there is an urgent need to develop drugs against SARS-CoV2 and its emerging variants. Here, we have carried out a detailed mechanistic analysis of the antiviral efficacy of flavonoids in terms of their potential targets and structural feature required for exerting their antiviral activity. A catalog of various promising flavonoid compounds has been shown to elicit inhibitory effects against SARS-CoV and MERS-CoV proteases. However, they act in the high-micromolar regime. Thus a proper lead-optimization against the various proteases of SARS-CoV2 can lead to high-affinity SARS-CoV2 protease inhibitors. To enable lead optimization, a quantitative structure-activity relationship (QSAR) analysis has been developed for the flavonoids that have shown antiviral activity against viral proteases of SARS-CoV and MERS-CoV. High sequence similarities between coronavirus proteases enable the applicability of the developed QSAR to SARS-CoV2 proteases inhibitor screening. The detailed mechanistic analysis of the antiviral flavonoids and the developed QSAR models is a step forward toward the development of flavonoid-based therapeutics or supplements to fight against COVID-19.

Background: Thromboembolism-associated stroke is the most feared complication of Atrial fibrillation (AF). Percutaneous left atrial appendage closure (pLAAC) is indicated for stroke prevention in patients with AF who can’t tolerate long-term anticoagulation. We aim to study gender differences in peri-procedural and readmissions outcomes in pLAAC patients. Methods: Using the national readmission database from January 2016 to December 2018, AF patients undergoing the pLAAC procedure were identified. We used multivariate logistic regression analyses and time-to-event Cox regression analyses to conduct the study. Propensity matching with the Greedy method was done for the accuracy of results. Result: 28,819 patients were included in our study. Among them 11,946 (41.5%) were women and 16,873 (58.6%) were men. The mean age of overall population was 76.1 ± 8.5 years, with women ~ 1 year older than men. The overall rate of complications was higher in women (8.6% vs 6.6%, P

An in silico drug repurposing strategy combining docking and molecular dynamics simulation identifies the anticancer potential of vitamins targeting the MCM7 protein.

Neural tube defects (NTDs) are among the common and severe congenital malformations in neonates. According to a WHO report, nearly three lakh babies are affected per year worldwide by NTDs. Most studies revealed that folate deficiency is the key element to promote NTD with other oligogenic and multifactorial elements. This folate is metabolized by the FOCM (folate one-carbon metabolism) pathway. The most important step in the FOCM pathway is the conversion of methionine to homocysteine, which is guided by the enzyme MTRR. Several single-nucleotide polymorphisms (SNPs) in the MTRR gene are strongly associated with the progression of NTD. A nonsynonymous allelic variant (rs1532268) of the protein leads to a missense mutation at the 202nd position from serine to leucine (S202L) and is associated with a higher disease prevalence in different populations. In our study, this SNP indicates a 2-fold increase in the risk of disease progression (p-value of 0.03; OR 2.76; 95% CI 1.08–7.11). Here, extensive molecular dynamics simulations and interaction network analysis reveal that the change of 202nd serine to leucine alters the structures of the FAD and NAD binding domains, which restricts the ligand binding. The S202L variation alters the functional dynamics that might impede the electron transport chain along the NADP(H)→ FAD→ FMN pathway and hamper phosphorylation by kinases like GSK-3 and CaM-II during the posttranscriptional modification of the protein. The present study provides functional insights into the effect of the genetic variations of the MTRR gene on the NTD disease pathogenesis.

Urgent transcatheter aortic valve implantation (TAVI) is a feasible option for aortic stenosis (AS) patients with decompensated heart failure (HF) and cardiogenic shock (CS) as compared to the more traditional urgent balloon aortic valvuloplasty (BAV).We conducted a retrospective analysis to compare risk and cause of readmission in these two high-risk groups.Nationwide Readmission Database (NRD) 2011-2014 was retrospectively analyzed to identify patients with AS having either urgent TAVI or urgent BAV using appropriate ICD-9 codes. Propensity scores were used to match patients with urgent TAVI as compared to patients with urgent BAV. Statistical analysis was performed using the Stata 15.1 software.We identified a weighted sample of 6,670 patients with urgent BAV and 6,964 patients with urgent TAVI. The all-cause 30- and 90-day readmission was lower in the urgent TAVI group compared to urgent BAV (15.4 vs. 22.5%, (aHR): 0.92 [0.90-0.95] p .001). 30-day readmission due to CV cause and HF was also lower in the urgent TAVI group (aHR, 0.93: p .001 and aHR, 0.98: p = .040, respectively). The 30-day gastrointestinal (GI) bleed readmission rate was three times higher in urgent TAVI group (aHR, 3.00:95% CI (1.23-7.33), p = .016), but was not statistically significant at 90-days. Cardiac causes of readmission were the predominant cause of readmission in both groups, but more pronounced in urgent BAV group (60.3 vs. 40.5%, p .001).Urgent TAVI appears beneficial in patients with AS and decompensated HF or CS driven by roughly 10 and 25% reductions in overall readmissions at 30 and 90 days, and marked reductions in reintervention, although offset partially by higher risk of readmission due to GI bleeding at 30 days.

The polygenic nature of Alzheimer's disease (AD) and cross-talk between several signaling cascades make it harder to decode the disease pathogenesis. β-secretase (BACE1) works upstream in the amyloidogenic processing of amyloid precursor protein (APP) to generate Aβ that rapidly aggregates to form fibrils, the most abundant component of plaques observed in AD brains. Here, we report dual inhibition of BACE1 and Aβ aggregation by neohesperidin, a flavonoid glycoconjugate, using multi-spectroscopic approaches, force microscopy, molecular modeling, and validated the potency in SH-SY5Y neuroblastoma cell lines. Steady-state and time-resolved fluorescence reveal that neohesperidin binds close to the catalytic aspartate dyad. This binding conformationally restricts the protein in closed form which possibly precludes APP recognition and thereby inhibits BACE1 activity. Neohesperidin also dose-dependently inhibits the amyloid fibril formation, as evident from ANS, ThT assay, and AFM. Neohesperidin ameliorates aggregated Aβ25-35 induced ROS generation and mitochondrial dysfunction in the SH-SY5Y cell line. As a result, the amyloid induced apoptosis is significantly prohibited and normal neuronal morphology is rescued. These findings suggest neohesperidin as an inhibitor of the pathogenic conversion of Aβ to fibrillar amyloid assembly. Neohesperidin thus emerges as a non-toxic multi-potent scaffold for the development of AD therapeutics.

Recent times witnessed an upsurge in the number of COVID cases which is primarily attributed to the emergence of several omicron variants, although there is substantial population vaccination coverage across the globe. Currently, many therapeutic antibodies have been approved for emergency usage. The present study critically evaluates the effect of mutations observed in several omicron variants on the binding affinities of different classes of RBD-specific antibodies using a combined approach of immunoinformatics and binding free energy calculations. Our binding affinity data clearly show that omicron variants achieve antibody escape abilities by incorporating mutations at the immunogenic hotspot residues for each specific class of antibody. K417N and Y505H point mutations are primarily accountable for the loss of class I antibody binding affinities. The K417N/Q493R/Q498R/Y505H combined mutant significantly reduces binding affinities for all the class I antibodies. E484A single mutation, on the other hand, drastically reduces binding affinities for most of the class II antibodies. E484A and E484A/Q493R double mutations cause a 33-38% reduction in binding affinity for the approved therapeutic monoclonal antibodies, Bamlanivimab (LY-CoV555). The Q498R RBD mutation observed across all the omicron variants can reduce ~12% binding affinity for REGN10987, a class III therapeutic antibody, and the L452R/Q498R double mutation causes a ~6% decrease in binding affinities for another class III therapeutic antibody, LY-CoV1404. Our data suggest that achieving the immune evasion abilities appears to be the selection pressure behind the emergence of omicron variants.

In this work, a novel memory capacitor structure has been presented with AlOx/Al2O3 bilayer dielectrics on high mobility Epitaxial-GaAs substrate. We have demonstrated the chemical and electrical properties of metal–electrode/AlOx/Al2O3/epi-GaAs-based memory device in detail. Sputter-grown non-stoichiometric AlOx has been used for both the charge trapping layer and blocking layer due to its intrinsic charge trapping capability and high bandgap. Ultra-thin tunneling layer of thicknesses 5 nm and 15 nm were prepared by atomic layer deposition technique and memory properties were compared on promising high mobility Epitaxial-GaAs/Ge heterostructure. The proposed device shows excellent charge trapping properties with a maximum memory window of 3.2 V at sweep voltage of ± 5 V, with good endurance and data retention properties. Oxygen-deficient AlOx layer acted as a charge trapping layer without any additional blocking layer which is impressive for non-volatile memory application on high mobility epi-GaAs substrate. In addition, density Functional Theory (DFT) has been employed to understand the physical origin of the intrinsic charge trapping defects in AlOx dielectric layer.

Neural tube defects (NTDs), one of the most common birth defects, are strongly associated with the variations of several single nucleotide polymorphisms (SNPs) in the MTRR gene. The gene codes a key enzyme that is involved in the rejuvenation of methionine synthase activity. An allelic variant of the protein leads to missense mutation at 49th position from isoleucine to methionine (I49M) is associated with higher disease prevalence in different populations. Here, extensive molecular dynamics simulations and interaction network analysis reveal that the 49th isoleucine is a crucial residue that allosterically regulates the dynamics between the flavin mononucleotide (FMN) and NADP(H) binding domains. I49M variation alters the functional dynamics in a way that might impede the electron transport chain along the NADP(H) → flavin adenine dinucleotide → FMN pathway. The present study provides functional insights into the effect of the genetic variations of the MTRR gene on the NTDs disease pathogenesis.

Background We compared the in-hospital complications, outcomes, cost, and length of stay (LOS) between angiography-guided percutaneous coronary intervention (PCI) and intravascular ultrasound (IVUS)-guided PCI in patients with ST-elevation myocardial infarction (STEMI) in the USA. Methods A nationwide inpatient database was queried to identify patients >18 years with STEMI who underwent angiography-guided and IVUS-guided PCI from January 2016 to December 2016. We compared the in-hospital mortality, complications, cost, and LOS between the two groups. Results We identified 100,485 patients who underwent angiography-guided PCI and 5,460 patients who underwent IVUS-guided PCI. In-hospital mortality was not statistically different (odds ratio [OR] 0.76, 95% CI 0.46 − 1.22, P = 0.24). Patients who underwent PCI with IVUS were more likely to have coronary artery dissection (OR 4.26, 95% CI 2.34 − 7.7, p =

Depression is a recognized predictor of adverse outcomes in patients with heart failure (HF) and is associated with poor quality of life, functional limitation, increased morbidity and mortality, decreased adherence to treatment, and increased rehospitalization. To understand the impact of depression on HF readmission, we conducted a retrospective cohort study using the Nationwide Readmission Database (NRD) 2010-2014.We identified all patients with the primary discharge diagnosis of HF by ICD-9-CM codes. The primary outcome of the study was to identify 30-day all-cause readmission and causes of readmission in patients with and without depression. Multivariate Cox regression analysis was used to estimate the adjusted hazard ratio for the primary and secondary outcomes.Among, 3,500,570 patients admitted with HF, 9.7% had concomitant depression. Patients with depression were more likely to be readmitted within 30 days (19.7% vs. 18.5%; P 0.001). Concomitant depression was associated with higher risk of all-cause readmissions within 30 days and 90 days [P 0.001] but was not associated with increased readmissions due to cardiovascular (CV) cause at 30 days and 90 days. The hazard of psychiatric causes of readmission was higher in patients with depression, both at 30 days [P 0.001], and 90 days [P 0.001]. Most of the readmissions were due to CV causes, with HF being the most common cause.Among patients hospitalized with HF, the presence of depression is associated with increased all-cause readmission driven mainly by psychiatric causes but not CV-related readmission. Standard interventions targeted toward HF are unlikely to modify this portion of all-cause readmission.

Antifreeze proteins (AFPs) show thermal hysteresis through specific interaction with the ice crystal. Hyperactive AFPs interact with the ice surface through a threonine-rich motif present at their ice-binding surface (IBS). Ordering of water around the IBS was extensively investigated. However, the role of non-IBS in ice growth inhibition is yet to be understood completely. The present study explores the nature of hydration and its length-scale evaluation around the non-IBS for hyperactive AFPs. We observed that the hydration layer of non-IBS is liquid-like, even in highly supercooled conditions, and the nature of hydration is drastically different from the hydration pattern of non-AFP surfaces. In similar conditions, the hydration layer around the IBS is ice-like ordered. Non-IBS of the hyperactive AFP exposes toward the bulk and is able to maintain the liquid-like character of its hydration water up to 15 Å. We also find that the amino acid compositions and their spatial distribution on the non-IBS are markedly different from those of the IBS and non-AFP surfaces. These results elucidate the combined role of IBS and non-IBS in ice-growth inhibition. While IBS is required to adsorb on ice efficiently, the exposed non-IBS may prevent ice nucleation/growth on top of the bound AFPs.

There have been no studies focusing on how pulmonary hypertension (PH) affects inpatient outcomes in patients with hypertrophic cardiomyopathy (HCM) hospitalized for acute decompensated heart failure or cardiogenic shock. This study explores inpatient outcomes of patients with HCM, and concomitant PH compared to patients with HCM. Based on the National Inpatient Sample (NIS) 2016-2018, patients admitted with a primary diagnosis of acute decompensated heart failure or cardiogenic shock were selected. The patients diagnosed with concomitant HCM were identified and divided into 2 groups based on the presence or absence of PH. After propensity matching 1545 matched pairs were generated. Patients with PH had a higher prevalence of chronic kidney disease (P0.001), anemia (P0.001), coagulopathy (P0.001), atrial fibrillation (P = 0.031), and valvular disease (P0.001) (Table 1). The primary outcome (all-cause in-hospital mortality) occurred in 110 patients (2.6%) without PH and 95 patients (5.2%) with PH, which was not statistically significant after propensity matching (odds ratio [OR]:1.53; 95% confidence interval [CI]: 0.70-3.33; P = 0. 28) (Table 3). Patients with PH had a higher incidence of transient ischemic attack (TIA) (OR: 9.52; 95% CI: 3.38-26.78; P0.001)] and respiratory failure [(OR: 1.49; 95% CI:1.05-2.11; P = 0.027], although with no difference in requirement for mechanical ventilation (= 0.64), as compared to patients without PH. PH in patients with HCM is associated with increased morbidity, including increased risk of TIA and respiratory failure.

Acquiring the human ACE2 receptor usage trait enables the coronaviruses to spill over to humans. However, the origin of the ACE2 usage trait in coronaviruses is poorly understood. Using a multi-disciplinary approach combining evolutionary bioinformatics and molecular dynamics simulation, we decode the principal driving force behind human ACE2 receptor recognition in coronaviruses. Genomic content, evolutionary divergence, and codon usage bias analysis reveal that SARS-CoV2 is evolutionarily divergent from other human ACE2-user CoVs, indicating that SARS-CoV2 originates from a different lineage. Sequence analysis shows that all the human ACE2-user CoVs contain two insertions in the receptor-binding motif (RBM) that directly interact with ACE2. However, the insertion sequences in SARS-CoV2 are divergent from other ACE2-user CoVs, implicating their different recombination origins. The potential of mean force calculations reveals that the high binding affinity of SARS-CoV2 RBD to human ACE2 is primarily attributed to its ability to form a higher number of hydrogen bonds than the other ACE2-user CoVs. The adaptive branch-site random effects likelihood method identifies positive selection bias across the ACE2 user CoVs lineages. Recombination and selection forces shape the spike evolution in human ACE2-using beta-CoVs to optimize the interfacial hydrogen bonds between RBD and ACE2. However, these evolutionary forces work within the constraints of nucleotide composition, ensuring optimum codon adaptation of the spike (S) gene within the host cell.

The aim of this study is to compare outcomes of rotational atherectomy and cutting balloon (RACB) versus rotational atherectomy and plain balloon (RAPB) before drug-eluting stent (DES) implantation in calcified coronary lesions.Randomized controlled trials (RCT) and observational studies comparing RACB with RAPB were identified through a systematic search of published literature across multiple databases. Random effect meta-analysis was performed to compare the outcome between the two groups.Four studies were included in the meta-analysis (three observational and one RCT) involving a total of 315 patients. 166 patients had RACB, and 149 patients had RAPB before DES placement with a median follow-up of 11.5 months. Compared with patients who had RAPB there was no difference in MACE (composite of death, myocardial infarction, and target vessel revascularization) (odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.25-2.18], slow flow/no reflow (OR: 0.71; 95% CI: 0.23-2.16), all-cause mortality (OR: 2.02; 95% CI: 0.28-14.60), and device success rate (OR: 1.79; 95% CI: 0.28-11.18) in the RACB approach. There was a benefit towards less target lesion revascularization in the RACB group; however, this outcome was reported in two studies (OR: 0.29; 95% CI: 0.08-0.99). On meta-regression there was no association between age, sex, diabetes, or lesion location with MACE and all-cause mortality. The studies were homogenous across all outcomes.RACB, as compared with RAPB, had a similar risk of MACE, all-cause mortality, device success, and complication, but a lower risk of target lesion revascularization.

The metabolites present in the crude methanolic extract of Leucas biflora were identified and characterized to obtain new leads for compounds with antibacterial effects. The plant extract showed antibacterial effects against both the gram-positive and gram-negative bacteria in disc-diffusion assay. Gas chromatography-mass spectrometry (GC-MS) results revealed nine types of high and low molecular weight chemical entities with varying quantities in the extract. An in silico target-fishing approach identified two compounds with multi-target-directed activities. Two metabolites, 3-Oxo-18-Nor-ent-ros-4-ene-15.alpha.,16-acetonide and 4-Dehydroxy-N-(4,5-methylenedioxy-2-nitrobenzylidene)-tyramine, inhibited two promising bacterial targets, FabH and DNA gyrase B.

The purpose of the study was to determine the in-hospital outcome and resource utilization in patients with acyanotic congenital heart disease (ACHD) undergoing transcatheter aortic valve replacement (TAVR). Current guidelines from professional societies do not support TAVR in patients with ACHD, likely from a lack of supportive evidence. Temporal trends in patients with ACHD undergoing TAVR were determined using the 2016-2018 National Inpatient Sample database appropriate ICS-10-PCS code. Stata 16.0 was used for statistical analysis. 0.87% of patients undergoing TAVR had concomitant ACHD, with ASD being the most common (78%). After matching, there was no increased risk of mortality in ACHD patients undergoing TAVR compared to patients without ACHD (OR 1.43, P = 0.59). Additionally, no difference was found in the incidence of overall cardiac complications between patients with ACHD and patients without ACHD, except STEMI (OR 4.16, 95% CI, 1.08-16.00, P = 0.038), which is likely due to more comorbidity burden in the later cohort. Complications such as acute kidney injury, ischemic stroke, and bleeding were similar. Hospital resource utilization was higher in the ACHD group in the form of increased length of stay and higher mean total cost. The comparable in-hospital all-cause mortality and complication rate in ACHD patients undergoing TAVR compared to patients without ACHD is encouraging and will be helpful to design future randomized controlled trials.

Introduction: Clopidogrel is the most frequently used P2Y12 inhibitor as a component of the dual antiplatelet regimen in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Prior studies have shown the variable efficacy of clopidogrel due to genotypic differences in the CYP2C19 enzyme function, which converts clopidogrel to its active metabolite. Hypothesis: The aim of this meta-analysis is to evaluate the effectiveness of genotype testing-guided P2Y12 inhibitor prescription therapy to patients after PCI for ACS compared to non-genotype guided conventional treatment. Methods: A comprehensive literature search was performed in PubMed, Embase, and Cochrane to identify relevant trials. Summary effects were calculated using a DerSimonian and Laird random-effects model as odds ratio with 95% confidence intervals for all the clinical endpoints. Results: Seven studies with 9617 patients were included. Genotype-guided strategy arm included prasugrel or ticagrelor prescription to patients with loss of function (LOF) of CYP219 alleles (most commonly alleles being *2 and *3) and clopidogrel prescription to those without the LOF allele. The conventional arm included patients treated with clopidogrel without genotype testing. Comparison of genotype arm with conventional arm showed decreased major adverse cardiovascular events (MACE) (RR 0.72, 95% CI 0.55-0.95; p=0.02, I 2 =23), improved cardiovascular (CV) mortality (RR 0.62, 95% CI 0.43-0.90; p=0.01, I 2 =0) and reduced incidence of myocardial infarction (MI) (RR 0.57, 95% CI 0.41-0.97; p< 0.01), and a similar stroke incidence (RR 0.65, 95% CI 0.35-1.21; p= 0.18). Regarding adverse events, the incidence of stent thrombosis was lower in the genotype arm than the conventional arm (RR 0.52, 95% CI 0.28-0.96; p=0.04). Conclusions: Our analysis illustrates the possible advantages of genotype-guided P2Y12 inhibitor prescription strategy compared to non-genotype-guided strategy with reductions in MACE, CV mortality, MI, and stent thrombosis. This analysis can be used as a stepping stone to conducting further trials determining the efficacy of this treatment strategy in various ACS subtypes.

Graphical abstract, SARS-CoV2 mutants B.1.1.7, B.1.351, and P.1 contain a key mutation N501Y. B.1.135 and P.1 lineages have another mutation, E484K. Here, we decode the effect of these two mutations on the host receptor, ACE2, and neutralizing antibody (B38) recognition. The N501Y RBD mutant binds to ACE2 with higher affinity due to improved π-π stacking and π-cation interactions. The higher binding affinity of the E484K mutant is caused due to the formation of additional hydrogen bond and salt-bridge interactions with ACE2. Both the mutants bind to the B38 antibody with reduced affinity due to the loss of several hydrogen-bonding interactions. The insights obtained from the study are crucial to interpret the increased transmissibility and reduced neutralization efficacy of rapidly emerging SARS-CoV2 VOCs.

Introduction Infective endocarditis (IE) is one of the feared diseases in septic patients, and incidences are rising due to the intravenous drug abuse epidemic. Sepsis causes an escalation of the platelet destructions leading to thrombocytopenia (1). Few independent hospital-based studies have proposed increase mortality with thrombocytopenia in patients with IE (2–5). We aim to evaluate the significance of thrombocytopenia in IE subjects from the national inpatient sample (NIS) database. Method We analyzed the NIS database from Jan-2016 to Dec-2018 using Stata 16.0. NIS is the largest publicly available all-payer inpatient care database in the United States, containing data on more than seven million hospital stays per year. We identified patients with IE with or without thrombocytopenia using ICD-10 codes. The primary outcome of interest was in-hospital mortality comparison. We adjusted potential confounders (age, sex, diabetes, hypertension, etc.) with multivariate logistic regression analysis. Further analysis was done after balancing the population co-morbidity using a Greedy propensity match for accuracy. Results A total of 174,495 subjects were included in this study with a diagnosis of IE. Among these individuals, 33,285 patients had a concurrent diagnosis of thrombocytopenia. The mean ages were 53±19.5 years for the thrombocytopenia group and 55±19.8 years for others. Females were equally represented in both cohorts. There were 4,945 (14.86%) vs 2,835 (2.01%) mortalities reported in with and without thrombocytopenia group respectively. After propensity matching, there was a pronounced increase in mortality [Odds ratio (OR): 1.93 (1.72 – 2.15), p-value: Conclusion In conclusion, IE patients with thrombocytopenia have higher incidences of in-patient mortality and poor outcomes than cohort without thrombocytopenia. Some of the adverse consequences could be temporally explained by complications related to underlying thrombocytopenia. Further investigations are needed to delineate the outcome in this group of subjects. Funding Acknowledgement Type of funding sources: None.

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting approximately 1–2% overall population (1). Its causal relationship with colorectal cancer (CRC) is much for debate. According to one hypothesis, the presence of autoantibodies directed against ionic channels or acetylcholine receptors can predispose to the development of atrial fibrillation (2–3). Thus, AF may be regarded as an inflammatory complication in patients with colon cancer. Our study objective was to determine if AF impacts the outcome of patients with CRC. Method We analyzed the National Inpatient Sample (NIS) database from Oct-2015 to Dec 2018 using Stata 16.0. The NIS databases are released under the Healthcare Cost and Utilization Project, which includes inpatient admissions from the United States' participating hospitals. Total population with CRC were identified using their respective ICD-10 diagnostic codes then divided based on AF. To determine atrial fibrillation association with mortality and complications, we used multivariate logistic regression analysis using weights to generate nationally representative results. Later, a propensity-matched population analysis was done for the accuracy of the results. Result We found 245,305 patients admitted with CRC between Oct 2015 to Dec-2018 in the USA, out of which 28,170 (11.5%) were having AF. The mean age for the patients with AF was 77±10 compare to 65±14 years in those without AF. Patients with AF were associated with higher comorbidities and had a high population percentage with Carlson category three or above. There were 1,456 (5.2%) mortalities in the AF group compared to 5,689 (2.6%) in the other. The higher odds of mortality in patients with AF was present in multivariate logistic regression analysis in both non-propensity matched [1.71 (1.45–2.02), P-value: Conclusion In our retrospective, propensity-matched national inpatient sample analyses of patients admitted with colorectal cancer, atrial fibrillation is associated with higher morbidity and mortality. AF was associated with a high burden of complications with prolonged hospital stay leading to increased health care expenditures. Funding Acknowledgement Type of funding sources: None.

Bicuspid aortic valve (BAV) is one of the most common inherited valvular anomalies, occurring either in isolation or as a part of other congenital syndromes. It is found in approximately 1% of the ...

Although acute myocardial infarction (AMI) is a disease predominantly affecting adults60 years of age, a significant proportion of the young population who have different risk profiles, are also affected. We undertook a retrospective analysis using National Inpatient Sample (NIS) 2010 to 2014 to evaluate gender differences in characteristics, treatments, and outcomes in the younger AMI population.The NIS 2010-2014 was used to identify all patient hospitalizations with AMI between 18 to45 years using ICD-9-CM codes. We demonstrated a gender-based difference of in-hospital all-cause mortality, other complications, and revascularization strategies in the overall AMI population and other subgroups of AMI [anterior wall ST-segment elevation MI (STEMI), and non-anterior wall STEMI and non-STEMI (NSTEMI)].A total of 156,018 weighted records of AMI hospitalizations were identified, of which 111,894 were men and 44,124 were women. Young women had a higher prevalence of anemia, chronic lung disease, obesity, peripheral vascular disease, and diabetes. Conversely, young men had a higher prevalence of dyslipidemia, smoking, and alcohol. Among non-traditional risk factors, women had a higher prevalence of depression and rheumatologic/collagen vascular disease. There was no difference in all-cause in-hospital mortality in women compared to men [2.03% vs 1.48%; OR 1.04, CI (0.84-1.29); P = .68], including in subgroup analysis of NSTEMI, anterior wall STEMI, and non-anterior wall STEMI. Women with AMI were less likely to undergo percutaneous coronary intervention [47.13% vs 61.17%; OR 0.66, 95% CI (0.62-0.70; P .001] and coronary artery bypass grafting [5.6% vs 6.0%; OR 0.73, 95% CI 0.64-0.83; P .001] compared to men. Women were also less likely to undergo percutaneous coronary intervention within 24 h of presentation (38.47% vs 51.42%, P .001).Despite higher baseline comorbidities in young women with AMI, there was no difference in in-hospital mortality in women compared to men. Additional studies are needed to evaluate the impact of gender on clinical presentation, treatment patterns, and outcomes of AMI in young patients.

The selective transport of ions across cell membranes, controlled by membrane proteins, is critical for a living organism. DNA-based systems have emerged as promising artificial ion transporters. However, the development of stable and selective artificial ion transporters remains a formidable task. We herein delineate the construction of an artificial ionophore using a telomeric DNA G-quadruplex (h-TELO) and a lipophilic guanosine (MG). MG stabilizes h-TELO by non-covalent interactions and, along with the lipophilic side chain, promotes the insertion of h-TELO within the hydrophobic lipid membrane. Fluorescence assays, electrophysiology measurements and molecular dynamics simulations reveal that MG/h-TELO preferentially transports K+-ions in a stimuli-responsive manner. The preferential K+-ion transport is presumably due to conformational changes of the ionophore in response to different ions. Moreover, the ionophore transports K+-ions across CHO and K-562 cell membranes. This study may serve as a design principle to generate selective DNA-based artificial transporters for therapeutic applications., DNA based ionophores can mediate efficient ion transport and are crucial to understand the biological role of their natural counterparts. Here authors engineer a telomeric DNA G-quadruplex based ionophore which transports K+ in a stimuli responsive manner.

Epithelial to mesenchymal transition (EMT) is compulsory for metastatic dissemination and is stimulated by TGF-β. Although targeting EMT has significant therapeutic potential, very few pharmacological agents have been shown to exert anti-metastatic effects. BI-69A11, a competitive Akt inhibitor, displays anti-tumor activity toward melanoma and colon carcinoma. This study provides molecular and biochemical insights into the effects of BI-69A11 on EMT in colon carcinoma cells in vitro and in vivo. BI-69A11 inhibited metastasis-associated cellular migration, invasion and adhesion by inhibiting the Akt-β-catenin pathway. The underlying mechanism of BI-69A11-mediated inhibition of EMT included suppression of nuclear transport of β-catenin and diminished phosphorylation of β-catenin, which was accompanied by enhanced E-cadherin-β-catenin complex formation at the plasma membrane. Additionally, BI-69A11 caused increased accumulation of vinculin in the plasma membrane, which fortified focal adhesion junctions leading to inhibition of metastasis. BI-69A11 downregulated activation of the TGF-β-induced non-canonical Akt/NF-κB pathway and blocked TGF-β-induced enhanced expression of Snail causing restoration of E-cadherin. Overall, this study enhances our understanding of the molecular mechanism of BI-69A11-induced reversal of EMT in colorectal carcinoma cells in vitro, in vivo and in TGF-β-induced model systems.

Two-dimensional (2D) nanostructures are an emerging class of materials for designing artificial light-harvesting system because of their unprecedented electronic properties. Here, we design 2D nano...

Presence of organic micro-pollutants in aquatic ecosystems is a major concern in public health. Designing effective strategies to remove organic pollutants are subject of intense research interests. Rhodamine B (Rb), a widely used stain in textile, food industries and biomedical laboratories, is highly cytotoxic and induce oxidative stress, hormonal imbalance and apoptosis. Thus devising an effective strategy for Rb removal from aquatic environment is an urgent need. Present study demonstrates the applicability of triclosan (TR)-2-hydroxypropyl–β–cyclodextrin (HP–β–CD) inclusion complex to effectively adsorb rhodamine B (Rb) from aqueous solution. Triclosan readily incorporates into HP–β–CD cavity and the calculated binding constant is 230.5 M−1. Both solid and solution state complexes have been prepared and detailed characterization have been carried out using fluorescence spectroscopy, MALDI–TOF, FT–IR, 1H NMR, XRD, FT-Raman and SEM methods. The TR:HP–β–CD complex exhibits excellent ability to remove Rb from aqueous solutions with maximum adsorption efficiency of 261.78 mg/g. The adsorption process is a pseudo-second order reaction. Adsorption isotherm analysis reveals that the isotherm data are well fitted to the Langmuir adsorption model. Details of the isotherm analysis reveal that the adsorption take place at specific homogeneous sites where the adsorbent forming monolayer coverage of Rb at the surface of the TR:HP–β–CD complex.

Background: Transcatheter aortic valve replacement (TAVR) is being increasingly used for decompensated severe symptomatic aortic stenosis. Data on urgent and elective TAVR readmission is scarce in the literature. Here, we have performed a retrospective cohort study with the Nationwide Readmission Database of 2016 to identify the rate of 30-day all-cause readmission, common causes of readmission, and distribution of morbidity in index admission and readmission after urgent and elective TAVR. Methods: We used International Classification of Diseases, Tenth Revision codes (02R.F38H, 02R.F38Z, 02R.F48Z) for identification of all TAVR procedures done in 2016 in patients >18 years old. We found 8379 patients who underwent urgent TAVR and 32,006 patients who underwent elective TAVR in 2016. Result: The mean age of patients undergoing urgent TAVR was 79 ± 9.97 years with 44.6% women. The mean age of patients undergoing elective TAVR was 80.7 ± 8.25 years with 46.2% women. We found the 30-day all-cause readmission rate of 15.5% and 9.5% in patients undergoing urgent and elective TAVR, respectively (p < 0.001). The cardiac cause was the predominant cause of readmission in both groups (43.77% vs. 42.11%, p = 0.57), followed by pulmonary cause, gastrointestinal (GI) cause, and renal cause. Among cardiac causes, congestive heart failure (CHF) was predominant cause of readmission and was similar in both groups (18.73 in urgent TAVR vs. 15.73 in elective TAVR, p = 0.12). Conclusion: We found that the all-cause 30-day readmission rate was higher in patients who had undergone urgent TAVR. Further studies are needed to better understand this difference.

Clopidogrel is the most frequently used P2Y12 inhibitor as a component of the dual antiplatelet regimen in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Prior studies have shown the variable efficacy of clopidogrel due to genotypic differences in the CYP2C19 enzyme function, which converts clopidogrel to its active metabolite. The aim of this meta-analysis is to evaluate the effectiveness of genotype testing-guided P2Y12 inhibitor prescription therapy to patients after PCI for ACS compared to non-genotype guided conventional treatment.A comprehensive literature search was performed in PubMed, Embase, and Cochrane to identify relevant trials. Summary effects were calculated using a DerSimonian and Laird random-effects model as odds ratio with 95% confidence intervals for all the clinical endpoints.Seven studies with 9617 patients were included. Genotype-guided strategy arm included prasugrel or ticagrelor prescription to patients with loss of function (LOF) of CYP219 alleles (most commonly alleles being *2 and *3) and clopidogrel prescription to those without the LOF allele. The conventional arm included patients treated with clopidogrel without genotype testing. Comparison of genotype arm with conventional arm showed decreased major adverse cardiovascular events (MACE), improved cardiovascular (CV) mortality, and reduced incidence of myocardial infarction (MI) in the genotype arm, and a similar stroke incidence in the two arms. Regarding adverse events, the incidence of stent thrombosis was lower in the genotype arm than the conventional arm.Our analysis illustrates the possible advantages of genotype-guided P2Y12 inhibitor prescription strategy compared to non-genotype-guided strategy with reductions in MACE, CV mortality, MI, and stent thrombosis. This analysis can be used as a stepping stone to conducting further trials determining the efficacy of this treatment strategy in various ACS subtypes.

Introduction: Despite advances in surgical and anesthetic techniques, perioperative cardiovascular complications are a major cause of 30-day perioperative mortality. Major cardiovascular complicati...

Acetylcholinesterase is a prime target for therapeutic intervention in Alzheimer's disease. Acetylcholinesterase inhibitors (ACKEIs) are used to improve cognitive abilities, playing therefore an important role in disease management. Drug repurposing screening has been performed on a corporate chemical library containing 11 353 compounds using a target fishing approach comprising three-dimensional (3D) shape similarity and pharmacophore modeling against an approved drug database, Drugbank. This initial screening identified 108 hits. Among them, eight molecules showed structural similarity to the known ACKEI drug, pyridostigmine. Further structure-based screening using a pharmacophore-guided restoring method identifies one more potential hit. Experimental evaluations of the identified hits sieve out a highly selective AChEI scaffold. Further lead optimization using a substructure search approach identifies 24 new potential hits. Three of the 24 compounds (compounds 10b, 10h, and 10i) based on a 6-(2-(pyrrolidin-1-yl)pyrimidin-4-yl)-thiazolo[3,2-alpha]pyrimidine scaffold showed highly promising AChE inhibition ability with IC50 values of 13.10 +/- 0.53, 16.02 +/- 0.46, and 6.22 +/- 0.54 mu M, respectively. Moreover, these compounds are highly selective toward AChE. Compound 10i shows AChE inhibitory activity similar to a known Food and Drug Administration (FDA)-approved drug, galantamine, but with even better selectivity. Interaction analysis reveals that hydrophobic and hydrogen-bonding interactions are the primary driving forces responsible for the observed high affinity of the compound with AChE.