Congenital Pouch Colon (CPC) is a rare anorectal anomaly common to northwestern India, specifically Rajasthan. Despite efforts to understand the clinical genetic makeup of CPC, no attempt on ...identifying non-coding RNAs was done. We have earlier reported CPC's rare variants from whole exome sequencing (WES) across 18 affected samples in a total of 64 subjects. A Smith⁻Waterman algorithm was used to infer a couple of lncRNAs from WES samples of CPC with predictions from the Noncode database. Further screening and quantification using polymerase chain reaction (PCR), we ascertained interactions using Micro Scale Thermophoresis (MST). We report the role of
-EPB41-1-1 shown to be promiscuously interacting with KIF13A substantiating their role in regulation.
In higher plants, the mitochondrial alternative oxidase (AOX) pathway plays an essential role in maintaining the TCA cycle/cellular carbon and energy balance under various physiological and stress ...conditions. Though the activation of AOX pathway upon exogenous addition of α-ketoacids/TCA cycle metabolites pyruvate, α-ketoglutarate (α-KG), oxaloacetic acid (OAA), succinate and malic acid to isolated mitochondria is known, the molecular mechanism of interaction of these metabolites with AOX protein is limited. The present study is designed to understand the biomolecular interaction of pure recombinant Arabidopsis thaliana AOX1A with TCA cycle metabolites under in vitro conditions using various biophysical and molecular docking studies. The binding of α-KG, fumaric acid and OAA to rAtAOX1A caused conformational change in the microenvironment of tryptophan residues as evidenced by red shift in the synchronous fluorescence spectra (∆λ = 60 nm). Besides, a decrease in conventional fluorescence emission spectra, tyrosine specific synchronous fluorescence spectra (∆λ = 15 nm) and α-helical content of CD spectra revealed the conformation changes in rAtAOX1A structure associated with binding of various TCA cycle metabolites. Further, surface plasmon resonance (SPR) and microscale thermophoresis (MST) studies revealed the binding affinity, while docking studies identified binding pocket residues, respectively, for these metabolites on rAtAOX1A.
•Synchronous fluorescence revealed differential binding of TCA metabolites to rAtAOX1A•CD spectra retained α-helical signal inspite of considerable change in α-helical content•TCA metabolites are bound to rAtAOX1A in reversible fashion•The binding pockets and potential residues of AtAOX1A, which interact with TCA cycle metabolites are identified by Molecular docking studies.
The Mycobacterium tuberculosis (Mtb) Rv2747 gene encodes for a functional protein known as ArgA, which plays an important role in the first step of the l-arginine biosynthesis pathway. ArgA transfers ...the acetyl group from the acetyl-CoA to either l-glutamate or l-glutamine, which are the known substrates. Here, we present two crystal structures of ArgA: one complexed with CoA and product bound N-acetylglutamine and the other complexed with acetyl-CoA and the inhibitor l-arginine at 2.3 and 3.0 Å resolution respectively. The Mtb ArgA protomer was found to have a “V” cleft and a “β” bulge, archetypal of a classical GCN5-related N-acetyltransferase superfamily of proteins. The product bound form implies that ArgA can also acetylate l-glutamine like l-glutamate. The active site is strongly inhibited by l-arginine resulting in a closed conformation of ArgA and both l-arginine and N-acetylglutamine were found to occupy at the same active site. Together with structural analysis, molecular docking studies, microscale thermophoresis and enzyme inhibition assays, we conclude that l-glutamine, l-glutamate and l-arginine, all occupy at the same active site of ArgA. Furthermore in case of Mtb ArgA, l-arginine does not act as an allosteric inhibitor unlike other N-acetylglutamate synthase family of proteins.
Conjugated linoleic acid (CLA), isomers of linoleic acid (C18:2) have many biological effects, including potential immunomodulatory potential. CLA is an unrecognized nutrient that significantly ...protects lymphoidal and nonlymphoidal tissues from lymphoid events during immune stimulation. This protection is through the regulation of lipid eicosanoid mediators while nonlymphoidal tissues prevent their negative feedback on the immune response. With lipid mediator modulation there is enhanced immunity, improved efficiency of feed use, changes in body composition, and decrease in diseases with immune response. With regard to the immune system, it is not clear whether individual isomers of CLA could act similarly or differently. In this chapter, we are trying to uncover most of the fundamental findings to explore the effects of CLA in relation to immunomodulation.
Purpose: Identification of nonresponders prior to anti-vascular endothelial growth factor (anti-VEGF) therapy would help in the judicious clinical management of diabetic macular edema (DME) patients. ...Thus, a systematic study was initiated to identify nonresponding DME patient population undergoing ranibizumab treatment to figure out additional inflammatory components that may contribute to their nonresponsiveness to anti-VEGF therapy. Methods: A total of 40 patients recruited to this investigator-initiated trial received intravitreal ranibizumab monthly for 3 months. The fourth- and fifth-month injections were according to PRN protocol and the sixth-month injection was mandatory. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and VEGF in aqueous humor were measured for all the patients. Patients were grouped into responders/nonresponders on the formulated criteria and the levels of key pro-inflammatory cytokines were also measured between the two groups at baseline, 2 month and 5 months using cytometric bead array (CBA). Results: Eleven patients were categorized (29.72%) as responders and 10 patients (27.02%) as nonresponders. Nonresponders showed poorer BCVA (P = 0.024, 0.045, and 0.048 for 4, 5, and 6 months) and higher CMT (P = 0.021, 0.0008 and <0.0001 for baseline, 1, 2, 3, 4, 5, and 6 months) compared to responders. The cytokines IL-8, MCP-1 were significantly up regulated (P = 0.0048 and 0.029 for MCP-1 and IL-8) in nonresponders. Conclusion: Elevated MCP-1 and IL-8 levels found in the nonresponders could be used as a prognostic marker to identify these groups of patients and can help in developing alternative treatment options along with anti-VEGF therapy.
INTRODUCTIONDuring the COVID-19 lockdown, India saw a major restriction in the movement of people. Patients with acute myocardial infarction (MI) required early interventions and follow-up of ...independent predictors like symptom-to-balloon (STB) time and door-to-balloon (DTB) time. This study aimed to determine changes in STB and DTB time before and after the COVID-19 lockdown and its associated risk factors.METHODSA hospital-based cross-sectional study of 105 patients admitted to the cardiac care units (CCU) of two tertiary care centers in a district of Southern India for six months was conducted to compare the changes in STB and DTB time before and after the COVID-19 lockdown (three months before March 2020 and three months after March 2020), and data was collected from medical records. The data collected was then entered into Microsoft Excel (Microsoft Corporation, Washington, USA), numerically coded, and analyzed using SPSS Statistics version 21 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.). The Chi-square and Mann-Whitney U tests assessed the association between the dependent and independent variables. The STB/DTB time (before and after the COVID-19 lockdown) was the dependent variable, while the age, gender, co-morbidities, smoking status, and date of admission of patients (before and after the COVID-19 lockdown) were taken as the independent variables. A p-value of <0.05 was considered statistically significant. The predictor variables were identified using the regression method, where all variables with a significance of <0.2 were taken.RESULTSThe overall mean (±SD) STB time was 408.7 (±307.1) minutes, and the mean (±SD) DTB time was 161.7 (±261.6) minutes. The pre-lockdown mean STB time was 404.6 minutes, and the mean DTB time was 153 minutes, whereas the post-lockdown mean STB and DTB time were higher at 413.3 minutes and 171.6 minutes, respectively. Out of the total 105 patients, 95 (90.5%) had an STB time of ≥120 minutes, and 77 (73.3%) had an ideal DTB time of <90 minutes. There was no statistically significant variation in the STB and DTB time before and after the lockdown. Only the age group >60 years (38 (97.4%)) was found to be statistically significant with an STB time of ≥120 minutes after the lockdown (p-value=0.040), and patients referred from primary and secondary care centers (AOR (95% CI)=4.669 (1.129-19.298)) were found to be an independent factor in reducing DTB time before and after the COVID-19 lockdown.CONCLUSIONThe efficiency of the health system, irrespective of the COVID-19 lockdown, was observed; nevertheless, a delay in the overall recognition of symptoms of MI was perceived. The importance of time factors in identifying the symptoms of non-communicable diseases (NCDs), especially MI and stroke, has to be ascertained among the general population.
Abstract Hypercholesterolemia (HC) induced endothelial cell dysfunction and decreased endothelial nitric oxide formation results in impaired angiogenesis and subsequent cardiovascular disorders. ...Therapeutic angiogenesis is known to be a novel strategy for treatment of patients with ischemic heart disease. We have shown that secoisolariciresinol diglucoside (SDG) is angiogenic as well as cardioprotective against myocardial ischemia. In the present study, we examined the efficacy of SDG in a hypercholesterolemic myocardial infarction (MI) model. The rats were maintained on a normal and high cholesterol diet (2%) for 8 weeks followed by oral administration of SDG (20 mg/kg) for 2 weeks. The rats were divided into four groups ( n = 24 in each): Control (C); SDG control (SDG); HC; and HC + SDG (HSDG). Isolated hearts subjected to 30 min of global ischemia followed by 120 min of reperfusion were used to measure the cardiac functions, infarct size and to examine the protein expression profile. After treatment, MI was induced by ligating the left anterior descending artery. Echocardiographic parameters were examined 30 days after MI. Significant reduction in total cholesterol, LDL-cholesterol, triglycerides and an increase in HDL-cholesterol levels were observed in HSDG as compared to the HC. Decreased infarct size was observed in the HSDG group (43%) compared to the HC (54%). Increased phosphorylation of endothelial nitric oxide synthase (p-eNOS) (3.1-fold), vascular endothelial growth factor (1.9-fold) and heme oxygenase-1 (2.3-fold) was observed in the HSDG group as compared to the HC group. Significant improvement in left ventricular functions was also observed in the HSDG group as evidenced by increased ejection fraction (55% vs. 45%), fractional shortening (28% vs. 22%) and decreased left ventricular inner diameter in systole (8 vs. 6 mm) in HSDG compared to HC. Moreover, MI model has shown increased capillary density (2531 vs. 1901) and arteriolar density (2.6 vs. 1.8) in SDG-treated rats as compared to the HC. The increased capillary and arteriolar density along with increased left ventricular functions on SDG treatment might be due to increased HO-1, VEGF and p-eNOS expression. In conclusion, our study demonstrates for the first time that SDG treatment reduces ventricular remodeling by neovascularization of the infarcted HC myocardium.
UK national guidelines recommend pancreatic enzyme replacement therapy (PERT) in pancreatic cancer. Over 80% of pancreatic cancers are unresectable and managed in non-surgical units. The aim was to ...assess variation in PERT prescribing, determine factors associated with its use and identify potential actions to improve prescription rates.
RICOCHET was a national prospective audit of malignant pancreatic, peri-ampullary lesions or malignant biliary obstruction between April and August 2018. This analysis focuses on pancreatic cancer patients and is reported to STROBE guidelines. Multivariable regression analysis was undertaken to assess factors associated with PERT prescribing.
Rates of PERT prescribing varied among the 1350 patients included. 74.4% of patients with potentially resectable disease were prescribed PERT compared to 45.3% with unresectable disease.
PERT prescription varied across surgical hospitals but high prescribing rates did not disseminate out to the respective referring network. PERT prescription appeared to be related to the treatment aim for the patient and the amount of clinician contact a patient has. PERT prescription in potentially resectable patients was positively associated with dietitian referral (p = 0.001) and management at hepaticopancreaticobiliary (p = 0.049) or pancreatic unit (p = 0.009). Prescription in unresectable patients also had a negative association with Charlson comorbidity score 5–7 (p = 0.045) or >7 (p = 0.010) and a positive association with clinical nurse specialist review (p = 0.028).
Despite national guidance, wide variation and under-treatment with PERT exists. Given that most patients with pancreatic cancer have unresectable disease and are treated in non-surgical hospitals, where prescribing is lowest, strategies to disseminate best practice and overcome barriers to prescribing are urgently required.
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