Whole genome expression and biochemical correlates of extreme constitutional types defined in Ayurveda

<p>Abstract</p> <p>Background</p> <p>Ayurveda is an ancient system of personalized medicine documented and practiced in India since 1500 B.C. According to this system an individual's basic constitution to a large extent determines predisposition and prognosis to diseases as well as therapy and life-style regime. Ayurveda describes seven broad constitution types (<it>Prakriti</it>s) each with a varying degree of predisposition to different diseases. Amongst these, three most contrasting types, <it>Vata</it>, <it>Pitta</it>, <it>Kapha</it>, are the most vulnerable to diseases. In the realm of modern predictive medicine, efforts are being directed towards capturing disease phenotypes with greater precision for successful identification of markers for prospective disease conditions. In this study, we explore whether the different constitution types as described in Ayurveda has molecular correlates.</p> <p>Methods</p> <p>Normal individuals of the three most contrasting constitutional types were identified following phenotyping criteria described in Ayurveda in Indian population of Indo-European origin. The peripheral blood samples of these individuals were analysed for genome wide expression levels, biochemical and hematological parameters. Gene Ontology (GO) and pathway based analysis was carried out on differentially expressed genes to explore if there were significant enrichments of functional categories among <it>Prakriti </it>types.</p> <p>Results</p> <p>Individuals from the three most contrasting constitutional types exhibit striking differences with respect to biochemical and hematological parameters and at genome wide expression levels. Biochemical profiles like liver function tests, lipid profiles, and hematological parameters like haemoglobin exhibited differences between <it>Prakriti </it>types. Functional categories of genes showing differential expression among <it>Prakriti </it>types were significantly enriched in core biological processes like transport, regulation of cyclin dependent protein kinase activity, immune response and regulation of blood coagulation. A significant enrichment of housekeeping, disease related and hub genes were observed in these extreme constitution types.</p> <p>Conclusion</p> <p>Ayurveda based method of phenotypic classification of extreme constitutional types allows us to uncover genes that may contribute to system level differences in normal individuals which could lead to differential disease predisposition. This is a first attempt towards unraveling the clinical phenotyping principle of a traditional system of medicine in terms of modern biology. An integration of Ayurveda with genomics holds potential and promise for future predictive medicine.</p

Socio-Economic Variations Determine the Clinical Presentation, Aetiology and Outcome of Infective Endocarditis: a Prospective Cohort Study from the ESC-EORP EURO-ENDO (European Infective Endocarditis) Registry.

peer reviewedBACKGROUND: Infective endocarditis (IE) is a life-threatening disease associated with high mortality and morbidity worldwide. We sought to determine how socio-economic factors might influence its epidemiology, clinical presentation, investigation and management, and outcome, in a large international multi-centre registry. METHODS: The EurObservationalProgramme (EORP) of the European Society of Cardiology (ESC) EURO-ENDO registry comprises a prospective cohort of 3113 adult patients admitted for IE in 156 hospitals in 40 countries between January 2016 and March 2018. Patients were separated in 3 groups, according to World Bank economic stratification (Group 1 - high income [75.6%]; Group 2 - upper-middle income [15.4%]; Group 3 - lower-middle income [9.1%]). RESULTS: Group 3 patients were younger (median age [IQR]: Group 1 - 66 [53-75] years; Group 2 - 57 [41-68] years; Group 3 - 33 [26-43] years; p<0.001) with a higher frequency of smokers, intravenous drug use and human immunodeficiency virus (HIV) infection (all p<0.001) and presented later (median [IQR) days since symptom onset: Group 1 - 12 [3-35]; Group 2 - 19 [6-54]; Group 3 - 31 [12-62]; p<0.001) with a higher likelihood of developing congestive heart failure (13.6%; 11.1%; and 22.6%, respectively; p<0.001) and persistent fever (9.8%; 14.2%; 27.9%; p<0.001). Among 2157 (69.3%) patients with theoretical indication for cardiac surgery, surgery was performed less frequently in Group 3 patients (75.5%, 76.8% and 51.3%, respectively p<0.001) who also demonstrated the highest mortality (15.0%, 23.0% and 23.7%, respectively; p<0.001). CONCLUSIONS: Socio-economic factors influence the clinical profile of patients presenting with IE across the world. Despite younger age, patients from the poorest countries presented with more frequent complications and higher mortality associated with delayed diagnosis and lower use of surgery

A Systematic Analysis of Eluted Fraction of Plasma Post Immunoaffinity Depletion: Implications in Biomarker Discovery

Plasma is the most easily accessible source for biomarker discovery in clinical proteomics. However, identifying potential biomarkers from plasma is a challenge given the large dynamic range of proteins. The potential biomarkers in plasma are generally present at very low abundance levels and hence identification of these low abundance proteins necessitates the depletion of highly abundant proteins. Sample pre-fractionation using immuno-depletion of high abundance proteins using multi-affinity removal system (MARS) has been a popular method to deplete multiple high abundance proteins. However, depletion of these abundant proteins can result in concomitant removal of low abundant proteins. Although there are some reports suggesting the removal of non-targeted proteins, the predominant view is that number of such proteins is small. In this study, we identified proteins that are removed along with the targeted high abundant proteins. Three plasma samples were depleted using each of the three MARS (Hu-6, Hu-14 and Proteoprep 20) cartridges. The affinity bound fractions were subjected to gelC-MS using an LTQ-Orbitrap instrument. Using four database search algorithms including MassWiz (developed in house), we selected the peptides identified at <1% FDR. Peptides identified by at least two algorithms were selected for protein identification. After this rigorous bioinformatics analysis, we identified 101 proteins with high confidence. Thus, we believe that for biomarker discovery and proper quantitation of proteins, it might be better to study both bound and depleted fractions from any MARS depleted plasma sample

High Resolution Methylome Map of Rat Indicates Role of Intragenic DNA Methylation in Identification of Coding Region

DNA methylation is crucial for gene regulation and maintenance of genomic stability. Rat has been a key model system in understanding mammalian systemic physiology, however detailed rat methylome remains uncharacterized till date. Here, we present the first high resolution methylome of rat liver generated using Methylated DNA immunoprecipitation and high throughput sequencing (MeDIP-Seq) approach. We observed that within the DNA/RNA repeat elements, simple repeats harbor the highest degree of methylation. Promoter hypomethylation and exon hypermethylation were common features in both RefSeq genes and expressed genes (as evaluated by proteomic approach). We also found that although CpG islands were generally hypomethylated, about 6% of them were methylated and a large proportion (37%) of methylated islands fell within the exons. Notably, we obeserved significant differences in methylation of terminal exons (UTRs); methylation being more pronounced in coding/partially coding exons compared to the non-coding exons. Further, events like alternate exon splicing (cassette exon) and intron retentions were marked by DNA methylation and these regions are retained in the final transcript. Thus, we suggest that DNA methylation could play a crucial role in marking coding regions thereby regulating alternative splicing. Apart from generating the first high resolution methylome map of rat liver tissue, the present study provides several critical insights into methylome organization and extends our understanding of interplay between epigenome, gene expression and genome stability

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Left ventricular myocardial performance assessed by 2-dimensional speckle tracking echocardiography in patients with sickle cell crisis

Background: The status of left ventricle in sickle cell anemia presenting in sickle crisis and follow up has been minimally studied in past. To determine the left ventricular (LV) myocardial performance in these patients, we performed the study to assess two dimensional strains imaging which allowed a rapid and an accurate analysis of global and regional LV myocardial performance in longitudinal, radial, and circumferential directions. Methods: In this prospective study, 2-dimensional echocardiography (2DE) images of the LV were obtained in 52 subjects which included 32 patients (23 ± 8yrs, 16 male) with homozygous sickle cell anemia (SCA) in sickle cell crisis and 20 healthy controls (23 ± 5 yrs, 11 male) using apical 4-chamber and parasternal short-axis at the basal, mid, and apical levels. Of these 32 patients, 2DE was performed again in 18 patients in follow up (8 months ± 5 days). Longitudinal, circumferential and radial strains (LS, CS and RS respectively) were quantified and compared in an 18-segment model using a novel speckle tracking system (2D Cardiac Performance Analysis, TomTec Imaging System, Munich, Germany). Results: There was no significant difference in LV ejection fraction between both the groups (59.32 ± 12.6 vs. 52.3 ± 7.9; p-value > 0.05). In comparison with normal controls and follow up of sickle cell patients, peak LS was significantly attenuated in the subendocardial and subepicardial regions during sickle cell crisis (p < 0.05). However, a significant reduction in circumferential strain was evident only in subepicardial region (p < 0.001). Also patients in sickle cell crisis showed significantly higher radial strain parameters than controls (p < 0.001). Conclusion: Patients with SCA presenting in sickle cell crisis have reduced longitudinal shortening. LV myocardial performance remains unaltered due to relatively preserved circumferential shortening and increased radial thickening