Fluctuating and Geographically Specific Selection Characterize Rapid Evolution of the Human KIR Region

The killer-cell immunoglobulin-like receptor (KIR) region comprises a fast-evolving family of genes that encode receptors for natural killer (NK) cells and have crucial role in host defense. Evolution of KIR was examined in the context of the human genome. Gene-content diversity and single nucleotide polymorphisms (SNP) in the KIR genes and flanking regions were compared to >660,000 genome-wide SNPs in over 800 individuals from 52 populations of the human genome diversity panel (HGDP). KIR allelic diversity was further examined using next generation sequencing in a subset of 56 individuals. We identified the SNP rs587560 located in KIR3DL3 as a marker of KIR2DL2 and KIR2DL3 and, consequently, Cen A and Cen B haplotypes. We also show that combinations of two KIR2DL4 SNPs (rs35656676 and rs592645) distinguish KIR3DL1 from KIR3DS1 and also define the major KIR3DL1 high- and low-expressing alleles lineages. Comparing the diversity of the SNPs within the KIR region to remainder of the genome, we observed a high diversity for the centromeric KIR region consistent with balancing selection (p < 0.01); in contrast, centromeric KIR diversity is significantly reduced in East Asian populations (p < 0.01), indicating purifying selection. By analyzing SNP haplotypes in a region spanning ~500 kb that includes the KIR cluster, we observed evidence of strong positive selection in Africa for high-expressing KIR3DL1 alleles, favored over the low-expressing alleles (p < 0.01). In sharp contrast, the strong positive selection (p < 0.01) that we also observed in the telomeric KIR region in Oceanic populations tracked with a high frequency of KIR3DS1. In addition, we demonstrated that worldwide frequency of high-expression KIR3DL1 alleles was correlated with virus with virus (r = 0.64, p < 10−6) and protozoa (r = 0.69, p < 10−6) loads, which points to selection globally on KIR3DL1 high-expressing alleles attributable to pathogen exposure

Intrathecal B-cell activation in LGI1 antibody encephalitis.

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies

Correction: Impact of cardiovascular magnetic resonance on management and clinical decision-making in heart failure patients

Background: Cardiovascular magnetic resonance (CMR) can provide important diagnostic and prognostic information in patients with heart failure. However, in the current health care environment, use of a new imaging modality like CMR requires evidence for direct additive impact on clinical management. We sought to evaluate the impact of CMR on clinical management and diagnosis in patients with heart failure. Methods: We prospectively studied 150 consecutive patients with heart failure and an ejection fraction ≤50% referred for CMR. Definitions for “significant clinical impact” of CMR were pre-defined and collected directly from medical records and/or from patients. Categories of significant clinical impact included: new diagnosis, medication change, hospital admission/discharge, as well as performance or avoidance of invasive procedures (angiography, revascularization, device therapy or biopsy). Results: Overall, CMR had a significant clinical impact in 65% of patients. This included an entirely new diagnosis in 30% of cases and a change in management in 52%. CMR results directly led to angiography in 9% and to the performance of percutaneous coronary intervention in 7%. In a multivariable model that included clinical and imaging parameters, presence of late gadolinium enhancement (LGE) was the only independent predictor of “significant clinical impact” (OR 6.72, 95% CI 2.56-17.60, p=0.0001). Conclusions: CMR made a significant additive clinical impact on management, decision-making and diagnosis in 65% of heart failure patients. This additive impact was seen despite universal use of prior echocardiography in this patient group. The presence of LGE was the best independent predictor of significant clinical impact following CMR

A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10-4; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD

Allele-Level KIR Genotyping of More Than a Million Samples: Workflow, Algorithm, and Observations

The killer-cell immunoglobulin-like receptor (KIR) genes regulate natural killer cell activity, influencing predisposition to immune mediated disease, and affecting hematopoietic stem cell transplantation (HSCT) outcome. Owing to the complexity of the KIR locus, with extensive gene copy number variation (CNV) and allelic diversity, high-resolution characterization of KIR has so far been applied only to relatively small cohorts. Here, we present a comprehensive high-throughput KIR genotyping approach based on next generation sequencing. Through PCR amplification of specific exons, our approach delivers both copy numbers of the individual genes and allelic information for every KIR gene. Ten-fold replicate analysis of a set of 190 samples revealed a precision of 99.9%. Genotyping of an independent set of 360 samples resulted in an accuracy of more than 99% taking into account consistent copy number prediction. We applied the workflow to genotype 1.8 million stem cell donor registry samples. We report on the observed KIR allele diversity and relative abundance of alleles based on a subset of more than 300,000 samples. Furthermore, we identified more than 2,000 previously unreported KIR variants repeatedly in independent samples, underscoring the large diversity of the KIR region that awaits discovery. This cost-efficient high-resolution KIR genotyping approach is now applied to samples of volunteers registering as potential donors for HSCT. This will facilitate the utilization of KIR as additional selection criterion to improve unrelated donor stem cell transplantation outcome. In addition, the approach may serve studies requiring high-resolution KIR genotyping, like population genetics and disease association studies

Profile of CT Brain in COVID 19 (Retrospective Study)

Background:Corona virus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus. Most people infected with the COVID-19 virus experienced mild to moderate respiratory illness. Elderly people and those with medical problems like cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness. Aims and Objectives:To study CT Brain findings in COVID-19 patients and their correlation with clinical profile and outcome. Material and Methods:  Retrospective study involved 22 patients admitted in MGM hospital, Kamothe MICU and wards from 1st April to 31st  July 2020. Results:Out of 22 patients, maximum number of patients were male i.e. 20(90.90%) and 2(9.10%) were female. Mean age of the patients was 64.59±12.97 years. Ischemic stroke was observed in 12(54.54%) patients and haemorrhagic stroke was found in 2(9.10%) patients. In 14(63.64%) patients, CT brain findings were found to be abnormal and in 8(36.36%) patients, it was normal. Seven(31.81%) patients needed ventilator support, 3(13.63%) used BiPAP, 1(4.54%) patient used Hudson mask and 4(18.18%) with NRM.  Out of 7 patients, who were on ventilator support, 6 died and one discharged from the hospital. Conclusion:High percentage of abnormal brain CT patients with severe COVID-19 infection was observed in the study. Ischemic stroke occurred in most of the cases with abnormal CT findings

Modelling and Optimisation of Chitosan Anchored Titanium Dioxide Nano-Adsorbent for Dairy Industry Effluent Treatment

The present study emphasised the efficiency of chitosan anchored titanium dioxide nano-adsorbent on dairy industry effluent treatment. Chitosan titanium dioxide nano-adsorbent was synthesised by using chemical precipitation method and characterised for its particle size, surface morphology and texture. A four-factor-three-level Box–Behnken design along with response surface methodology was used to optimise the adsorption process parameters. Linear, two factor interaction, quadratic and cubic model techniques were used to demonstrate the influence of each parameter and their interaction effects on the responses. The quadratic models derived from the experimental data were used to predict the maximum per cent reduction of biological oxygen demand (BOD) and chemical oxygen demand (COD). The optimised treatment combination for maximum per cent reduction in BOD (90.48%) and COD (82.10%) was found to be initial concentration of 100 mg L-1, pH of 7, dosage of 1.25 mg L-1 and contact time of 100 min