Antigen-specific clonal expansion and cytolytic effector function of CD8+ T lymphocytes depend on the transcription factor Bcl11b

CD8+ T lymphocytes mediate the immune response to viruses, intracellular bacteria, protozoan parasites, and tumors. We provide evidence that the transcription factor Bcl11b/Ctip2 controls hallmark features of CD8+ T cell immunity, specifically antigen (Ag)-dependent clonal expansion and cytolytic activity. The reduced clonal expansion in the absence of Bcl11b was caused by altered proliferation during the expansion phase, with survival remaining unaffected. Two genes with critical roles in TCR signaling were deregulated in Bcl11b-deficient CD8+ T cells, CD8 coreceptor and Plcγ1, both of which may contribute to the impaired responsiveness. Bcl11b was found to bind the E8I, E8IV, and E8V, but not E8II or E8III, enhancers. Thus, Bcl11b is one of the transcription factors implicated in the maintenance of optimal CD8 coreceptor expression in peripheral CD8+ T cells through association with specific enhancers. Short-lived Klrg1hiCD127lo effector CD8+ T cells were formed during the course of infection in the absence of Bcl11b, albeit in smaller numbers, and their Ag-specific cytolytic activity on a per-cell basis was altered, which was associated with reduced granzyme B and perforin

Investigation of Genetic Variation Underlying Central Obesity amongst South Asians

The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966,G0700931), the Wellcome Trust (084723/Z/08/Z), and the NIHR (RP-PG-0407-10371). The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The Sikh Diabetes Study is supported by National Institute of Health grants KO1TW006087, funded by the Fogarty International Center, R01DK082766, funded by National Institute of Diabetes and Digestive and Kidney Diseases, and a seed grant from University of Oklahoma Health Sciences Center, Oklahoma City, USA. The Mauritius Family Study is supported by the Mauritius Ministry of Health and Quality of Life, Australian Government National Health and Medical Research Council NHMRC project grant numbers 1020285 and 1037916, the Victorian Government’s OIS Program, and partly funded by US National Institutes of Health Grant DK-25446. We thank the participants and research staff who made the study possible.South Asians are 1/4 of the world’s population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10−6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.Yeshttp://www.plosone.org/static/editorial#pee

Ion homeostasis in the Chloroplast

peer reviewedThe chloroplast is an organelle of high demand for macro- and micro-nutrient ions, which are required for the maintenance of the photosynthetic process. To avoid deficiency while preventing excess, homeostasis mechanisms must be tightly regulated. Here, we describe the needs for nutrient ions in the chloroplast and briefly highlight their functions in the chloroplastidial metabolism. We further discuss the impact of nutrient deficiency on chloroplasts and the acclimation mechanisms that evolved to preserve the photosynthetic apparatus. We finally present what is known about import and export mechanisms for these ions. Whenever possible, a comparison between cyanobacteria, algae and plants is provided to add an evolutionary perspective to the description of ion homeostasis mechanisms in photosynthesis

The Effect of Oral Care on Intracranial Pressure in Critically Ill Adults

A major goal in the care of patients with neurological problems is to prevent or minimize episodes of increased intracranial pressure (ICP). Elevations in ICP in response to nursing interventions have been acknowledged since the 1960s when ICP monitoring was first introduced in the clinical setting. Until recently, few studies have specifically examined the effect of oral care on ICP, and oral care and other hygiene measures were combined or not specified, prohibiting a direct interpretation of the influence of oral care alone on ICP. The purpose of this study was to describe the relationship between routine oral care interventions and the changes in ICP specifically focusing on the effect of intensity and duration of this intervention. Twenty-three patients with a clinical condition requiring ICP monitoring were enrolled over a 12-month period. Oral care provided by neuroscience intensive care nurses was observed and videotaped. Characteristics of the intervention were documented including products used, patient positioning, and duration of the intervention. A 1-5 subjective scale was used to score intensity of oral care. Wrist actigraphy data were collected from the nurses to provide an objective measure of intensity. Patient physiologic data were collected at 12-second epochs 5 minutes before, during, and 5 minutes after oral care. The mixed-effect repeated measures analysis of variance model indicated that there was a statistically significant increase in ICP in response to oral care (p = .0031). There was, however, no clinically significant effect on ICP. This study provides evidence that oral care is safe to perform in patients in the absence of preexisting elevated ICP

Outcome measures for clinical trials in neurotrauma

Under the auspices of the American Brain Injury Consortium and the Joint Section of Neurotrauma and Critical Care of the American Association of Neurological Surgeons, the authors have reviewed and formulated opinions based on the evidence on protocol design and the outcome measures used for clinical trials in patients with a severe or moderate traumatic brain injury (TBI). First, in view of the heterogeneity of the population under study, the authors suggest that block randomization and stratification should always be used in the design of neurotrauma trials. Second, although the Glasgow Outcome Scale (GOS) remains the most widely used and accepted instrument for TBI trials, the authors believe the eight-point expanded scale that has recently been designed will ultimately provide greater discrimination, and narrower categories and will ultimately prove superior for detecting more subtle changes in outcome. Furthermore, the authors recommend, in view of the profound cognitive impairment in survivors of TBI, that neuropsychological tests be explored further as an adjunct to the GOS. Future research should focus on the development of more sensitive and specific surrogate outcome measures such as magnetic resonance imaging, neurochemical, neuropsychological, and quality of life measures in order to detect a neuroprotective effect in patients with TBI

A blinded evaluation of privacy preserving record linkage with Bloom filters

Background: Privacy preserving record linkage (PPRL) methods using Bloom filters have shown promise for use in operational linkage settings. However real-world evaluations are required to confirm their suitability in practice. Methods: An extract of records from the Western Australian (WA) Hospital Morbidity Data Collection 2011–2015 and WA Death Registrations 2011–2015 were encoded to Bloom filters, and then linked using privacy-preserving methods. Results were compared to a traditional, un-encoded linkage of the same datasets using the same blocking criteria to enable direct investigation of the comparison step. The encoded linkage was carried out in a blinded setting, where there was no access to un-encoded data or a ‘truth set’. Results: The PPRL method using Bloom filters provided similar linkage quality to the traditional un-encoded linkage, with 99.3% of ‘groupings’ identical between privacy preserving and clear-text linkage. Conclusion: The Bloom filter method appears suitable for use in situations where clear-text identifiers cannot be provided for linkage