Bystander B cells rapidly acquire antigen receptors from activated B cells by membrane transfer: a novel mechanism for enhancing specific antigen presentation

The B cell antigen receptor (BCR) efficiently facilitates the capture and processing of a specific antigen for presentation on MHC class II molecules to antigen specific CD4+ T cells (1). Despite this, the majority of B cells are only thought to play a limited role in CD4+ T cell activation since BCRs are clonotypically expressed. Here we show, however, that activated B cells can, both in vitro and in vivo, rapidly donate their BCR to bystander B cells, a process that is mediated by direct membrane transfer between adjacent B cells and is amplified by the interaction of the BCR with specific antigen. This results in a dramatic expansion in the number of antigen-binding B cells in vivo, with the transferred BCR endowing recipient B cells with the ability to present specific antigen to antigen-specific CD4+ T cells

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

Clinicopathological data of the 20 biliary tract cancer cases and 100 gender- and age-matched controls included in plasma study. (XLSX 116 kb

Multipoint Schur algorithm and orthogonal rational functions: convergence properties, I

Classical Schur analysis is intimately connected to the theory of orthogonal polynomials on the circle [Simon, 2005]. We investigate here the connection between multipoint Schur analysis and orthogonal rational functions. Specifically, we study the convergence of the Wall rational functions via the development of a rational analogue to the Szeg\H o theory, in the case where the interpolation points may accumulate on the unit circle. This leads us to generalize results from [Khrushchev,2001], [Bultheel et al., 1999], and yields asymptotics of a novel type.Comment: a preliminary version, 39 pages; some changes in the Introduction, Section 5 (Szeg\H o type asymptotics) is extende

LFI 30 and 44 GHz receivers Back-End Modules

The 30 and 44 GHz Back End Modules (BEM) for the Planck Low Frequency Instrument are broadband receivers (20% relative bandwidth) working at room temperature. The signals coming from the Front End Module are amplified, band pass filtered and finally converted to DC by a detector diode. Each receiver has two identical branches following the differential scheme of the Planck radiometers. The BEM design is based on MMIC Low Noise Amplifiers using GaAs P-HEMT devices, microstrip filters and Schottky diode detectors. Their manufacturing development has included elegant breadboard prototypes and finally qualification and flight model units. Electrical, mechanical and environmental tests were carried out for the characterization and verification of the manufactured BEMs. A description of the 30 and 44 GHz Back End Modules of Planck-LFI radiometers is given, with details of the tests done to determine their electrical and environmental performances. The electrical performances of the 30 and 44 GHz Back End Modules: frequency response, effective bandwidth, equivalent noise temperature, 1/f noise and linearity are presented

MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors

BACKGROUND MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers

Aneuploidy in pluripotent stem cells and implications for cancerous transformation

Owing to a unique set of attributes, human pluripotent stem cells (hPSCs) have emerged as a promising cell source for regenerative medicine, disease modeling and drug discovery. Assurance of genetic stability over long term maintenance of hPSCs is pivotal in this endeavor, but hPSCs can adapt to life in culture by acquiring non-random genetic changes that render them more robust and easier to grow. In separate studies between 12.5% and 34% of hPSC lines were found to acquire chromosome abnormalities over time, with the incidence increasing with passage number. The predominant genetic changes found in hPSC lines involve changes in chromosome number and structure (particularly of chromosomes 1, 12, 17 and 20), reminiscent of the changes observed in cancer cells. In this review, we summarize current knowledge on the causes and consequences of aneuploidy in hPSCs and highlight the potential links with genetic changes observed in human cancers and early embryos. We point to the need for comprehensive characterization of mechanisms underpinning both the acquisition of chromosomal abnormalities and selection pressures, which allow mutations to persist in hPSC cultures. Elucidation of these mechanisms will help to design culture conditions that minimize the appearance of aneuploid hPSCs. Moreover, aneuploidy in hPSCs may provide a unique platform to analyse the driving forces behind the genome evolution that may eventually lead to cancerous transformation

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes.Systematic review and meta-analysis.We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE.Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to 'low quality' due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence).This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable increased risk in non-serious adverse events. The analyses may overestimate the intervention benefit due bias

Individual and combined impacts of carbon dioxide enrichment, heatwaves, flow velocity variability, and fine sediment deposition on stream invertebrate communities

Climate change and land‐use change are widely altering freshwater ecosystem functioning and there is an urgent need to understand how these broad stressor categories may interact in future. While much research has focused on mean temperature increases, climate change also involves increasing variability of both water temperature and flow regimes and increasing concentrations of atmospheric CO2, all with potential to alter stream invertebrate communities. Deposited fine sediment is a pervasive land‐use stressor with widespread impacts on stream invertebrates. Sedimentation may be managed at the catchment scale; thus, uncovering interactions with these three key climate stressors may assist mitigation of future threats. This is the first experiment to investigate the individual and combined effects of enriched CO2, heatwaves, flow velocity variability, and fine sediment on realistic stream invertebrate communities. Using 128 mesocosms simulating small stony‐bottomed streams in a 7‐week experiment, we manipulated dissolved CO2 (ambient; enriched), fine sediment (no sediment; 300 g dry sediment), temperature (ambient; two 7‐day heatwaves), and flow velocity (constant; variable). All treatments changed community composition. CO2 enrichment reduced abundances of Orthocladiinae and Chironominae and increased Copepoda abundance. Variable flow velocity had only positive effects on invertebrate abundances (7 of 13 common taxa and total abundance), in contrast to previous experiments showing negative impacts of reduced velocity. CO2 was implicated in most stressor interactions found, with CO2 × sediment interactions being most common. Communities forming under enriched CO2 conditions in sediment‐impacted mesocosms had ~20% fewer total invertebrates than those with either treatment alone. Copepoda abundances doubled in CO2‐enriched mesocosms without sediment, whereas no CO2 effect occurred in mesocosms with sediment. Our findings provide new insights into potential future impacts of climate change and land use in running freshwaters, in particular highlighting the potential for elevated CO2 to interact with fine sediment deposition in unpredictable ways

Gene dose influences cellular and calcium channel dysregulation in heterozygous and homozygous T4826I-RYR1 malignant hyperthermia-susceptible muscle

Malignant hyperthermia susceptibility (MHS) is primarily conferred by mutations within ryanodine receptor type 1 (RYR1). Here we address how the MHS mutation T4826I within the S4-S5 linker influences excitation-contraction coupling and resting myoplasmi