Consistent Regression using Data-Dependent Coverings

In this paper, we introduce a novel method to generate interpretable regression function estimators. The idea is based on called data-dependent coverings. The aim is to extract from the data a covering of the feature space instead of a partition. The estimator predicts the empirical conditional expectation over the cells of the partitions generated from the coverings. Thus, such estimator has the same form as those issued from data-dependent partitioning algorithms. We give sufficient conditions to ensure the consistency, avoiding the sufficient condition of shrinkage of the cells that appears in the former literature. Doing so, we reduce the number of covering elements. We show that such coverings are interpretable and each element of the covering is tagged as significant or insignificant. The proof of the consistency is based on a control of the error of the empirical estimation of conditional expectations which is interesting on its own

Impact of an extension tube on operator radiation exposure during coronary procedures performed through the radial approach

SummaryBackgroundOperator radiation exposure is high during coronary procedures. The radial access decreases the rate of local vascular complications but increases operator radiation exposure. As the X-ray exposure is related to the distance between the operator and the radiation source, the use of an extension tube between the proximal part of the coronary catheter and the ‘injection device’ might decrease operator radiation exposure.AimsTo demonstrate that the use of an extension tube during coronary procedures performed through the radial approach decreases operator radiation.MethodsOverall, 230 patients were included consecutively and randomized to procedures performed with or without an extension tube. Radiation exposure measures were obtained using two electronic dosimeters, one under the lead apron and the other exposed on the physician's left arm.ResultsA non-significant trend towards lower left-arm operator exposure was noted in the extension tube group (28.7±31.0μSv vs 38.4±44.2μSv, p=0.0739). No significant difference was noted according to the type of procedure. Radiation levels were low compared with the series published previously and decreased for each operator during the study.ConclusionThe use of an extension tube did not reduce operator radiation exposure during procedures performed through the radial approach. However, physician awareness was increased during the study due to the use of an exposed electronic dosimeter. The use of exposed electronic dosimeters could therefore be recommended to allow operators to improve their protection techniques

Membrane stress is coupled to a rapid translational control of gene expression in chlorpromazine-treated cells

Chlorpromazine (CPZ) is a small permeable cationic amphiphilic molecule that inserts into membrane bilayers and binds to anionic lipids such as poly-phosphoinositides (PIs). Since PIs play important roles in many cellular processes, including signaling and membrane trafficking pathways, it has been proposed that CPZ affects cellular growth functions by preventing the recruitment of proteins with specific PI-binding domains. In this study, we have investigated the biological effects of CPZ in the yeast Saccharomyces cerevisiae. We screened a collection of approximately 4,800 gene knockout mutants, and found that mutants defective in membrane trafficking between the late-Golgi and endosomal compartments are highly sensitive to CPZ. Microscopy and transport analyses revealed that CPZ affects membrane structure of organelles, blocks membrane transport and activates the unfolded protein response (UPR). In addition, CPZ-treatment induces phosphorylation of the translation initiation factor (eIF2α), which reduces the general rate of protein synthesis and stimulates the production of Gcn4p, a major transcription factor that is activated in response to environmental stresses. Altogether, our results reveal that membrane stress within the cells rapidly activates an important gene expression program, which is followed by a general inhibition of protein synthesis. Remarkably, the increase of phosphorylated eIF2α and protein synthesis inhibition were also detected in CPZ-treated NIH-3T3 fibroblasts, suggesting the existence of a conserved mechanism of translational regulation that operates during a membrane stres

Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity.

The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1-deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1-targeting strategies

The Sydney declaration – Revisiting the essence of forensic science through its fundamental principles

Unlike other more established disciplines, a shared understanding and broad acceptance of the essence of forensic science, its purpose, and fundamental principles are still missing or mis-represented. This foundation has been overlooked, although recognised by many forensic science forefathers and seen as critical to this discipline's advancement. The Sydney Declaration attempts to revisit the essence of forensic science through its foundational basis, beyond organisations, technicalities or protocols. It comprises a definition of forensic science and seven fundamental principles that emphasise the pivotal role of the trace as a vestige, or remnant, of an investigated activity. The Sydney Declaration also discusses critical features framing the forensic scientist's work, such as context, time asymmetry, the continuum of uncertainties, broad scientific knowledge, ethics, critical thinking, and logical reasoning. It is argued that the proposed principles should underpin the practice of forensic science and guide education and research directions. Ultimately, they will benefit forensic science as a whole to be more relevant, effective and reliable

From the northern ice shield to the Alpine glaciations

The route of the field trip described in this excursion guide follows a section through Germany from North to South, from the area of the Northern glaciation, to the Alpine glacial advances. It includes several places of historical importance, where milestones in Quaternary research have been achieved in the past, as well as new interesting sites where results of recent research is presented.excursionguid

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.

Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas

Study protocol for a randomized controlled trial : prophylactic swallowing exercises in head-and-neck cancer patients treated with (chemo)radiotherapy (PRESTO trial)

Background: Dysphagia is a common and serious complication after (chemo)radiotherapy (CRT) for head-and-neck cancer (HNC) patients. Prophylactic swallowing exercises (PSE) can have a significantly positive effect on post-treatment swallowing function. However, low adherence rates are a key issue in undermining this positive effect. This current randomized trial will investigate the effect of adherence-improving measures on patients' swallowing function, adherence and quality of life (QOL). Methods: This ongoing trial will explore the difference in adherence and swallowing-related outcome variables during and after PSE in HNC patients performing the same therapy schedule, receiving different delivery methods. One hundred and fifty patients treated in various hospitals will be divided into three groups. Group 1 performs PSE at home, group 2 practices at home with continuous counseling through an app and group 3 receives face-to-face therapy by a speech and language pathologist. The exercises consist of tongue-strengthening exercises and chin-tuck against resistance with effortful swallow. The Iowa Oral Performance Instrument and the Swallowing Exercise Aid are used for practicing. Patients are evaluated before, during and after treatment by means of strength measurements, swallowing and QOL questionnaires. Discussion: Since low adherence rates undermine the positive impact of PSE on post-treatment swallowing function, there is need to develop an efficient PSE protocol maximizing adherence rates