Showing papers by "University of Rouen published in 2017"

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Riemannian Approaches in Brain-Computer Interfaces: A Review

Abstract: Although promising from numerous applications, current brain–computer interfaces (BCIs) still suffer from a number of limitations. In particular, they are sensitive to noise, outliers and the non-stationarity of electroencephalographic (EEG) signals, they require long calibration times and are not reliable. Thus, new approaches and tools, notably at the EEG signal processing and classification level, are necessary to address these limitations. Riemannian approaches, spearheaded by the use of covariance matrices, are such a very promising tool slowly adopted by a growing number of researchers. This article, after a quick introduction to Riemannian geometry and a presentation of the BCI-relevant manifolds, reviews how these approaches have been used for EEG-based BCI, in particular for feature representation and learning, classifier design and calibration time reduction. Finally, relevant challenges and promising research directions for EEG signal classification in BCIs are identified, such as feature tracking on manifold or multi-task learning.

Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour

Abstract: The life of all animals is dominated by alternating feelings of hunger and satiety - the main involuntary motivations for feeding-related behaviour. Gut bacteria depend fully on their host for providing the nutrients necessary for their growth. The intrinsic ability of bacteria to regulate their growth and to maintain their population within the gut suggests that gut bacteria can interfere with molecular pathways controlling energy balance in the host. The current model of appetite control is based mainly on gut-brain signalling and the animal's own needs to maintain energy homeostasis; an alternative model might also involve bacteria-host communications. Several bacterial components and metabolites have been shown to stimulate intestinal satiety pathways; at the same time, their production depends on bacterial growth cycles. This short-term bacterial growth-linked modulation of intestinal satiety can be coupled with long-term regulation of appetite, controlled by the neuropeptidergic circuitry in the hypothalamus. Indeed, several bacterial products are detected in the systemic circulation, which might act directly on hypothalamic neurons. This Review analyses the data relevant to possible involvement of the gut bacteria in the regulation of host appetite and proposes an integrative homeostatic model of appetite control that includes energy needs of both the host and its gut bacteria.

Structure, function and regulation of Pseudomonas aeruginosa porins

Abstract: Pseudomonas aeruginosa is a Gram-negative bacterium belonging to the γ-proteobacteria. Like other members of the Pseudomonas genus, it is known for its metabolic versatility and its ability to colonize a wide range of ecological niches, such as rhizosphere, water environments and animal hosts, including humans where it can cause severe infections. Another particularity of P. aeruginosa is its high intrinsic resistance to antiseptics and antibiotics, which is partly due to its low outer membrane permeability. In contrast to Enterobacteria, pseudomonads do not possess general diffusion porins in their outer membrane, but rather express specific channel proteins for the uptake of different nutrients. The major outer membrane 'porin', OprF, has been extensively investigated, and displays structural, adhesion and signaling functions while its role in the diffusion of nutrients is still under discussion. Other porins include OprB and OprB2 for the diffusion of glucose, the two small outer membrane proteins OprG and OprH, and the two porins involved in phosphate/pyrophosphate uptake, OprP and OprO. The remaining nineteen porins belong to the so-called OprD (Occ) family, which is further split into two subfamilies termed OccD (8 members) and OccK (11 members). In the past years, a large amount of information concerning the structure, function and regulation of these porins has been published, justifying why an updated review is timely.

Urinary incontinence in women.

Abstract: Urinary incontinence symptoms are highly prevalent among women, have a substantial effect on health-related quality of life and are associated with considerable personal and societal expenditure. Two main types are described: stress urinary incontinence, in which urine leaks in association with physical exertion, and urgency urinary incontinence, in which urine leaks in association with a sudden compelling desire to void. Women who experience both symptoms are considered as having mixed urinary incontinence. Research has revealed overlapping potential causes of incontinence, including dysfunction of the detrusor muscle or muscles of the pelvic floor, dysfunction of the neural controls of storage and voiding, and perturbation of the local environment within the bladder. A full diagnostic evaluation of urinary incontinence requires a medical history, physical examination, urinalysis, assessment of quality of life and, when initial treatments fail, invasive urodynamics. Interventions can include non-surgical options (such as lifestyle modifications, pelvic floor muscle training and drugs) and surgical options to support the urethra or increase bladder capacity. Future directions in research may increasingly target primary prevention through understanding of environmental and genetic risks for incontinence.

Hartmann's Procedure or Primary Anastomosis for Generalized Peritonitis due to Perforated Diverticulitis: A Prospective Multicenter Randomized Trial (DIVERTI).

Abstract: Background About 25% of patients with acute diverticulitis require emergency intervention. Currently, most patients with diverticular peritonitis undergo a Hartmann's procedure. Our objective was to assess whether primary anastomosis (PA) with a diverting stoma results in lower mortality rates than Hartmann's procedure (HP) in patients with diverticular peritonitis. Study Design We conducted a multicenter randomized controlled trial conducted between June 2008 and May 2012: the DIVERTI (Primary vs Secondary Anastomosis for Hinchey Stage III-IV Diverticulitis) trial. Follow-up duration was up to 18 months. A random sample of 102 eligible participants with purulent or fecal diverticular peritonitis from tertiary care referral centers and associated centers in France were equally randomized to either a PA arm or to an HP arm. Data were analyzed on an intention-to-treat basis. The primary end point was mortality rate at 18 months. Secondary outcomes were postoperative complications, operative time, length of hospital stay, rate of definitive stoma, and morbidity. Results All 102 patients enrolled were comparable for age (p = 0.4453), sex (p = 0.2347), Hinchey stage III vs IV (p = 0.2347), and Mannheim Peritonitis Index (p = 0.0606). Overall mortality did not differ significantly between HP (7.7%) and PA (4%) (p = 0.4233). Morbidity for both resection and stoma reversal operations were comparable (39% in the HP arm vs 44% in the PA arm; p = 0.4233). At 18 months, 96% of PA patients and 65% of HP patients had a stoma reversal (p = 0.0001). Conclusions Although mortality was similar in both arms, the rate of stoma reversal was significantly higher in the PA arm. This trial provides additional evidence in favor of PA with diverting ileostomy over HP in patients with diverticular peritonitis. ClinicalTrials.gov Identifier: NCT 00692393.

Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2)

Abstract: Background Randomized, controlled trials demonstrated efficacy and safety of apremilast for moderate-to-severe plaque psoriasis and psoriatic arthritis. Objective Assess long-term safety of oral apremilast in psoriasis patients. Methods Safety findings are reported for 0 to ≥156 weeks from the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2. Results The 0 to ≥156–week apremilast-exposure period included 1184 patients treated twice daily with apremilast 30 mg (1902.2 patient-years). During 0 to ≤52 weeks, the adverse events (AEs) that occurred in ≥5% of patients included diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. From 0 to ≥156 weeks, no new AEs (affecting ≥5% of the population) were reported. AEs, serious AEs, and study drug discontinuations caused by AEs did not increase with long-term exposure. During the 0 to ≥156–week period, the rates of major cardiac events (exposure-adjusted incidence rate [EAIR] 0.5/100 patient-years), malignancies (EAIR 1.2/100 patient-years), depression (EAIR 1.8/100 patient-years), or suicide attempts (EAIR 0.1/100 patient-years) did not increase in comparison with the rates found during the 0 to ≤52–week period. No serious opportunistic infections, reactivation of tuberculosis, or clinically meaningful effects on laboratory measurements were reported. Limitations This study had a high dropout rate (21% of patients ongoing >156 weeks); most were unrelated to safety concerns. Conclusions Apremilast demonstrated an acceptable safety profile and was generally well tolerated for ≥156 weeks.

Ecological cognition: expert decision-making behaviour in sport

Abstract: Expert decision-making can be directly assessed, if sport action is understood as an expression of embedded and embodied cognition. Here, we discuss evidence for this claim, starting with a critica...

X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

Abstract: By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins.

The Type VI Secretion System: A Dynamic System for Bacterial Communication?

Abstract: Numerous studies in Gram-negative bacteria have focused on the Type VI Secretion Systems (T6SSs), Quorum Sensing (QS), and social behavior, such as in biofilms. These interconnected mechanisms are important for bacterial survival; T6SSs allow bacteria to battle other cells, QS is devoted to the perception of bacterial cell density, and biofilm formation is essentially controlled by QS. Here, we review data concerning T6SS dynamics and T6SS-QS cross-talk that suggest the existence of inter-bacterial communication via T6SSs.

Maximum correntropy unscented filter

Abstract: The unscented transformation UT is an efficient method to solve the state estimation problem for a non-linear dynamic system, utilising a derivative-free higher-order approximation by approximating a Gaussian distribution rather than approximating a non-linear function. Applying the UT to a Kalman filter type estimator leads to the well-known unscented Kalman filter UKF. Although the UKF works very well in Gaussian noises, its performance may deteriorate significantly when the noises are non-Gaussian, especially when the system is disturbed by some heavy-tailed impulsive noises. To improve the robustness of the UKF against impulsive noises, a new filter for non-linear systems is proposed in this work, namely the maximum correntropy unscented filter MCUF. In MCUF, the UT is applied to obtain the prior estimates of the state and covariance matrix, and a robust statistical linearisation regression based on the maximum correntropy criterion is then used to obtain the posterior estimates of the state and covariance matrix. The satisfying performance of the new algorithm is confirmed by two illustrative examples.

Clinical Impact of Baseline Right Bundle Branch Block in Patients Undergoing Transcatheter Aortic Valve Replacement

Abstract: Objectives This study sought to assess the influence of baseline right bundle branch block (RBBB) on all-cause and cardiovascular mortality as well as sudden cardiac death (SCD) among patients undergoing transcatheter aortic valve replacement (TAVR). Background Few data exist regarding the late clinical impact of pre-existing RBBB in TAVR recipients. Methods A total of 3,527 patients (mean age 82 ± 8 years, 50.1% men) were evaluated according to the presence of RBBB on baseline electrocardiography. Intraventricular conduction abnormalities were classified according to the American Heart Association, American College of Cardiology Foundation, and Heart Rhythm Society recommendations for standardization and interpretation of the electrocardiogram. TAVR complications and causes of death were defined according to Valve Academic Research Consortium 2 definitions. Results RBBB was present on baseline electrocardiography in 362 patients (10.3%) and associated with higher 30-day rates of permanent pacemaker implantation (PPI) (40.1% vs. 13.5%; p Conclusions Pre-existing RBBB was found in 10% of TAVR recipients and was associated with poorer clinical outcomes. Patients with baseline RBBB without permanent pacemakers at hospital discharge may be at especially high risk for high-degree atrioventricular block and/or SCD during follow-up. Future studies should evaluate strategies aimed at the early detection of patients at risk for late development of high-degree atrioventricular block.

Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis.

Abstract: Ribosomally synthesized peptides are built out of L-amino acids, whereas D-amino acids are generally the hallmark of non-ribosomal synthetic processes. Here we show that the model bacterium Bacillus subtilis is able to produce a novel type of ribosomally synthesized and post-translationally modified peptide that contains D-amino acids, and which we propose to call epipeptides. We demonstrate that a two [4Fe-4S]-cluster radical S-adenosyl-L-methionine (SAM) enzyme converts L-amino acids into their D-counterparts by catalysing Cα-hydrogen-atom abstraction and using a critical cysteine residue as the hydrogen-atom donor. Unexpectedly, these D-amino acid residues proved to be essential for the activity of a peptide that induces the expression of LiaRS, a major component of the bacterial cell envelope stress-response system. Present in B. subtilis and in several members of the human microbiome, these epipeptides and radical SAM epimerases broaden the landscape of peptidyl structures accessible to living organisms.

Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Abstract: Purpose:MYD88 mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL), leading to constitutive NFκB pathway activation. The aim of this study was to examine the distinct genomic profiles of MYD88-mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants.Experimental Design: A cohort of 361 DLBCL cases (94 MYD88 mutant and 267 MYD88 wild-type) was submitted to next-generation sequencing (NGS) focusing on 34 genes to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses.Results: Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P-mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis also segregated subgroups according to associated genetic alterations among patients with the same MYD88 mutation. We showed that associated CD79B and MYD88 L265P mutations act synergistically to increase NFκB pathway activation, although the majority of MYD88 L265P-mutant cases harbors downstream NFκB alterations, which can predict BTK inhibitor resistance. Finally, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associated CD79B mutations significantly improved the survival of MYD88 L265P-mutant ABC DLBCL in our cohort.Conclusions: This study highlights the relative heterogeneity of MYD88-mutant DLBCL, adding to the field's knowledge of the theranostic importance of MYD88 mutations, but also of associated alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy. Clin Cancer Res; 23(9); 2232-44. ©2016 AACR.

Management of rectal cancer: the 2016 French guidelines.

Abstract: Aim Rectal cancer is a malignant disease requiring multidisciplinary management. The increasing number of studies published over the past decade has called for a comprehensive update to draw recommendations for clinical practice mandated by the French Research Group of Rectal Cancer Surgery (GRECCAR) and the French National Coloproctology Society (SNFCP). Method Seven questions summarizing the treatment of rectal cancer were selected. A search for evidence in the literature from January 2004 to December 2015 was performed. A Drafting Committee and a large group of expert reviewers contributed to validate the statements. Results Recommendations include the indications for neoadjuvant therapy, the quality criteria of surgical resection, the management of postoperative disordered function, the role of local excision in early rectal cancer, the place of conservative strategies after neoadjuvant treatment, the management of synchronous liver metastases and the indications for adjuvant therapy. A level of evidence was assigned to each statement. Conclusion The current clinical practice guidelines are useful for the treatment of rectal cancer. Some statements require a higher level of evidence due to a lack of studies. This article is protected by copyright. All rights reserved.

Synthetic, Switchable Enzymes

Abstract: The construction of switchable, radiation-controlled, aptameric enzymes - "swenzymes" - is, in principle, feasible. We propose a strategy to make such catalysts from 2 (or more) aptamers each selected to bind specifically to one of the substrates in, for example, a 2-substrate reaction. Construction of a combinatorial library of candidate swenzymes entails selecting a set of a million aptamers that bind one substrate and a second set of a million aptamers that bind the second substrate; the aptamers in these sets are then linked pairwise by a linker, thus bringing together the substrates. In the presence of the substrates, some linked aptamer pairs catalyze the reaction when exposed to external energy in the form of a specific frequency of low-intensity, nonionizing electromagnetic or acoustic radiation. Such swenzymes are detected via a separate product-capturing aptamer that changes conformation on capturing the product; this altered conformation allows it (1) to bind to every potential swenzyme in its vicinity (thereby giving a higher probability of capture to the swenzymes that generate the product) and (2) to bind to a sequence on a magnetic bead (thereby permitting purification of the swenzyme plus product-capturing aptamer by precipitation). Attempts to implement the swenzyme strategy may help elucidate fundamental problems in enzyme catalysis.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18F-Misonidazole PET/CT in Patients with Non–Small Cell Lung Carcinoma (RTEP5 Study)

Abstract: See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-β = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the 18F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

A phase field model for snow crystal growth in three dimensions

Abstract: Snowflake growth provides a fascinating example of spontaneous pattern formation in nature. Attempts to understand this phenomenon have led to important insights in non-equilibrium dynamics observed in various active scientific fields, ranging from pattern formation in physical and chemical systems, to self-assembly problems in biology. Yet, very few models currently succeed in reproducing the diversity of snowflake forms in three dimensions, and the link between model parameters and thermodynamic quantities is not established. Here, we report a modified phase field model that describes the subtlety of the ice vapour phase transition, through anisotropic water molecules attachment and condensation, surface diffusion, and strong anisotropic surface tension, that guarantee the anisotropy, faceting and dendritic growth of snowflakes. We demonstrate that this model reproduces the growth dynamics of the most challenging morphologies of snowflakes from the Nakaya diagram. We find that the growth dynamics of snow crystals matches the selection theory, consistently with previous experimental observations. A model that reproduces complex 3D snowflake growth using versatile interface descriptors may benefit other dendritic materials. Snow crystals solidify by expanding outward from an initial seed, capturing water molecules as they travel through the atmosphere. While most simulation methods treat this growing interface as a sharp boundary, Gilles Demange and colleagues from the University of Rouen in France report that a less rigid approach yields highly realistic results. Their technique uses a phase field model to represents the snowflake’s surface as a thin moveable layer where ice and vapour mix, and a new surface tension function to explain the anisotropic crystallisation. Including a special algorithm to simulate 3D crystal faceting enabled the model to duplicate essential snowflake morphologies and potentially predict ice water content in clouds under various weather conditions.