A common BACE1 polymorphism is a risk factor for sporadic Creutzfeldt-Jakob disease

The β site APP cleaving enzyme 1 (BACE1) is the rate-limiting β-secretase enzyme in the amyloidogenic processing of APP and Aβ formation, and therefore it has a prominent role in Alzheimer"s disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its β-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by Aβ oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimer"s and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, Aβ oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players

Quest for Orthologs Entails Quest for Tree of Life: In Search of the Gene Stream.

Quest for Orthologs (QfO) is a community effort with the goal to improve and benchmark orthology predictions. As quality assessment assumes prior knowledge on species phylogenies, we investigated the congruency between existing species trees by comparing the relationships of 147 QfO reference organisms from six Tree of Life (ToL)/species tree projects: The National Center for Biotechnology Information (NCBI) taxonomy, Opentree of Life, the sequenced species/species ToL, the 16S ribosomal RNA (rRNA) database, and trees published by Ciccarelli et al. (Ciccarelli FD, et al. 2006. Toward automatic reconstruction of a highly resolved tree of life. Science 311:1283-1287) and by Huerta-Cepas et al. (Huerta-Cepas J, Marcet-Houben M, Gabaldon T. 2014. A nested phylogenetic reconstruction approach provides scalable resolution in the eukaryotic Tree Of Life. PeerJ PrePrints 2:223) Our study reveals that each species tree suggests a different phylogeny: 87 of the 146 (60%) possible splits of a dichotomous and rooted tree are congruent, while all other splits are incongruent in at least one of the species trees. Topological differences are observed not only at deep speciation events, but also within younger clades, such as Hominidae, Rodentia, Laurasiatheria, or rosids. The evolutionary relationships of 27 archaea and bacteria are highly inconsistent. By assessing 458,108 gene trees from 65 genomes, we show that consistent species topologies are more often supported by gene phylogenies than contradicting ones. The largest concordant species tree includes 77 of the QfO reference organisms at the most. Results are summarized in the form of a consensus ToL (http://swisstree.vital-it.ch/species_tree) that can serve different benchmarking purposes.

A Gradient based algorithm for blind inversion of Wiener System using multi-variate score functions

A Wiener system is a linear time-invariant filter, followed by an invertible nonlinear distortion. Assuming that the input signal is an independent and identically distributed (iid) sequence, we propose an algorithm for estimating the input signal only by observing the output of the Wiener system. The algorithm is based on minimizing the mutual information of the output samples, by means of a steepest descent gradient approach.

Improving algorithm speed in PNL mixture separation and Wiener system inversion

This paper proposes a very simple method for increasing the algorithm speed for separating sources from PNL mixtures or invertingWiener systems. The method is based on a pertinent initialization of the inverse system, whose computational cost is very low. The nonlinear part is roughly approximated by pushing the observations to be Gaussian; this method provides a surprisingly good approximation even when the basic assumption is not fully satisfied. The linear part is initialized so that outputs are decorrelated. Experiments shows the impressive speed improvement.

Quantitative proteomics in the characterization of T helper lymphocyte differentiation

The term proteome is used to define the complete set of proteins expressed in cells or tissues of an organism at a certain timepoint. Respectively, proteomics is used to describe the methods, which are used to study such proteomes. These methods include chromatographic and electrophoretic techniques for protein or peptide fractionation, mass spectrometry for their identification, and use of computational methods to assist the complicated data analysis. A primary aim in this Ph.D. thesis was to set-up, optimize, and develop proteomics methods for analysing proteins extracted from T-helper (Th) lymphocytes. First, high-throughput LC-MS/MS and ICAT labeling methods were set-up and optimized for analysing the microsomal fraction proteins extracted from Th lymphocytes. Later, iTRAQ method was optimized to study cytokine regulated protein expression in the nuclei of Th lymphocytes. High-throughput LC-MS/MS analyses, like ICAT and iTRAQ, produce large quantities of data and robust software and data analysis pipelines are needed. Therefore, different software programs used for analysing such data were evaluated. Moreover, a pre-filtering algorithm was developed to classify good-quality and bad-quality spectra prior to the database searches. Th-lymphocytes can differentiate into Th1 or Th2 cells based on surrounding antigens, co-stimulatory molecules, and cytokines. Both subsets have individual cytokine secretion profiles and specific functions. Th1 cells participate in the cellular immunity against intracellular pathogens, while Th2 cells have important role in the humoral immunity against extracellular parasites. An abnormal response of Th1 and Th2 cells and imbalance between the subsets are charasteristic of several diseases. Th1 specific reactions and cytokines have been detected in autoimmune diseases, while Th2 specific response and cytokine profile is common in allergy and asthma. In this Ph. D. thesis mass spectrometry-based proteomics was used to study the effects of Th1 and Th2 promoting cytokines IL-12 and IL-4 on the proteome of Th lymphocytes. Characterization of microsomal fraction proteome extracted from IL-12 treated lymphobasts and IL-4 stimulated cord blood CD4+ cells resulted in finding of cytokine regulated proteins. Galectin-1 and CD7 were down-regulated in IL-12 treated cells, while IL-4 stimulation decreased the expression of STAT1, MXA, GIMAP1, and GIMAP4. Interestingly, the transcription of both GIMAP genes was up-regulated in Th1 polarized cells and down-regulated in Th2 promoting conditions.

An efficient total variation algorithm for super-resolution in fetal brain MRI with adaptive regularization.

Although fetal anatomy can be adequately viewed in new multi-slice MR images, many critical limitations remain for quantitative data analysis. To this end, several research groups have recently developed advanced image processing methods, often denoted by super-resolution (SR) techniques, to reconstruct from a set of clinical low-resolution (LR) images, a high-resolution (HR) motion-free volume. It is usually modeled as an inverse problem where the regularization term plays a central role in the reconstruction quality. Literature has been quite attracted by Total Variation energies because of their ability in edge preserving but only standard explicit steepest gradient techniques have been applied for optimization. In a preliminary work, it has been shown that novel fast convex optimization techniques could be successfully applied to design an efficient Total Variation optimization algorithm for the super-resolution problem. In this work, two major contributions are presented. Firstly, we will briefly review the Bayesian and Variational dual formulations of current state-of-the-art methods dedicated to fetal MRI reconstruction. Secondly, we present an extensive quantitative evaluation of our SR algorithm previously introduced on both simulated fetal and real clinical data (with both normal and pathological subjects). Specifically, we study the robustness of regularization terms in front of residual registration errors and we also present a novel strategy for automatically select the weight of the regularization as regards the data fidelity term. Our results show that our TV implementation is highly robust in front of motion artifacts and that it offers the best trade-off between speed and accuracy for fetal MRI recovery as in comparison with state-of-the art methods.

Randomization tests for ABAB designs: Comparing-data-division-specific and common distributions

Monte Carlo simulations were used to generate data for ABAB designs of different lengths. The points of change in phase are randomly determined before gathering behaviour measurements, which allows the use of a randomization test as an analytic technique. Data simulation and analysis can be based either on data-division-specific or on common distributions. Following one method or another affects the results obtained after the randomization test has been applied. Therefore, the goal of the study was to examine these effects in more detail. The discrepancies in these approaches are obvious when data with zero treatment effect are considered and such approaches have implications for statistical power studies. Data-division-specific distributions provide more detailed information about the performance of the statistical technique.

New Algorithm for Managing Childhood Illness Using Mobile Technology (ALMANACH): A Controlled Non-Inferiority Study on Clinical Outcome and Antibiotic Use in Tanzania.

INTRODUCTION: The decline of malaria and scale-up of rapid diagnostic tests calls for a revision of IMCI. A new algorithm (ALMANACH) running on mobile technology was developed based on the latest evidence. The objective was to ensure that ALMANACH was safe, while keeping a low rate of antibiotic prescription. METHODS: Consecutive children aged 2-59 months with acute illness were managed using ALMANACH (2 intervention facilities), or standard practice (2 control facilities) in Tanzania. Primary outcomes were proportion of children cured at day 7 and who received antibiotics on day 0. RESULTS: 130/842 (15∙4%) in ALMANACH and 241/623 (38∙7%) in control arm were diagnosed with an infection in need for antibiotic, while 3∙8% and 9∙6% had malaria. 815/838 (97∙3%;96∙1-98.4%) were cured at D7 using ALMANACH versus 573/623 (92∙0%;89∙8-94∙1%) using standard practice (p<0∙001). Of 23 children not cured at D7 using ALMANACH, 44% had skin problems, 30% pneumonia, 26% upper respiratory infection and 13% likely viral infection at D0. Secondary hospitalization occurred for one child using ALMANACH and one who eventually died using standard practice. At D0, antibiotics were prescribed to 15∙4% (12∙9-17∙9%) using ALMANACH versus 84∙3% (81∙4-87∙1%) using standard practice (p<0∙001). 2∙3% (1∙3-3.3) versus 3∙2% (1∙8-4∙6%) received an antibiotic secondarily. CONCLUSION: Management of children using ALMANACH improve clinical outcome and reduce antibiotic prescription by 80%. This was achieved through more accurate diagnoses and hence better identification of children in need of antibiotic treatment or not. The building on mobile technology allows easy access and rapid update of the decision chart. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201011000262218.

Managing the Sick Child in the Era of Declining Malaria Transmission: Development of ALMANACH, an Electronic Algorithm for Appropriate Use of Antimicrobials.

OBJECTIVE: To review the available knowledge on epidemiology and diagnoses of acute infections in children aged 2 to 59 months in primary care setting and develop an electronic algorithm for the Integrated Management of Childhood Illness to reach optimal clinical outcome and rational use of medicines. METHODS: A structured literature review in Medline, Embase and the Cochrane Database of Systematic Review (CDRS) looked for available estimations of diseases prevalence in outpatients aged 2-59 months, and for available evidence on i) accuracy of clinical predictors, and ii) performance of point-of-care tests for targeted diseases. A new algorithm for the management of childhood illness (ALMANACH) was designed based on evidence retrieved and results of a study on etiologies of fever in Tanzanian children outpatients. FINDINGS: The major changes in ALMANACH compared to IMCI (2008 version) are the following: i) assessment of 10 danger signs, ii) classification of non-severe children into febrile and non-febrile illness, the latter receiving no antibiotics, iii) classification of pneumonia based on a respiratory rate threshold of 50 assessed twice for febrile children 12-59 months; iv) malaria rapid diagnostic test performed for all febrile children. In the absence of identified source of fever at the end of the assessment, v) urine dipstick performed for febrile children <2 years to consider urinary tract infection, vi) classification of 'possible typhoid' for febrile children >2 years with abdominal tenderness; and lastly vii) classification of 'likely viral infection' in case of negative results. CONCLUSION: This smartphone-run algorithm based on new evidence and two point-of-care tests should improve the quality of care of <5 year children and lead to more rational use of antimicrobials.

Impact of common risk factors of fibrosis progression in chronic hepatitis C.

OBJECTIVE: The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN: We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥20 g/day for ≥5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS: Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS: Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.

CLARIN: common language resources and technology infrastructure

Presentamos el proyecto CLARIN, un proyecto cuyo objetivo es potenciar el uso de instrumentos tecnológicos en la investigación en las Humanidades y Ciencias Sociales