270 research outputs found
Robust Fuzzy Clustering via Trimming and Constraints
ProducciĂłn CientĂficaA methodology for robust fuzzy clustering is proposed. This
methodology can be widely applied in very different statistical problems given
that it is based on probability likelihoods. Robustness is achieved by trimming
a fixed proportion of âmost outlyingâ observations which are indeed
self-determined by the data set at hand. Constraints on the clustersâ scatters
are also needed to get mathematically well-defined problems and to avoid the
detection of non-interesting spurious clusters. The main lines for computationally
feasible algorithms are provided and some simple guidelines about
how to choose tuning parameters are briefly outlined. The proposed methodology
is illustrated through two applications. The first one is aimed at heterogeneously
clustering under multivariate normal assumptions and the second
one migh be useful in fuzzy clusterwise linear regression problems.Ministerio de EconomĂa, Industria y Competitividad (MTM2014-56235-C2-1-P)Junta de Castilla y LeĂłn (programa de apoyo a proyectos de investigaciĂłn â Ref. VA212U13
A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer's disease.
Tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer's patients' brains (Braak I nâ=â3; Braak II nâ=â6, Braak III nâ=â3, Braak IV nâ=â1, and Braak V nâ=â10, Braak VI nâ=â8) with respect to non-demented control subjects (nâ=â9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3ÎČ, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer's disease and other tauopathies.This work was supported by the Ministerio de Ciencia, InnovaciĂłn y Universidades from Spain (PGC2018-096177-B-00). Institutional grants from the FundaciĂłn RamĂłn Areces and Banco de Santander to CBMSO are also acknowledged. The AsociaciĂłn Española Contra el CĂĄncer Scientific Foundation has financed Ricardo Gargini. We would like to acknowledge Daniela Rosiles for her technical support in cloning.S
The GALANTE photometric survey of the northern Galactic plane: Project description and pipeline
The GALANTE optical photometric survey is observing the northern Galactic
plane and some adjacent regions using seven narrow- and intermediate-filters,
covering a total of 1618 square degrees. The survey has been designed with
multiple exposure times and at least two different air masses per field to
maximize its photometric dynamic range, comparable to that of Gaia, and ensure
the accuracy of its photometric calibration. The goal is to reach at least 1%
accuracy and precision in the seven bands for all stars brighter than AB
magnitude 17 while detecting fainter stars with lower values of the
signal-to-noise ratio.The main purposes of GALANTE are the identification and
study of extinguished O+B+WR stars, the derivation of their extinction
characteristics, and the cataloguing of F and G stars in the solar
neighbourhood. Its data will be also used for a variety of other stellar
studies and to generate a high-resolution continuum-free map of the H{\alpha}
emission in the Galactic plane. We describe the techniques and the pipeline
that are being used to process the data, including the basis of an innovative
calibration system based on Gaia DR2 and 2MASS photometry.Comment: 18 pages, accepted for publication in MNRA
Huntington's disease-specific mis-splicing unveils key effector genes and altered splicing factors
Correction of mis-splicing events is a growing therapeutic approach for neurological diseases such as spinal muscular atrophy or neuronal ceroid lipofuscinosis 7, which are caused by splicing-affecting mutations. Mis-spliced effector genes that do not harbour mutations are also good candidate therapeutic targets in diseases with more complex aetiologies such as cancer, autism, muscular dystrophies or neurodegenerative diseases. Next-generation RNA sequencing (RNA-seq) has boosted investigation of global mis-splicing in diseased tissue to identify such key pathogenic mis-spliced genes. Nevertheless, while analysis of tumour or dystrophic muscle biopsies can be informative on early stage pathogenic mis-splicing, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntington's disease pathogenesis, here we performed intersect-RNA-seq analyses of human post-mortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the Huntington's disease-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked mis-spliced effector genes that-together with the deregulated splicing factors-become new possible therapeutic targets. In summary, here we report pathogenic global mis-splicing in Huntington's disease striatum captured by our new intersect-RNA-seq approach that can be readily applied to other neurodegenerative diseases for which bona fide animal models are available.Extremadura Research Centre for Advanced Technologies (CETA-CIEMAT), funded by the European Regional Development Fund (ERDF). CETA-CIEMAT belongs to CIEMAT and the Government of Spai
Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis
BACKGROUND AND AIMS: Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy, but also has pleiotropic deleterious effects on several organ systems, impacting on immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. METHODS: We collected data from 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analysis and fast unified random forest were performed to predict complications and mortality. External validation was carried out using prospective data from 130 cirrhotic patients in an independent tertiary liver centre. RESULTS: Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (HR=2.13; 95%CI=1.89-2.40; p<0.001) and mortality (HR=1.45; 95%CI=1.20-1.76; p<0.001). AUROC of AMM-ULN was 77.9% for 1-year complications, higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p<0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation. CONCLUSION: Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications. LAY SUMMARY: We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients
The Latin American Social Medicine database
BACKGROUND: Public health practitioners and researchers for many years have been attempting to understand more clearly the links between social conditions and the health of populations. Until recently, most public health professionals in English-speaking countries were unaware that their colleagues in Latin America had developed an entire field of inquiry and practice devoted to making these links more clearly understood. The Latin American Social Medicine (LASM) database finally bridges this previous gap. DESCRIPTION: This public health informatics case study describes the key features of a unique information resource intended to improve access to LASM literature and to augment understanding about the social determinants of health. This case study includes both quantitative and qualitative evaluation data. Currently the LASM database at The University of New Mexico brings important information, originally known mostly within professional networks located in Latin American countries to public health professionals worldwide via the Internet. The LASM database uses Spanish, Portuguese, and English language trilingual, structured abstracts to summarize classic and contemporary works. CONCLUSION: This database provides helpful information for public health professionals on the social determinants of health and expands access to LASM
Coupled C, H, N, S and Fe biogeochemical cycles operating in the continental deep subsurface of the Iberian Pyrite Belt
Microbial activity is a major contributor to the biogeochemical cycles that
make up the life support system of planet Earth. A 613 m deep geomicrobiological perforation and a systematic multi-analytical characterization
revealed an unexpected diversity associated with the rock matrix microbiome that operates in the subsurface of the Iberian Pyrite Belt (IPB). Members of 1 class and 16 genera were deemed the most representative
microorganisms of the IPB deep subsurface and selected for a deeper analysis. The use of fluorescence in situ hybridization allowed not only the identification of microorganisms but also the detection of novel activities in the
subsurface such as anaerobic ammonium oxidation (ANAMMOX) and
anaerobic methane oxidation, the co-occurrence of microorganisms able to
maintain complementary metabolic activities and the existence of biofilms.
The use of enrichment cultures sensed the presence of five different complementary metabolic activities along the length of the borehole and isolated
29 bacterial species. Genomic analysis of nine isolates identified the genes
involved in the complete operation of the light-independent coupled C, H, N,
S and Fe biogeochemical cycles. This study revealed the importance of
nitrate reduction microorganisms in the oxidation of iron in the anoxic conditions existing in the subsurface of the IPBFP7 Ideas: European Research Council,
Grant/Award Number: ERC Advanced Grant
#250-35
Cutibacterium spp. Infections after Instrumented Spine Surgery Have a Good Prognosis Regardless of Rifampin Use: A Cross-Sectional Study
Infection after spinal instrumentation (IASI) by Cutibacterium spp. is being more frequently reported. The aim of this study was to analyse the incidence, risk factors, clinical characteristics, and outcome of a Cutibacterium spp. IASI (CG) compared with non-Cutibacterium IASI (NCG) infections, with an additional focus on the role of rifampin in the treatment. All patients from a multicentre, retrospective, observational study with a confirmed IASI between January 2010 and December 2016 were divided into two groups: (CG and NCG) IASI. Baseline, medical, surgical, infection treatment, and follow-up data were compared for both groups. In total, 411 patients were included: 27 CG and 384 NCG. The CG patients were significantly younger. They had a longer median time to diagnosis (23 vs. 13 days) (p = 0.025), although 55.6% debuted within the first month after surgery. Cutibacterium patients were more likely to have the implant removed (29.6% vs. 12.8%; p = 0.014) and received shorter antibiotic regimens (p = 0.014). In 33% of Cutibacterium cases, rifampin was added to the baseline therapy. None of the 27 infections resulted in treatment failure during follow-up regardless of rifampin use. Cutibacterium spp. is associated with a younger age and may cause both early and late IASIs. In our experience, the use of rifampin to improve the outcome in the treatment of a Cutibacterium spp. IASI is not relevant since, in our series, none of the cases had therapeutic failure regardless of the use of rifampin
The cadherinâcatenin complex in laryngeal squamous cell carcinoma
Abnormal Wnt signaling and impaired cellâcell adhesion due to abnormal E-cadherin and ÎČ-catenin function have been implicated in many cancers, but have not been fully explored in laryngeal squamous cell carcinoma. In this study, ÎČ-catenin cellular location and E-cadherin expression levels were analyzed in 16 laryngeal squamous cell carcinomas (LSCCs) (9 glottic and 7 supraglottic) and 11 samples of non-tumoral inflammatory larynx tissue, using immunohistochemical methods. All non-tumoral tissues showed equally strong membranous expression of ÎČ-catenin, while cytoplasmic expression was found in only 3 of the 11 samples. By contrast, whereas 8/9 glottic LSCCs exhibited only membranous expression of ÎČ-catenin, 6/7 supraglottic LSCCs displayed both membranous and cytoplasmic expression (p = 0.003). Strong E-cadherin staining was observed in 9/11 non-tumoral tissues and 7/9 glottic LSCCs, whereas 4/7 supraglottic LSCCs exhibited weak expression. Reduced membrane expression of E-cadherin and cytoplasmic retention of ÎČ-catenin in supraglottic LSCC seems to be related with more aggressive biological behavior which has been described in clinical studies. Further research is required to clarify the involvement of ÎČ-catenin in the mechanism associated with malignant transformation in laryngeal tissues
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