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showing 10 items of 10618 documents
FastaHerder2: Four Ways to Research Protein Function and Evolution with Clustering and Clustered Databases.
2016
The accelerated growth of protein databases offers great possibilities for the study of protein function using sequence similarity and conservation. However, the huge number of sequences deposited in these databases requires new ways of analyzing and organizing the data. It is necessary to group the many very similar sequences, creating clusters with automated derived annotations useful to understand their function, evolution, and level of experimental evidence. We developed an algorithm called FastaHerder2, which can cluster any protein database, putting together very similar protein sequences based on near-full-length similarity and/or high threshold of sequence identity. We compressed 50…
Quantitative analysis of the impact of a human pathogenic mutation on the CCT5 chaperonin subunit using a proxy archaeal ortholog
2017
The human chaperonin complex is a ~ 1 MDa nanomachine composed of two octameric rings formed from eight similar but non-identical subunits called CCT. Here, we are elucidating the mechanism of a heritable CCT5 subunit mutation that causes profound neuropathy in humans. In previous work, we introduced an equivalent mutation in an archaeal chaperonin that assembles into two octameric rings like in humans but in which all subunits are identical. We reported that the hexadecamer formed by the mutant subunit is unstable with impaired chaperoning functions. This study quantifies the loss of structural stability in the hexadecamer due to the pathogenic mutation, using differential scanning calorim…
Multi-level integration of environmentally perturbed internal phenotypes reveals key points of connectivity between them
2017
The genotype and external phenotype of organisms are linked by so-called internal phenotypes which are influenced by environmental conditions. In this study, we used five existing -omics datasets representing five different layers of internal phenotypes, which were simultaneously measured in dietarily perturbed mice. We performed 10 pair-wise correlation analyses verified with a null model built from randomized data. Subsequently, the inferred networks were merged and literature mined for co-occurrences of identified linked nodes. Densely connected internal phenotypes emerged. Forty-five nodes have links with all other data-types and we denote them "connectivity hubs." In literature, we fou…
Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions
2016
A major cause of respiratory failure during influenza A virus (IAV) infection is damage to the epithelial–endothelial barrier of the pulmonary alveolus. Damage to this barrier results in flooding of the alveolar lumen with proteinaceous oedema fluid, erythrocytes and inflammatory cells. To date, the exact roles of pulmonary epithelial and endothelial cells in this process remain unclear.Here, we used an in vitro co-culture model to understand how IAV damages the pulmonary epithelial–endothelial barrier. Human epithelial cells were seeded on the upper half of a transwell membrane while human endothelial cells were seeded on the lower half. These cells were then grown in co-culture and IAV wa…
Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis
2020
BackgroundPulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum of SLC34A2 has not been well investigated and it is not yet known whether a genotype–phenotype correlation exists.MethodsWe collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each va…
A Tuft Cell-Like Signature Is Highly Prevalent in Thymic Squamous Cell Carcinoma and Delineates New Molecular Subsets Among the Major Lung Cancer His…
2020
Abstract Introduction In-depth genomic characterization of thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs), failed to identify targetable mutations and suggested unique biology of TETs, including KIT expression in most TCs. Recently, tuft cell–like medullary thymic epithelial cells were identified in the murine thymus, and our reanalysis of the published gene expression data revealed that these cells express KIT. In addition, recently, a minor subset of SCLCs with tuft cell–like features was described. Methods We interrogated mRNA expression data from our tumor cohorts (N = 60) and publicly available, independent data sets from TETs and NSCLC (N = 1199) for …
Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency.
2016
Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2–18 years) diagnosed with AATD and 18 controls (aged 3–16 years).Our results show that intermediate-risk (MZ; SZ) and …
Bacterial-viral load and the immune response in stable and exacerbated COPD: significance and therapeutic prospects.
2016
Silvestro Ennio D’Anna,1 Bruno Balbi,2 Francesco Cappello,3,4 Mauro Carone,2 Antonino Di Stefano21Department of Rehabilitation, Cardiorespiratory Unit, Fondazione Istituto G. Giglio di Cefalù, 2Pneumology Unit and Laboratory of Cytoimmunopathology of Heart and Lung, Fondazione Salvatore Maugeri, IRCCS, Veruno (NO) and Cassano delle Murge (BA), 3Human Anatomy Section, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy; 4Euro-Mediterranean Institute of Science and Technology, Palermo, ItalyAbstract: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and an abnormal inflammatory respon…
JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study
2018
BackgroundPulmonary hypertension (PH) is a common disorder in patients with idiopathic pulmonary fibrosis (IPF) and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation (V)/perfusion (Q) mismatching and oxygen desaturation. Janus kinase type 2 (JAK2) is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown.ObjectiveThe study of JAK2 as potential target to treat PH in IPF.Methods and resultsJAK2 expression was increased in pulmonary arteries (PAs) from IPF (n=10; 1.93-fold; P=0.0011) and IPF+PH (n=9; 2.65-fold; P<0.00…
Metabolites related to purine catabolism and risk of type 2 diabetes incidence; modifying effects of the TCF7L2-rs7903146 polymorphism
2019
Studies examining associations between purine metabolites and type 2 diabetes (T2D) are limited. We prospectively examined associations between plasma levels of purine metabolites with T2D risk and the modifying effects of transcription factor-7-like-2 (TCF7L2) rs7903146 polymorphism on these associations. This is a case-cohort design study within the PREDIMED study, with 251 incident T2D cases and a random sample of 694 participants (641 non-cases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 years). Metabolites were semi-quantitatively profiled with LC-MS/MS. Cox regression analysis revealed that high plasma allantoin levels, including allantoin-to-uric acid rat…