An essential prerequisite for any systems-level understanding of cellular functions is to correctly uncover and annotate all functional interactions among proteins in the cell. Toward this goal, ...remarkable progress has been made in recent years, both in terms of experimental measurements and computational prediction techniques. However, public efforts to collect and present protein interaction information have struggled to keep up with the pace of interaction discovery, partly because protein-protein interaction information can be error-prone and require considerable effort to annotate. Here, we present an update on the online database resource Search Tool for the Retrieval of Interacting Genes (STRING); it provides uniquely comprehensive coverage and ease of access to both experimental as well as predicted interaction information. Interactions in STRING are provided with a confidence score, and accessory information such as protein domains and 3D structures is made available, all within a stable and consistent identifier space. New features in STRING include an interactive network viewer that can cluster networks on demand, updated on-screen previews of structural information including homology models, extensive data updates and strongly improved connectivity and integration with third-party resources. Version 9.0 of STRING covers more than 1100 completely sequenced organisms; the resource can be reached at http://string-db.org.
Abstract Fast X-ray Transients (FXTs) are extragalactic bursts of soft X-rays first identified ≳10 yr ago. Since then, nearly 40 events have been discovered, although almost all of these have been ...recovered from archival Chandra and XMM-Newton data. To date, optical sky surveys and follow-up searches have not revealed any multiwavelength counterparts. The Einstein Probe, launched in 2024 January, has started surveying the sky in the soft X-ray regime (0.5–4 keV) and will rapidly increase the sample of FXTs discovered in real time. Here we report the first discovery of both an optical and radio counterpart to a distant FXT, the fourth source publicly released by the Einstein Probe. We discovered a fast-fading optical transient within the 3′ localization radius of EP 240315a with the all-sky optical survey ATLAS, and our follow-up Gemini spectrum provides a redshift, z = 4.859 ± 0.002. Furthermore, we uncovered a radio counterpart in the S band (3.0 GHz) with the MeerKAT radio interferometer. The optical (rest-frame UV) and radio luminosities indicate that the FXT most likely originates from either a long gamma-ray burst or a relativistic tidal disruption event. This may be a fortuitous early mission detection by the Einstein Probe or may signpost a mode of discovery for high-redshift, high-energy transients through soft X-ray surveys, combined with locating multiwavelength counterparts.
Syndromic retinal diseases (SRDs) are a group of complex inherited systemic disorders, with challenging molecular underpinnings and clinical management. Our main goal is to improve clinical and ...molecular SRDs diagnosis, by applying a structured phenotypic ontology and next-generation sequencing (NGS)-based pipelines. A prospective and retrospective cohort study was performed on 100 probands with an a priori diagnosis of non-Usher SRDs, using available clinical data, including Human Phenotype Ontology annotation, and further classification into seven clinical categories (ciliopathies, specific syndromes and five others). Retrospective molecular diagnosis was assessed using different molecular and bioinformatic methods depending on availability. Subsequently, uncharacterized probands were prospectively screened using other NGS approaches to extend the number of analyzed genes. After phenotypic classification, ciliopathies were the most common SRD (35%). A global characterization rate of 52% was obtained, with six cases incompletely characterized for a gene that partially explained the phenotype. An improved characterization rate was achieved addressing prospective cases (83%) and well-recognizable syndrome (62%) subgroups. The 27% of the fully characterized cases were reclassified into a different clinical category after identification of the disease-causing gene. Clinical-exome sequencing is the most appropriate first-tier approach for prospective cases, whereas whole-exome sequencing and bioinformatic reanalysis increases the diagnosis of uncharacterized retrospective cases to 45%, mostly those with unspecific symptoms. Our study describes a comprehensive approach to SRDs in daily clinical practice and the importance of thorough clinical assessment and selection of the most appropriate molecular test to be used to solve these complex cases and elucidate novel associations.
ABSTRACT
GW190425 is the second of two binary neutron star (BNS) merger events to be significantly detected by the Laser Interferometer Gravitational Wave (GW) Observatory (LIGO), Virgo and the ...Kamioka Gravitational Wave (KAGRA) detector network. With a detection only in LIGO Livingston, the skymap containing the source was large and no plausible electromagnetic counterpart was found in real-time searching in 2019. Here, we summarize Asteroid Terrestrial-Impact Last Alert System (ATLAS) and Panoramic Survey Telescope and Rapid Response System (Pan-STARRS) wide-field optical coverage of the skymap beginning within 1 and 3 h, respectively, of the GW190425 merger time. More recently, a potential coincidence between GW190425 and a fast radio burst FRB 20190425A has been suggested, given their spatial and temporal coincidences. The smaller sky localization area of FRB 20190425A and its dispersion measure led to the identification of a likely host galaxy, UGC 10667 at a distance of 141 ± 10 Mpc. Our optical imaging covered the galaxy 6.0 h after GW190425 was detected and 3.5 h after the FRB 20190425A. No optical emission was detected and further imaging at +1.2 and +13.2 d also revealed no emission. If the FRB 20190425A and GW190425 association were real, we highlight our limits on kilonova emission from a BNS merger in UGC 10667. The model for producing FRB 20190425A from a BNS merger involves a supramassive magnetized neutron star spinning down by dipole emission on the time-scale of hours. We show that magnetar-enhanced kilonova emission is ruled out by optical upper limits. The lack of detected optical emission from a kilonova in UGC 10667 disfavours, but does not disprove, the FRB–GW link for this source.
Despite the improved accuracy of next-generation sequencing (NGS), it is widely accepted that variants need to be validated using Sanger sequencing before reporting. Validation of all NGS variants ...considerably increases the turnaround time and costs of clinical diagnosis. We comprehensively assessed this need in 1109 variants from 825 clinical exomes, the largest sample set to date assessed using Illumina chemistry reported. With a concordance of 100%, we conclude that Sanger sequencing can be very useful as an internal quality control, but not so much as a verification method for high-quality single-nucleotide and small insertion/deletions variants. Laboratories might validate and establish their own thresholds before discontinuing Sanger confirmation studies. We also expand and validate 23 copy number variations detected by exome sequencing in 20 samples, observing a concordance of 95.65% (22/23).
We present Babelomics, a complete suite of web tools for the functional analysis of groups of genes in high-throughput experiments, which includes the use of information on Gene Ontology terms, ...interpro motifs, KEGG pathways, Swiss-Prot keywords, analysis of predicted transcription factor binding sites, chromosomal positions and presence in tissues with determined histological characteristics, through five integrated modules: FatiGO (fast assignment and transference of information), FatiWise, transcription factor association test, GenomeGO and tissues mining tool, respectively. Additionally, another module, FatiScan, provides a new procedure that integrates biological information in combination with experimental results in order to find groups of genes with modest but coordinate significant differential behaviour. FatiScan is highly sensitive and is capable of finding significant asymmetries in the distribution of genes of common function across a list of ordered genes even if these asymmetries were not extreme. The strong multiple-testing nature of the contrasts made by the tools is taken into account. All the tools are integrated in the gene expression analysis package GEPAS. Babelomics is the natural evolution of our tool FatiGO (which analysed almost 22 000 experiments during the last year) to include more sources on information and new modes of using it. Babelomics can be found at http://www.babelomics.org.
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Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma with indolent behavior, mostly present in women and associated with immunological diseases ...whose pathogenic background is still poorly understood. SPTCL is associated with lupus erythematosus panniculitis (LEP) and histologically misdiagnosed.
The aim of our study was to identify mutations affecting the pathogenesis of both SPTCL and LEP.
We studied a total of 10 SPTCL and 10 LEP patients using targeted next-generation sequencing and pyrosequencing. Differences in gene expression between molecular subgroups were investigated using NanoString technology. Clinical data were collected, and correlations sought with the molecular data obtained.
The mutational profile of SPTCL and LEP is different. We identified fewer pathogenic mutations than previously reported in SPTCL, noting a single HAVCR2-mutated SPTCL case. Interestingly, 40% of our SPTCL cases showed the pathogenic TP53 (p.Pro72Arg) (P72R) variant. Although cases showing HAVCR2 mutations or the TP53 (P72R) variant had more severe symptomatic disease, none developed hemophagocytic syndrome (HPS). Furthermore, TP53 (P72R)-positive cases were characterized by a lower metabolic signaling pathway and higher levels of CD28 expression and Treg signaling genes. In addition, 30% of our cases featured the same mutation (T735C) of the epigenetic modificatory gene DNMT3A. None of the LEP cases showed mutations in any of the studied genes.
The mutational landscape of SPTCL is broader than previously anticipated. We describe, for the first time, the involvement of the TP53 (P72R) pathogenic variant in this subgroup of tumors, consider the possible role of different genetic backgrounds in the development of SPTCL, and conclude that LEP does not follow the same pathogenic pathway as SPTCL.
El linfoma T paniculítico (LTP) es un linfoma de células T citotóxico poco frecuente, de comportamiento indolente, más frecuente en mujeres, relacionado con enfermedades autoinmunes, y cuyos antecedentes patogénicos aún no se conocen bien. Se asocia y se confunde histológicamente con la paniculitis lúpica (PL).
El objetivo de nuestro estudio fue identificar mutaciones implicadas en la patogénesis del LTP y de la PL.
Se estudiaron 10 pacientes con LTP y 10 con PL mediante secuenciación masiva (con un panel de genes customizados) y pirosecuenciación dirigida. Se investigaron diferencias en la expresión genética mediante NanoString entre diferentes subgrupos moleculares encontrados. Se recopilaron datos clínicos y se correlacionaron con los datos moleculares obtenidos.
El perfil mutacional del LTP y el de la LP son diferentes. El porcentaje de mutaciones encontradas en el subgrupo de LTP fue inferior al ya publicado en la literatura. Solo un paciente con LTP mostraba mutaciones en el gen HAVCR2. Curiosamente, el 40% de los LTP mostraron la variante patogénica TP53 (p.Pro72Arg) (P72R). Los pacientes con mutaciones en el gen HAVCR2 o con la variante TP53(P72R) sufrían enfermedad sintomática, aunque ninguno desarrolló síndrome hemofagocítico (SPH). El estudio de NanoString identificó que las muestras con alteración de TP53(P72R) se caracterizaban por una down-regulation de la vía de señalización del metabolismo y de una mayor expresión de los genes de las vías de señalización de CD28 y Treg si se comparaban con los casos negativos para TP53 (P72R). Además, el 30% de nuestros casos presentaban la misma mutación (T735C) en el gen modificador epigenético DNMT3A. Ninguno de los pacientes con PL mostró mutaciones en ninguno de los genes estudiados.
Ampliamos el perfil mutacional del LTP, describiendo por primera vez la implicación de la variante patogénica TP53 (P72R) en este subgrupo de tumores. Además, sugerimos el posible papel de un fondo genético en el desarrollo de los LTP. La aparición de PL no parece seguir la misma vía patogénica que la de los LTP.
The Gene Expression Profile Analysis Suite, GEPAS, has been running for more than three years. With >76 000 experiments analysed during the last year and a daily average of almost 300 analyses, GEPAS ...can be considered a well-established and widely used platform for gene expression microarray data analysis. GEPAS is oriented to the analysis of whole series of experiments. Its design and development have been driven by the demands of the biomedical community, probably the most active collective in the field of microarray users. Although clustering methods have obviously been implemented in GEPAS, our interest has focused more on methods for finding genes differentially expressed among distinct classes of experiments or correlated to diverse clinical outcomes, as well as on building predictors. There is also a great interest in CGH-arrays which fostered the development of the corresponding tool in GEPAS: InSilicoCGH. Much effort has been invested in GEPAS for developing and implementing efficient methods for functional annotation of experiments in the proper statistical framework. Thus, the popular FatiGO has expanded to a suite of programs for functional annotation of experiments, including information on transcription factor binding sites, chromosomal location and tissues. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://www.gepas.org.
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