There is growing evidence that coronavirus disease 2019 (COVID-19) can lead to a dysregulation of the immune system with the development of autoimmune phenomena. The consequence of this immune ...dysregulation ranges from the production of autoantibodies to the onset of rheumatic autoimmune disease. In this context, we conducted a systematic review to analyze the current data regarding the new-onset systemic and rheumatic autoimmune diseases in COVID-19 patients. A literature search in PubMed and Scopus databases from December 2019 to September 2021 identified 99 patients that fulfilled the specific diagnostic/classification criteria and/or nomenclature for each rheumatic autoimmune disease. The main diseases reported were vasculitis and arthritis. Idiopathic inflammatory myopathies, systemic lupus erythematosus, and sarcoidosis were also reported in a limited number of patients, as well as isolated cases of systemic sclerosis and adult-onset Still's disease. These findings highlight the potential spectrum of systemic and rheumatic autoimmune diseases that could be precipitated by SARS-CoV-2 infection. Complementary studies are needed to discern the link between the SARS-CoV-2 and new onset-rheumatic diseases so that this knowledge can be used in early diagnosis and the most suitable management.
Given a complete graph on~
n nodes with metric edge costs, the
minimum-cost
k-
hop spanning tree (
k
HMST) problem asks for a spanning tree of minimum total cost such that the longest root-leaf-path ...in the tree has at most
k edges. We present an algorithm that computes such a tree of total expected cost
O(
log
n)
times that of a minimum-cost
k-hop spanning-tree.
Role of POLE and POLD1 in familial cancer Mur, Pilar; García-Mulero, Sandra; Del Valle, Jesús ...
Genetics in medicine,
12/2020, Letnik:
22, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and ...exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study.
POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case-control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation.
Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome.
Polymerase proofreading-associated syndrome constitutes 0.1-0.4% of familial cancer cases, reaching 0.3-0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.
Different studies have demonstrated multiple effects of arsenite on human physiology. However, there are many open questions concerning the mechanism of response to arsenite. Schizosaccharomyces ...pombe activates the Sty1 MAPK pathway as a common response to several stress conditions. The specificity of the response is due to the activation of different transcription factors and specific targets such the Cmk2 MAPKAP kinase. We have previously shown that Cmk2 is phosphorylated and activated by the MAPK Sty1 in response to oxidative stress. Here, we report that Cmk2 kinase is specifically necessary to overcome the stress caused by metalloid agents, in particular arsenite. Deletion of cmk2 increases the protein level of various components of the MAPK pathway. Moreover, Cmk2 negatively regulates translation through the Cpc2 kinase: the RACK1 orthologue in fission yeast. RACK1 is a receptor for activated C-kinase. Interestingly, RACK1 is a constituent of the eukaryotic ribosome specifically localized in the head region of the 40 S subunit. Cmk2 controls arsenite response through Cpc2 and it does so through Cpc2 ribosomal function, as observed in genetic analysis using a Cpc2 mutant unable to bind to ribosome. These findings suggest a role for Cmk2 in regulating translation and facilitating adaptation to arsenite stress in the ribosome.
Display omitted
•The MAPKAP Cmk2 kinase is required for resistance to arsenite.•Loss of Cmk2 is lethal in arsenic stress conditions.•Deletion of Cmk2 increases the activity of the Hri2, the specific eIF2α kinase in response to arsenite.•A crosstalk between stress response and translation by Cmk2, through Cpc2 kinase, at the ribosome.
The cancer syndrome polymerase proofreading-associated polyposis results from germline mutations in the
POLE
and
POLD1
genes. Mutations in the exonuclease domain of these genes are associated with ...hyper- and ultra-mutated tumors with a predominance of base substitutions resulting from faulty proofreading during DNA replication. When a new variant is identified by gene testing of
POLE
and
POLD1
, it is important to verify whether the variant is associated with PPAP or not, to guide genetic counseling of mutation carriers. In 2015, we reported the likely pathogenic (class 4) germline
POLE
c.1373A > T p.(Tyr458Phe) variant and we have now characterized this variant to verify that it is a class 5 pathogenic variant. For this purpose, we investigated (1) mutator phenotype in tumors from two carriers, (2) mutation frequency in cell-based mutagenesis assays, and (3) structural consequences based on protein modeling. Whole-exome sequencing of two tumors identified an ultra-mutator phenotype with a predominance of base substitutions, the majority of which are C > T. A SupF mutagenesis assay revealed increased mutation frequency in cells overexpressing the variant of interest as well as in isogenic cells encoding the variant. Moreover, exonuclease repair yeast-based assay supported defect in proofreading activity. Lastly, we present a homology model of human POLE to demonstrate structural consequences leading to pathogenic impact of the p.(Tyr458Phe) mutation. The three lines of evidence, taken together with updated co-segregation and previously published data, allow the germline variant
POLE
c.1373A > T p.(Tyr458Phe) to be reclassified as a class 5 variant. That means the variant is associated with PPAP.
Actualmente en las industrias, la búsqueda de optimizar controladores de nivel en depósitos o tanques es uno de los requisitos más buscados. Gran parte de los procesos industriales cuentan con estos ...sistemas, bien para el bombeo de líquidos o su almacenamiento en tanques, un claro ejemplo es en sistemas de prevención como el almacenamiento de agua para incendios o para fines reutilizables como el tratamiento de aguas residuales. Teniendo en cuenta lo mencionado se tomará como objeto de estudio el control de nivel de agua en un tanque en el entorno Factory IO. La planta tendrá dos válvulas para el control de caudal, una de flujo constante y la otra de flujo variable. Primero se planteó el objetivo de control, establecer la estructura de control, identificación y descripción de elementos, obtener el modelo de la planta y diseñar el controlador. Para el control PID se usó la sintonización Ziegler Nichols. También se planteó la optimización de los parámetros PID por medio de algoritmos genéticos (AG), algoritmo de colonia de abejas (ABC), algoritmo de enjambre de partículas (PSO) y algoritmo de evolución diferencial. Esto algoritmos nos permitió comparar y analizar las diferentes respuestas del controlador en tiempos de establecimiento y sobreelongación para obtener los mejores resultados. Finalmente, los valores obtenidos para los algoritmos en tiempos de establecimiento: AG: 2.17seg, PSO: 8.04seg, ABC: 6.87seg, ED:7.69seg. Además, en términos de sobreelongación se obtuvo AG:1.24 %, PSO: 1.01, ABC: 6.87seg, ED:7.69seg.
Emergent bioelectronic technologies are underpinned by the organic electrochemical transistor (OECT), which employs an electrolyte medium to modulate the conductivity of its organic semiconductor ...channel. Here we utilize postpolymerization modification (PPM) on a conjugated polymer backbone to directly introduce glycolated or anionic side chains via fluoride displacement. The resulting polymers demonstrated increased volumetric capacitances, with subdued swelling, compared to their parent polymer in p-type enhancement mode OECTs. This increase in capacitance was attributed to their modified side chain configurations enabling cationic charge compensation for thin film electrochemical oxidation, as deduced from electrochemical quartz crystal microbalance measurements. An overall improvement in OECT performance was recorded for the hybrid glycol/ionic polymer compared to the parent, owing to its low swelling and bimodal crystalline orientation as imaged by grazing-incidence wide-angle X-ray scattering, enabling its high charge mobility at 1.02 cm2·V–1·s–1. Compromised device performance was recorded for the fully glycolated derivative compared to the parent, which was linked to its limited face-on stacking, which hindered OECT charge mobility at 0.26 cm2·V–1·s–1, despite its high capacitance. These results highlight the effectiveness of anionic side chain attachment by PPM as a means of increasing the volumetric capacitance of p-type conjugated polymers for OECTs, while retaining solid-state macromolecular properties that facilitate hole transport.
Genome‐scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high‐quality interpretation requires multiple ...specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health, is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen variant curation expert panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants.
ClinGen is organizing Variant Curation Expert Panels (VCEPs) to develop specifications to the ACMG/AMP guidelines for genes or diseases of interest, interpret variants according to these guidelines, and publish the expert interpretations through the publicly available ClinVar database. A stepwise process was iteratively developed for ClinGen VCEPs to apply to submit variant assertions to ClinVar at the Expert Panel level of review. Other groups that wish to assemble as VCEPs are encouraged, though not required, to follow these steps.
Simple synthetic routes, high active layer thickness tolerance as well as stable organic solar cells are relentlessly pursued as key enabling traits for the upscaling of organic photovoltaics. Here, ...the potential to address these issues by tuning donor polymer molecular weight is investigated. Specifically, the focus is on PTQ10, a polymer with low synthetic complexity, with number average molecular weights of 2.4, 6.2, 16.8, 52.9, and 54.4 kDa, in combination with three different non‐fullerene acceptors, namely Y6, Y12, and IDIC. Molecular weight, indeed, unlocks a threefold increase in power conversion efficiency for these blends. Importantly, efficiencies above 10% for blade coated devices with thicknesses between 200 and 350 nm for blends incorporating high molecular weight donor are shown. Spectroscopic, GIWAXS and charge carrier mobility data suggest that the strong photocurrent improvement with molecular weight is related to both, improved electronic transport and polymer contribution to exciton generation. Moreover, it is demonstrated that solar cells based on high molecular weight PTQ10 are more thermally stable due to a higher glass transition temperature, thus also improving device stability.
This work shows how increasing the molecular weight of a low synthetic complexity polymer, PTQ10, when paired with different acceptors yielded a notable threefold enhancement in power conversion efficiency. These high‐efficiency blends show good thickness tolerance, and exhibited both improved stability and efficiency, underscoring the potential of cost‐effective organic solar cells.
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