The Epstein-Barr virus BamHI C promoter is not essential for B cell immortalization in vitro, but it greatly enhances B cell growth transformation

Epstein-Barr virus (EBV) infection of B cells leads to the sequential activation of two viral promoters, Wp and Cp, resulting in the expression of six EBV nuclear antigens (EBNAs) and the viral Bcl2 homologue BHRF1. The viral transactivator EBNA2 is required for this switch from Wp to Cp usage during the initial stages of infection. EBNA2-dependent Cp transcription is mediated by the EBNA2 response element (E2RE), a region that contains at least two binding sites for cellular factors; one of these sites, CBF1, interacts with RBP-JK, which then recruits EBNA2 to the transcription initiation complex. Here we demonstrate that the B cell-specific transcription factor BSAP/Pax5 binds to a second site, CBF2, in the E2RE. Deletion of the E2RE in the context of a recombinant virus greatly diminished levels of Cp-initiated transcripts during the initial stages of infection but did not affect the levels of Wp-initiated transcripts or EBNA mRNAs. Consistent with this finding, viruses deleted for the E2RE were not markedly impaired in their ability to induce B cell transformation in vitro. In contrast, a larger deletion of the entire Cp region did reduce EBNA mRNA levels early after infection and subsequently almost completely ablated lymphoblastoid cell line (LCL) outgrowth. Notably, however, rare LCLs could be established following infection with Cp-deleted viruses, and these were indistinguishable from wild-type-derived LCLs in terms of steady-state EBV gene transcription. These data indicate that, unlike Wp, Cp is dispensable for the virus' growth-transforming activity. IMPORTANCE Epstein-Barr virus (EBV), a B lymphotropic herpesvirus etiologically linked to several B cell malignancies, efficiently induces B cell proliferation leading to the outgrowth of lymphoblastoid cell lines (LCLs). The initial stages of this growth-transforming infection are characterized by the sequential activation of two viral promoters, Wp and Cp, both of which appear to be preferentially active in target B cells. In this work, we have investigated the importance of Cp activity in initiating B cell proliferation and maintaining LCL growth. Using recombinant viruses, we demonstrate that while Cp is not essential for LCL outgrowth in vitro, it enhances transformation efficiency by >100-fold. We also show that Cp, like Wp, interacts with the B cell-specific activator protein BSAP/Pax5. We suggest that EBV has evolved this two-promoter system to ensure efficient colonization of the host B cell system in vivo

Diferencias intra e inter individuales en inteligencia social de estudiantes portugueses

Social intelligence is a favorable condition for career decision-making and development. The social intelligence indices of Portuguese students in school years prior to a career transition are characterized and intra and interindividual differences are analyzed. Participants were 1095 students (552, 50.4% women) with a mean age of 14.78 years (SD = 1.86), in the 8th (542, 49.5%), 10th (295, 26.9%) and 11th (258, 23.6%) grades. The Cognitive Test of Social Intelligence (PCIS) was administered at two moments, six months apart. Results indicate that the 8th grade obtained higher average scores in Problem Solving, Motivation and Self-confidence (time 1), while the 10th grade obtained better results in Problem Solving, Motivation and Familiarity (time 2). Between the assessment moments, all school years register an increase in Problem Solving and Self-confidence in social situations. These results constitute favorable psychological conditions for the promotion of ethical questioning in career guidance interventions.A inteligência social constitui uma condição favorável à tomada de decisão e ao desenvolvimento vocacional. Este trabalho visa caracterizar os níveis de inteligência social, e analisar as diferenças intra e interindividuais, em alunos portugueses em anos de pré-transição vocacional. Participaram 1095 alunos (552, 50% mulheres), com uma média de idades de 14,78 anos (DP = 1,86), do 8º, 10º, e 11º níveis escolares. Administrou-se a Prova Cognitiva de Inteligência Social (PCIS), em dois momentos (T1 e T2), com seis meses de intervalo. Os resultados indicam que o 8º ano obteve resultados médios superiores, nos índices de Resolução de Problemas, Motivação e Autoconfiança (T1), enquanto o 10º ano obteve resultados superiores, em Resolução de Problemas, Motivação e Familiaridade (T2). Entre momentos de avaliação, registra-se, para todos os níveis escolares, um aumento em Resolução de Problemas e Autoconfiança em situações sociais. Estes resultados constituem condições psicológicas favoráveis à promoção do questionamento ético nas intervenções de orientação vocacional.La inteligencia social es una condición favorable para la toma de decisiones y el desarrollo de la carrera. Se caracterizan los niveles de inteligencia social y sus diferencias intra e interindividuales en estudiantes portugueses en transición pre-profesional. Participaron 1095 estudiantes (552, 50.4% mujeres) con una edad media de 14.78 (DE = 1.86), del 8º (542, 49,5%), 10º (295, 26.9%) y 11º (258, 23.6%) años escolares. Se administró la Prueba Cognitiva de Inteligencia Social (PCIS) en dos ocasiones, con seis meses de diferencia. Los resultados indican que los estudiantes del 8º grado obtuvieron puntajes medios más altos en la Resolución de Problemas, Motivación y Confianza (T1), mientras que los del 10º grado obtuvieron mejores resultados en la Resolución de Problemas, Motivación y Familiaridad (T2). Entre momentos de evaluación se registra, para todos los años, un aumento en la Resolución de Problemas y Confianza en situaciones sociales. Estos resultados constituyen condiciones psicológicas favorables a la promoción del cuestionamiento ético en las intervenciones de orientación profesional.Project coordinated by the fourth author and co-funded by the Foundation for Science and Technology and the Compete Program - PTDC/CPE-CED/098896/200

The potential-dependent structure of Pt3Ni alloy electrocatalysts and its effect on electrocatalytic activity

NWOECCM.TT.ECCM.001Catalysis and Surface Chemistr

Genetic variation in the myeloperoxidase gene and cognitive impairment in Multiple Sclerosis

There is evidence that multiple sclerosis (MS) may associated with cognitive impairment in 25 to 40% of cases. The gene encoding myeloperoxidase (MPO) is involved in molecular pathways leading to β-amyloid deposition. We investigated a functional biallelic (G/A) polymorphism in the promoter region (-463) of the MPO gene in 465 patients affected by MS, divided into 204 cognitively normal and 261 impaired. We did not find significant differences in allele or genotype distributions between impaired and preserved MS patients. Our findings suggest that MPO polymorphism is not a risk factor for cognitive impairment in MS

Gout incidence and management during the COVID-19 pandemic in England, UK: a nationwide observational study using OpenSAFELY

BackgroundGout is the most prevalent inflammatory arthritis, yet one of the worst managed. Our objective was to assess how the COVID-19 pandemic impacted incidence and quality of care for people with gout in England, UK.MethodsWith the approval of National Health Service England, we did a population-level cohort study using primary care and hospital electronic health record data for 17·9 million adults registered with general practices using TPP health record software, via the OpenSAFELY platform. The study period was from March 1, 2015, to Feb 28, 2023. Individuals aged 18–110 years were defined as having incident gout if they were assigned index diagnostic codes for gout, were registered with TPP practices in England for at least 12 months before diagnosis, did not receive prescriptions for urate-lowering therapy more than 30 days before diagnosis, and had not been admitted to hospital or attended an emergency department for gout flares more than 30 days before diagnosis. Outcomes assessed were incidence and prevalence of people with recorded gout diagnoses, incidence of gout hospitalisations, initiation of urate-lowering therapy, and attainment of serum urate targets (≤360 μmol/L).FindingsFrom a reference population of 17 865 145 adults, 246 695 individuals were diagnosed with incident gout. The mean age of individuals with incident gout was 61·3 years (SD 16·2). 66 265 (26·9%) of 246 695 individuals were female, 180 430 (73·1%) were male, and 189 035 (90·9%) of 208 050 individuals with available ethnicity data were White. Incident gout diagnoses decreased by 30·9% in the year beginning March, 2020, compared with the preceding year (1·23 diagnoses vs 1·78 diagnoses per 1000 adults). Gout prevalence was 3·07% in 2015–16, and 3·21% in 2022–23. Gout hospitalisations decreased by 30·1% in the year commencing March, 2020, compared with the preceding year (9·6 admissions vs 13·7 admissions per 100 000 adults). Of 228 095 people with incident gout and available follow-up, 66 560 (29·2%) were prescribed urate-lowering therapy within 6 months. Of 65 305 individuals who initiated urate-lowering therapy with available follow-up, 16 790 (25·7%) attained a serum urate concentration of 360 μmol/L or less within 6 months of urate-lowering therapy initiation. In interrupted time-series analyses, urate-lowering therapy prescribing improved modestly during the pandemic, compared with pre-pandemic, whereas urate target attainment was similar.InterpretationUsing gout as an exemplar disease, we showed the complexity of how health care was impacted during the COVID-19 pandemic. We observed a reduction in gout diagnoses but no effect on treatment metrics. We showed how country-wide, routinely collected data can be used to map disease epidemiology and monitor care quality

Albumin and multiple sclerosis

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Leakage of the blood–brain barrier (BBB) is a common pathological feature in multiple sclerosis (MS). Following a breach of the BBB, albumin, the most abundant protein in plasma, gains access to CNS tissue where it is exposed to an inflammatory milieu and tissue damage, e.g., demyelination. Once in the CNS, albumin can participate in protective mechanisms. For example, due to its high concentration and molecular properties, albumin becomes a target for oxidation and nitration reactions. Furthermore, albumin binds metals and heme thereby limiting their ability to produce reactive oxygen and reactive nitrogen species. Albumin also has the potential to worsen disease. Similar to pathogenic processes that occur during epilepsy, extravasated albumin could induce the expression of proinflammatory cytokines and affect the ability of astrocytes to maintain potassium homeostasis thereby possibly making neurons more vulnerable to glutamate exicitotoxicity, which is thought to be a pathogenic mechanism in MS. The albumin quotient, albumin in cerebrospinal fluid (CSF)/albumin in serum, is used as a measure of blood-CSF barrier dysfunction in MS, but it may be inaccurate since albumin levels in the CSF can be influenced by multiple factors including: 1) albumin becomes proteolytically cleaved during disease, 2) extravasated albumin is taken up by macrophages, microglia, and astrocytes, and 3) the location of BBB damage affects the entry of extravasated albumin into ventricular CSF. A discussion of the roles that albumin performs during MS is put forth

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (OR = 46.5, p = 1.74 × 10). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)