Polo kinase recruitment via the constitutive centromere-associated network at the kinetochore elevates centromeric RNA

The kinetochore, a multi-protein complex assembled on centromeres, is essential to segregate chromosomes during cell division. Deficiencies in kinetochore function can lead to chromosomal instability and aneuploidy-a hallmark of cancer cells. Kinetochore function is controlled by recruitment of regulatory proteins, many of which have been documented, however their function often remains uncharacterized and many are yet to be identified. To identify candidates of kinetochore regulation we used a proteome-wide protein association strategy in budding yeast and detected many proteins that are involved in post-translational modifications such as kinases, phosphatases and histone modifiers. We focused on the Polo-like kinase, Cdc5, and interrogated which cellular components were sensitive to constitutive Cdc5 localization. The kinetochore is particularly sensitive to constitutive Cdc5 kinase activity. Targeting Cdc5 to different kinetochore subcomplexes produced diverse phenotypes, consistent with multiple distinct functions at the kinetochore. We show that targeting Cdc5 to the inner kinetochore, the constitutive centromere-associated network (CCAN), increases the levels of centromeric RNA via an SPT4 dependent mechanism

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1–4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0–8·4) while the total sum of global YLDs increased from 562 million (421–723) to 853 million (642–1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6–9·2) for males and 6·5% (5·4–7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782–3252] per 100 000 in males vs s1400 [1279–1524] per 100 000 in females), transport injuries (3322 [3082–3583] vs 2336 [2154–2535]), and self-harm and interpersonal violence (3265 [2943–3630] vs 5643 [5057–6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

Search for long-lived heavy neutral leptons with lepton flavour conserving or violating decays to a jet and a charged lepton

A preprint version of the article is available at arXiv:2312.07484v3 [hep-ex], https://arxiv.org/abs/2312.07484 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/EXO-21-013 (CMS Public Pages)A search for long-lived heavy neutral leptons (HNLs) is presented, which considers the hadronic final state and coupling scenarios involving all three lepton generations in the 2-20 GeV HNL mass range for the first time. Events comprising two leptons (electrons or muons) and jets are analyzed in a data sample of proton-proton collisions, recorded with the CMS experiment at the CERN LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb−1. A novel jet tagger, based on a deep neural network, has been developed to identify jets from an HNL decay using various features of the jet and its constituent particles. The network output can be used as a powerful discriminating tool to probe a broad range of HNL lifetimes and masses. Contributions from background processes are determined from data. No excess of events in data over the expected background is observed. Upper limits on the HNL production cross section are derived as functions of the HNL mass and the three coupling strengths VℓN to each lepton generation ℓ and presented as exclusion limits in the coupling-mass plane, as lower limits on the HNL lifetime, and on the HNL mass. In this search, the most stringent limit on the coupling strength is obtained for pure muon coupling scenarios; values of |VμN|2 > 5 (4) × 10−7 are excluded for Dirac (Majorana) HNLs with a mass of 10 GeV at a confidence level of 95% that correspond to proper decay lengths of 17 (10) mm.SCOAP3

Teoria da resposta ao item aplicada ao Inventário de Depressão Beck Item response theory applied to the Beck Depression Inventory

O Inventário de Depressão Beck (BDI), uma escala que mede o traço latente de intensidade de sintomas depressivos, pode ser avaliado através da Teoria da Resposta ao Item (TRI). Este estudo utilizou o modelo TRI de Resposta Gradual na avaliação da intensidade de sintomas depressivos de 4.025 indivíduos que responderam ao BDI, de modo a explorar eficientemente a informação disponível nos diferentes aspectos possibilitados pelo uso desta metodologia. O ajuste foi efetuado no software PARSCALE. Foram identificados 13 itens do BDI nos quais pelo menos uma categoria de resposta não tinha chance maior que as demais de ser escolhida, de modo que estes itens tiveram de ser recategorizados. Os itens com maior capacidade de discriminação são relativos à tristeza, pessimismo, sentimento de fracasso, insatisfação, auto-aversão, indecisão e dificuldade para trabalhar. Os itens mais graves são aqueles relacionados com perda de peso, retraimento social e idéias suicidas. O grupo dos 202 indivíduos com as maiores intensidades de sintomas depressivos foi composto por 74% de mulheres, e praticamente 84% possuíam diagnóstico de algum transtorno psiquiátrico. Os resultados evidenciam alguns dos inúmeros ganhos advindos da utilização da TRI na análise de traços latentes.<br>The Beck Depression Inventory (BDI), a scale that measures the latent trait intensity of depression symptoms, can be assessed by the Item Response Theory (IRT). This study used the Graded-Response model (GRM) to assess the intensity of depressive symptoms in 4,025 individuals who responded to the BDI, in order to efficiently use the information available on different aspects enabled by the use of this methodology. The fit of this model was done in PARSCALE software. We identified 13 items of the BDI in which at least one response category was not more likely than others to be chosen, so that these items had to be categorized again. The items with greater power of discrimination were sadness, pessimism, feeling of failure, dissatisfaction, self-hatred, indecision, and difficulty of work. The most serious items were weight loss, suicidal ideas, and social withdrawal. The group of 202 individuals with the highest levels of depressive symptoms was comprised by 74% of women and almost 84% had a diagnosis of a psychiatric disorder. The results show gains resulting from use of IRT in the analysis of latent traits