The mesh is a network of microtubule connectors that stabilizes individual kinetochore fibers of the mitotic spindle

Kinetochore fibers (K-fibers) of the mitotic spindle are force-generating units that power chromosome movement during mitosis. K-fibers are composed of many microtubules that are held together throughout their length. Here we show, using 3D electron microscopy, that K-fiber microtubules are connected by a network of microtubule connectors. We term this network 'the mesh'. The K-fiber mesh is made of linked multipolar connectors. Each connector has up to four struts, so that a single connector can link up to four microtubules. Molecular manipulation of the mesh by overexpression of TACC3 causes disorganization of the K-fiber microtubules. Optimal stabilization of K-fibers by the mesh is required for normal progression through mitosis. We propose that the mesh stabilizes K-fibers by pulling MTs together and thereby maintaining the integrity of the fiber. Our work thus identifies the K-fiber meshwork of linked multipolar connectors as a key integrator and determinant of K-fiber structure and function

Beta-3 adrenergic receptor blockade prevents alterations in feeding behavior in lymphoma-bearing mice in a sex-dependent manner

Introduction: Cancer cachexia is a metabolic syndrome defined by an ongoing loss of adipose and muscular tissue and is characterized by a reduced food intake. Local b-3 adrenergic receptor activation in adipose tissue induces lipolysis, whereas b-3 signaling in tumors has been shown to be tumorigenic in some cancer models. Therefore, b-3 signaling may be a therapeutic target in cancer cachexia. The aim of this study was to assess the role of b-3 adrenergic signaling in feeding behavior, body composition, and tumor progression in the L5178Y-R murine lymphoma model. Methods: In our study we used BALB/c mice of both sexes, which were divided in tumor-free and tumor-bearing groups. For the tumor model, L5178Y-R lymphoma cells were subcutaneously administered into animals right flank. These groups of mice intraperitoneally received L-748,337, a beta-3 antagonist, at a 50 mg/kg/day dose, starting the day after tumor implantation. Food and water intake were monitored every other day and body mass index (BMI) was calculated at the end of the experiment. Animals were euthanized for necropsy, when endpoint criteria were achieved. Transcriptional expression of Ucp-1, a molecular marker of thermogenesis, was quantified in interscapular adipose tissue. Results: We observed a 15% and 35% reduction in food intake in tumor-bearing male and female mice, respectively. This effect was not observed in male mice treated with the b-3 adrenergic receptor antagonist L-748,337. In females, such an effect persisted despite beta-3 blocking. Reduced water intake was also observed in tumor-bearing animals, which was not altered by beta-3 antagonism. We also observed that tumor-free mice of both sexes showed reduced water intake after L-748,337 treatment. Furthermore, reduced BMI was observed in tumor-bearing animals of both sexes, which was not changed by b-3 blocking. Interscapular adipose tissue loss was observed in females (51.06%) but not in males. Additionally, 1.7-fold and 4.4-fold reduction in Ucp-1 gene expression was shown in tumor-bearing males and females, respectively. Decreased final tumor weight was observed only in tumor-bearing females treated with L-748,337 (p \u3c 0.05). Conclusion: In L5178Y-R tumor-bearing BALB/c mice, selective blocking of beta-3 adrenergic signaling prevents alterations in food intake in a sex-dependent manner

Preparando el escenario para dejar de fumar en el paciente con Trastorno Bipolar: intervención breve en la práctica clínica

Tobacco consumption is the main preventable factor of mortality in smokers with bipolar disorder (BD), and any possible solutions are often blocked by prejudices over desire, and the possibilities and risks for these patients in giving up tobacco consumption. Adults with BD were recruited at 8 Mental Health Centres. Smokers were evaluated before and after a brief intervention based on the 3 A's and classified into a 'Stage of Change' (SOC) and their 'Readiness to Change' (RTC). A multiple linear regression was used to analyze the progression in their RTC and the independent effect of different variables (pharmacological treatment, history of psychotic symptoms, current anxiety symptoms, willingness, self-perceived capacity to quit smoking and subjective perception of cognitive functioning). Of 212 stable patients diagnosed with BD, current smokers (n=101; 47.6%) were included in the intervention phase, and 80.2% completed it. At baseline, 75.2% were considering the idea of giving up smoking and, after the brief intervention, 30.9% of the patients progressed in their SOC. A significant increase in the level of RTC was observed (53.3 vs 59.3, P=0.019). Perception of cognitive performance (β=-0.35;P=0.002), the degree of willing to quit (β=0.32;P=0.008), self-perceived capacity to quit tobacco smoking (β=-0.30;P=0.012), the patient's age (β=-0.72;P=0.004), the age of onset of smoking (β=0.48;P=0.022) and years as a smoker (β=0.48;P=0.025) were all factors that significantly influenced the chances of improving after the short intervention. Smokers with BD consider the idea of quitting and a brief intervention developed in the every day mental health care setting improves the level of readiness. The neurocognitive dysfunction associated with BD may limit patients' readiness to quit smoking.El consumo de tabaco es el principal factor prevenible de mortalidad en pacientes con trastorno bipolar (TB), y las posibles soluciones se encuentran bloqueadas por prejuicios acerca del deseo, posibilidades y riesgos al dejar el consumo de tabaco en estos pacientes. En 8 Centros de Salud Mental se reclutaron consecutivamente pacientes con TB. Los fumadores fueron evaluados antes y después de una intervención breve basada en las 3 As y clasificados según los “estadios de cambio” (EC) y su “disposición para el cambio” (DC). Mediante una regresión lineal múltiple se analizó la evolución del DC y su efecto sobre otras variables independientes (tratamiento farmacológico, historias de síntomas psicóticos, presencia de síntomas de ansiedad, deseo de abandono, capacidad auto-percibida y la percepción subjetiva de funcionamiento cognitivo). Se incluyeron 212 pacientes con TB estabilizados, los fumadores activos (n=101; 47.6%) pasaron a la fase de intervención, y un 80.2% la completaron. Basalmente, 75.2% consideraban la idea de dejar de fumar, después de la intervención breve, el 30.9% de los pacientes progresó en su EC. Se observó un incremento significativo del nivel de DC (53.3 vs 59.3, P=0.019). La autopercepción del rendimiento cognitivo (β=-0.35;P=0.002), el deseo de abandono (β=0.32;P=0.008), la autopercepción de la capacidad para dejar de fumar (β=-0.30;P=0.012), la edad del paciente (β=-0.72;P=0.004), la edad de inicio del tabaquismo (β=0.48;P=0.022) y los años fumando (β=0.48;P=0.025) fueron los factores que influyeron significativamente en la posibilidad de cambio tras la intervención breve. Los fumadores con TB consideran la idea de dejar de fumar y una intervención breve desarrollada en el marco de la atención a la salud mental diaria, mejoraría el nivel de preparación. La disfunción neurocognitiva asociada con el TB podría limitar la disposición de los pacientes a dejar de fumar

Basophil-lineage commitment in acute promyelocytic leukemia predicts for severe bleeding after starting therapy

Severe hemorrhagic events occur in a significant fraction of acute promyelocytic leukemia patients, either at presentation and/or early after starting therapy, leading to treatment failure and early deaths. However, identification of independent predictors for high-risk of severe bleeding at diagnosis, remains a challenge. Here, we investigated the immunophenotype of bone marrow leukemic cells from 109 newly diagnosed acute promyelocytic leukemia patients, particularly focusing on the identification of basophil-related features, and their potential association with severe bleeding episodes and patient overall survival. From all phenotypes investigated on leukemic cells, expression of the CD203c and/or CD22 basophil-associated markers showed the strongest association with the occurrence and severity of bleeding (p ≤ 0.007); moreover, aberrant expression of CD7, coexpression of CD34+/CD7+ and lack of CD71 was also more frequently found among patients with (mild and severe) bleeding at baseline and/or after starting treatment (p ≤ 0.009). Multivariate analysis showed that CD203c expression (hazard ratio: 26.4; p = 0.003) and older age (hazard ratio: 5.4; p = 0.03) were the best independent predictors for cumulative incidence of severe bleeding after starting therapy. In addition, CD203c expression on leukemic cells (hazard ratio: 4.4; p = 0.01), low fibrinogen levels (hazard ratio: 8.8; p = 0.001), older age (hazard ratio: 9.0; p = 0.002), and high leukocyte count (hazard ratio: 5.6; p = 0.02) were the most informative independent predictors for overall survival. In summary, our results show that the presence of basophil-associated phenotypic characteristics on leukemic cells from acute promyelocytic leukemia patients at diagnosis is a powerful independent predictor for severe bleeding and overall survival, which might contribute in the future to (early) risk-adapted therapy decisions.This work was supported by the Fundación Científica de la Asociación Española Contra el Cáncer (AECC, Madrid, Spain) and the Fundación Rafael del Pino (Madrid, Spain) and both CIBERONC (CB16/12/00400, CB16/12/00233, CB16/12/00480) and grant PI16/00787 from Instituto de Salud Carlos III (Ministerio de Economía y Competitividad, Madrid, Spain)

Standard comparison of local mental health care systems in eight European countries

Aims. There is a need of more quantitative standardised data to compare local Mental Health Systems (MHSs) across international jurisdictions. Problems related to terminological variability and commensurability in the evaluation of services hamper like-with-like comparisons and hinder the development of work in this area. This study was aimed to provide standard assessment and comparison of MHS in selected local areas in Europe, contributing to a better understanding of MHS and related allocation of resources at local level and to lessen the scarcity in standard service comparison in Europe. This study is part of the Seventh Framework programme REFINEMENT (Research on Financing Systems' Effect on the Quality of Mental Health Care in Europe) project. Methods. A total of eight study areas from European countries with different systems of care (Austria, England, Finland, France, Italy, Norway, Romania, Spain) were analysed using a standard open-access classification system (Description and Evaluation of Services for Long Term Care in Europe, DESDE-LTC). All publicly funded services universally accessible to adults (>= 18 years) with a psychiatric disorder were coded. Care availability, diversity and capacity were compared across these eight local MHS. Results. The comparison of MHS revealed more community-oriented delivery systems in the areas of England (Hampshire) and Southern European countries (Verona - Italy and Girona - Spain). Community-oriented systems with a higher proportion of hospital care were identified in Austria (Industrieviertel) and Scandinavian countries (Sor-Trondelag in Norway and Helsinki-Uusimaa in Finland), while Loiret (France) was considered as a predominantly hospital-based system. The MHS in Suceava (Romania) was still in transition to community care. Conclusions. There is a significant variation in care availability and capacity across MHS of local areas in Europe. This information is relevant for understanding the process of implementation of community-oriented mental health care in local areas. Standard comparison of care provision in local areas is important for context analysis and policy planning.Peer reviewe

Measurement of the Higgs boson width and evidence of its off-shell contributions to ZZ production

Since the discovery of the Higgs boson in 2012, detailed studies of its properties have been ongoing. Besides its mass, its width—related to its lifetime—is an important parameter. One way to determine this quantity is to measure its off-shell production, where the Higgs boson mass is far away from its nominal value, and relating it to its on-shell production, where the mass is close to the nominal value. Here we report evidence for such off-shell contributions to the production cross-section of two Z bosons with data from the CMS experiment at the CERN Large Hadron Collider. We constrain the total rate of the off-shell Higgs boson contribution beyond the Z boson pair production threshold, relative to its standard model expectation, to the interval [0.0061, 2.0] at the 95% confidence level. The scenario with no off-shell contribution is excluded at a p-value of 0.0003 (3.6 standard deviations). We measure the width of the Higgs boson as $\Gamma$$_H$=3.2$^{+2.4}_{−1.7}$MeV, in agreement with the standard model expectation of 4.1 MeV. In addition, we set constraints on anomalous Higgs boson couplings to W and Z boson pairs

Measurement of differential t(t)over-bar production cross sections in the full kinematic range using lepton plus jets events from proton-proton collisions at root s=13 TeV

Measurements of differential and double-differential cross sections of top-quark pair (t (t) over bar) production arc presented in the lepton + jets channels with a single electron or muon and jets in the final state. The analysis combines for the first time signatures of top quarks with low transverse momentum p(T), where the top-quark decay products can be identified as separated jets and isolated leptons, and with high p(T), where the decay products are collimated and overlap. The measurements arc based on proton-proton collision data at is - = 13 TeV collected by the CMS experiment at the LHC, corresponding to an integrated luminosity of 137 fb(-1). The cross sections are presented at the parton and particle levels, where the latter minimizes extrapolations based on theoretical assumptions. Most of the measured differential cross sections are well described by standard model predictions with the exception of some double-differential distributions. The inclusive t (t) over bar production cross section is measured to be sigma(t (t) over bar) = 791 +/- 25 pb, which constitutes the most precise measurement in the lepton + jets channel to date.Peer reviewe

Efficacy of clozapine versus standard treatment in adult individuals with intellectual disability and treatment-resistant psychosis (CLOZAID): study protocol of a multicenter randomized clinical trial

BackgroundIntellectual disability (ID) affects approximately 1% of the worldwide population and individuals with ID have a higher comorbidity with mental illness, and specifically psychotic disorders. Unfortunately, among individuals with ID, limited research has been conducted since ID individuals are usually excluded from mental illness epidemiological studies and clinical trials. Here we perform a clinical trial to investigate the effectiveness of clozapine in the treatment of resistant psychosis in individuals with ID. The article highlights the complexity of diagnosing and treating psychopathological alterations associated with ID and advocates for more rigorous research in this field.MethodsA Phase IIB, open-label, randomized, multicenter clinical trial (NCT04529226) is currently ongoing to assess the efficacy of oral clozapine in individuals diagnosed with ID and suffering from treatment-resistant psychosis. We aim to recruit one-hundred and fourteen individuals (N=114) with ID and resistant psychosis, who will be randomized to TAU (treatment as usual) and treatment-with-clozapine conditions. As secondary outcomes, changes in other clinical scales (PANSS and SANS) and the improvement in functionality, assessed through changes in the Euro-QoL-5D-5L were assessed. The main outcome variables will be analyzed using generalized linear mixed models (GLMM), assessing the effects of status variable (TAU vs. Clozapine), time, and the interaction between them.DiscussionThe treatment of resistant psychosis among ID individuals must be directed by empirically supported research. CLOZAID clinical trial may provide relevant information about clinical guidelines to optimally treat adults with ID and treatment-resistant psychosis and the benefits and risks of an early use of clozapine in this underrepresented population in clinical trials.Trial registrationClinicaltrials.gov: NCT04529226. EudraCT: 2020-000091-37