Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

8 figuras, 2 tablasBackground Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. Methodology/Principal Findings We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. Conclusion/Significance The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDPThis work has been supported by grants from Ministry of Education and Science (SAF2007-61701, SAF2010-15700, SAF2011-28603), Fundación Eugenio Rodríguez Pascual, and Basque Government (Saiotek program 2008–2009). NE holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

PHYSICAL TRAINING PROMOTES TELOMERE ELONGATION IN OBESE WOMEN

Introduction: While sedentary and obese individuals have shorter telomere lengths (TL) due to their inflammatory status, physical activity may be associated with longer TL. In line of this, physical activity may protect against the deleterious effects of obesity on shortening TL. This study aimed to evaluate the changes of TL of obese women submitted to a concurrent physical training intervention.Materials and Methods: This is a cross-sectional interventional study conducted with 7 obese (BMI>30 kg/m²) women (35.1±7 years). The concurrent exercise intervention (strength and aerobic) was performed for 8 weeks (3 times a week with high intensity). Anthropometric (weight, height and body mass index - BMI), body composition assessment (fat mass, by Deuterium oxide), blood collection for TL (by quantitative PCR) and inflammatory cytokines analysis (by Multiplex assays using Luminex) were performed before and after intervention. Shapiro-Wilk test, Wilcoxon test, and Spearman correlation were performed as statistical analyses (p<0.05).Results: There was a significant increase on TL after the intervention (0.007±0.008 to 0.084±0.1 T/S ratio; p=0.043) and a decrease of fat mass (40±4.9 to 38.2±5.8 kg, p=0.018). However, there were no significant weight loss (83.2±7.7 to 84.2±7.7 kg, p=0.204) or changes of cytokines (IL-6: 1.51±0.42 to 1.33±0.41; p=0.091; IL-10: 1.37±0.25 to 1.33±0.19; p=0.336; IL-4: 26.2±28.1 to 23.6±24.4; p=0.176; IL-1beta: 7.6±9.7 to 6.5±7.2; p=0.172; IL-17a: 1.15±0.15 to 1.1±0.1; p=0.317). Indeed, we observed a tendency for positive correlation between baseline TL and weight changes (r= 0.750; p=0.052). We did not find a correlation between TL and inflammatory biomarkers.Conclusion: Concurrent physical training intervention promotes telomere elongation in obese women, fat mass decrease, but the obesity inflammatory status is not associated with TL.Acknowledgements: National Council of Scientific and Technological Development (CNPq

Cross-country income mobility comparisons under panel attrition: the relevance of weighting schemes

This article aims to present an assessment of the effects of panel attrition on income mobility comparisons for some EU countries by using the European Community Household Panel (ECHP). There are different possibilities of correcting the attrition problem by means of alternative longitudinal weighting schemes. The sensitivity of mobility estimates to these attrition correction procedures is tested in this article. Our results show that ECHP attrition is characterized by a certain degree of selectivity but only affecting some variables and countries. Different probability models corroborate the existence of a certain nonrandom attrition. The model chosen to construct the longitudinal weights to correct attrition offers up rather different results than those obtained when Eurostat's longitudinal weights are used. Although attrition does not seem to have a great effect on aggregated mobility indicators, it does have a decisive effect on decomposition exercises. Our tests reveal certain sensitivity of income mobility measures to the weighting system used.

UCP1 and UCP3 Expression Is Associated with Lipid and Carbohydrate Oxidation and Body Composition.

BACKGROUND/OBJECTIVE:Uncoupling proteins (UCPs) are located in the inner membrane of mitochondria. These proteins participate in thermogenesis and energy expenditure. This study aimed to evaluate how UCP1 and UCP3 expression influences substrate oxidation and elicits possible changes in body composition in patients submitted to bariatric surgery. SUBJECTS/METHODS:This is a longitudinal study comprising 13 women with obesity grade III that underwent bariatric surgery and 10 healthy weight individuals (control group). Body composition was assessed by bioelectrical impedance. Carbohydrate and fat oxidation was determined by indirect calorimetry. Subcutaneous adipose tissue was collected for gene expression analysis. QPCR was used to evaluate UCP1 and UCP3 expression. RESULTS:Obese patients and the control group differed significantly in terms of lipid and carbohydrate oxidation. Six months after bariatric surgery, the differences disappeared. Lipid oxidation correlated with the percentage of fat mass in the postoperative period. Multiple linear regression analysis showed that the UCP1 and UCP3 genes contributed to lipid and carbohydrate oxidation. Additionally, UCP3 expression was associated with BMI, percentage of lean body mass, and percentage of mass in the postoperative period. CONCLUSIONS:UCP1 and UCP3 expression is associated with lipid and carbohydrate oxidation in patients submitted to bariatric surgery. In addition, UCP3 participates in body composition modulation six months postoperatively

UCP1 and UCP3 Expression Is Associated with Lipid and Carbohydrate Oxidation and Body Composition.

BACKGROUND/OBJECTIVE:Uncoupling proteins (UCPs) are located in the inner membrane of mitochondria. These proteins participate in thermogenesis and energy expenditure. This study aimed to evaluate how UCP1 and UCP3 expression influences substrate oxidation and elicits possible changes in body composition in patients submitted to bariatric surgery. SUBJECTS/METHODS:This is a longitudinal study comprising 13 women with obesity grade III that underwent bariatric surgery and 10 healthy weight individuals (control group). Body composition was assessed by bioelectrical impedance. Carbohydrate and fat oxidation was determined by indirect calorimetry. Subcutaneous adipose tissue was collected for gene expression analysis. QPCR was used to evaluate UCP1 and UCP3 expression. RESULTS:Obese patients and the control group differed significantly in terms of lipid and carbohydrate oxidation. Six months after bariatric surgery, the differences disappeared. Lipid oxidation correlated with the percentage of fat mass in the postoperative period. Multiple linear regression analysis showed that the UCP1 and UCP3 genes contributed to lipid and carbohydrate oxidation. Additionally, UCP3 expression was associated with BMI, percentage of lean body mass, and percentage of mass in the postoperative period. CONCLUSIONS:UCP1 and UCP3 expression is associated with lipid and carbohydrate oxidation in patients submitted to bariatric surgery. In addition, UCP3 participates in body composition modulation six months postoperatively

Dysfunctional family environment in affected versus unaffected offspring of parents with bipolar disorder

Objective: Children of parents with bipolar disorder (BD) are at heightened risk for developing mood and other psychiatric disorders. We proposed to evaluate the environment of families with at least one parent with BD type I (BDF) with affected offspring (aBDF) and unaffected offspring (uBDF) compared with control families without a history of DSM-IV Axis I disorder (CF).Method: We used the Family Environment Scale (FES) to evaluate 47 BDF (aBDF + uBDF) and 30 CF. Parents were assessed through the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Diagnosis of the offspring was determined through the Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version (K-SADS-PL) interview.Results: There were statistically significant differences between aBDF, uBDF and CF in cohesion (p = 0.003), intellectual-cultural orientation (p = 0.01), active-recreational orientation (p = 0.007), conflict (p = 0.001), control (p = 0.01), moral-religious emphasis (p = 0.01) and organization (p = 0.001). the aBDF showed higher levels of control (p = 0.02) when compared to the uBDF.Conclusions: Families with a BD parent presented more dysfunctional interactions among members. Moreover, the presence of BD or other psychiatric disorders in the offspring of parents with BD is associated with higher levels of control. These results highlight the relevance of psychosocial interventions to improve resilience and family interactions.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Alliance for Research on Schizophrenia and Depression (NARSAD)American Psychiatric Association/AstraZeneca Young Minds in Psychiatry International AwardsL'Oreal-ABC-Unesco - Para Mulheres na Ciencia, Brazil.Univ São Paulo, Sch Med, Dept Psychiat, Bipolar Res Program, São Paulo, BrazilUniv São Paulo, Sch Med, Dept Psychiat, Lab Psychiat Neuroimaging LIM 21, São Paulo, BrazilUniv São Paulo, Ctr Support Res Appl Neurosci, NAPNA, São Paulo, BrazilUniv Texas Med Sch, Dept Psychiat & Behav Sci, Houston, TX USAFed Univ São Paulo UNIFESP, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, São Paulo, BrazilWeb of Scienc

Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

Extracted text; Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/ß-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets