Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency.

Respiratory chain complexes assemble into functional quaternary structures called supercomplexes (RCS) within the folds of the inner mitochondrial membrane, or cristae. Here, we investigate the relationship between respiratory function and mitochondrial ultrastructure and provide evidence that cristae shape determines the assembly and stability of RCS and hence mitochondrial respiratory efficiency. Genetic and apoptotic manipulations of cristae structure affect assembly and activity of RCS in vitro and in vivo, independently of changes to mitochondrial protein synthesis or apoptotic outer mitochondrial membrane permeabilization. We demonstrate that, accordingly, the efficiency of mitochondria-dependent cell growth depends on cristae shape. Thus, RCS assembly emerges as a link between membrane morphology and function.

SPLICE-q: a Python tool for genome-wide quantification of splicing efficiency.

BACKGROUND: Introns are generally removed from primary transcripts to form mature RNA molecules in a post-transcriptional process called splicing. An efficient splicing of primary transcripts is an essential step in gene expression and its misregulation is related to numerous human diseases. Thus, to better understand the dynamics of this process and the perturbations that might be caused by aberrant transcript processing it is important to quantify splicing efficiency. RESULTS: Here, we introduce SPLICE-q, a fast and user-friendly Python tool for genome-wide SPLICing Efficiency quantification. It supports studies focusing on the implications of splicing efficiency in transcript processing dynamics. SPLICE-q uses aligned reads from strand-specific RNA-seq to quantify splicing efficiency for each intron individually and allows the user to select different levels of restrictiveness concerning the introns' overlap with other genomic elements such as exons of other genes. We applied SPLICE-q to globally assess the dynamics of intron excision in yeast and human nascent RNA-seq. We also show its application using total RNA-seq from a patient-matched prostate cancer sample. CONCLUSIONS: Our analyses illustrate that SPLICE-q is suitable to detect a progressive increase of splicing efficiency throughout a time course of nascent RNA-seq and it might be useful when it comes to understanding cancer progression beyond mere gene expression levels. SPLICE-q is available at: https://github.com/vrmelo/SPLICE-q.

Shaping the role of mitochondria in the pathogenesis of Huntington's disease.

Intense research on the pathogenesis of Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, revealed multiple potential mechanisms, among which mitochondrial alterations had emerged as key determinants of the natural history of the disease. Pharmacological and genetic animal models of mitochondrial dysfunction in the striatum, which is mostly affected in HD corroborated a key role for these organelles in the pathogenesis of the disease. Here, we will give an account of the recent evidence indicating that the mitochondria-shaping machinery is altered in HD models and patients. Since its correction can counteract HD mitochondrial dysfunction and cellular damage, drugs impacting on mitochondrial shape are emerging as a new possibility of treatment for this devastating condition.

Role of adult hippocampal neurogenesis in cognition in physiology and disease: pharmacological targets and biomarkers.

Adult hippocampal neurogenesis is a remarkable form of brain structural plasticity by which new functional neurons are generated from adult neural stem cells/precursors. Although the precise role of this process remains elusive, adult hippocampal neurogenesis is important for learning and memory and it is affected in disease conditions associated with cognitive impairment, depression, and anxiety. Immature neurons in the adult brain exhibit an enhanced structural and synaptic plasticity during their maturation representing a unique population of neurons to mediate specific hippocampal function. Compelling preclinical evidence suggests that hippocampal neurogenesis is modulated by a broad range of physiological stimuli which are relevant in cognitive and emotional states. Moreover, multiple pharmacological interventions targeting cognition modulate adult hippocampal neurogenesis. In addition, recent genetic approaches have shown that promoting neurogenesis can positively modulate cognition associated with both physiology and disease. Thus the discovery of signaling pathways that enhance adult neurogenesis may lead to therapeutic strategies for improving memory loss due to aging or disease. This chapter endeavors to review the literature in the field, with particular focus on (1) the role of hippocampal neurogenesis in cognition in physiology and disease; (2) extrinsic and intrinsic signals that modulate hippocampal neurogenesis with a focus on pharmacological targets; and (3) efforts toward novel strategies pharmacologically targeting neurogenesis and identification of biomarkers of human neurogenesis.

Evaluation of the dietary inflammatory index in children and adolescents with type 1 diabetes mellitus and its relationship with nutritional status and metabolic control.

OBJECTIVES: The aim of this study was to evaluate the association of the dietary inflammatory index (DII) with the nutritional status and metabolic control of children and adolescents with type 1 diabetes mellitus. METHODS: This was a cross-sectional study that examined data of children and adolescents ages 7 to 16 y diagnosed with type 1 diabetes mellitus. Dietary intake was assessed using a 24-h dietary recall, from which the DII was calculated. The outcomes were body mass index, lipid profiles (low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol), and glycated hemoglobin. The DII was evaluated in tertiles and in a continuous way. Multiple linear regression was adopted in the analysis, with P < 0.05 considered significant. RESULTS: Overall, 120 children and adolescents with a mean age of 11.7 (± 2.8) y were included, 53.3% (n = 64) of whom were girls. Excess weight was present in 31.7% participants (n = 38). The average DII was +0.25, ranging from -1.11 to +2.67. Higher values of selenium (P = 0.011), zinc (P = 0.001), fiber (P < 0.001), and other micronutrients were observed in the first tertile of the DII (diet with more antiinflammatory potential). The DII appeared as a predictor of body mass index (P = 0.002; ß = 0.23; 95% confidence interval [CI], 0.39-1.75) and non-high-density lipoprotein cholesterol (P = 0.034; ß = 0.19; 95% CI, -13.5 to 0.55). There was a tendency for DII to be associated with glycemic control (P = 0.09; ß = 0.19; 95% CI, -0.04 to 0.51). CONCLUSIONS: The inflammatory potential of the diet was associated with increased body mass index and aspects related to metabolic control in children and adolescents with type 1 diabetes mellitus.

Cancer Impacts Prognosis on Mortality in Patients with Acute Heart Failure: Analysis of the EPICTER Study.

INTRODUCTION: Heart failure (HF) and cancer are currently the leading causes of death worldwide, with an increasing incidence with age. Little is known about the treatment received and the prognosis of patients with acute HF and a prior cancer diagnosis. OBJECTIVE: to determine the clinical characteristics, palliative treatment received, and prognostic impact of patients with acute HF and a history of solid tumor. METHODS: The EPICTER study ("Epidemiological survey of advanced heart failure") is a cross-sectional, multicenter project that consecutively collected patients admitted for acute HF in 74 Spanish hospitals. Patients were classified into two groups according to whether they met criteria for acute HF with and without solid cancer, and the groups were subsequently compared. A multivariable logistic regression analysis was conducted, using the forward stepwise method. A Kaplan-Meier survival analysis was performed to evaluate the impact of solid tumor on prognosis in patients with acute HF. RESULTS: A total of 3127 patients were included, of which 394 patients (13%) had a prior diagnosis of some type of solid cancer. Patients with a history of cancer presented a greater frequency of weight loss at admission: 18% vs. 12% (p = 0.030). In the cancer group, functional impairment was noted more frequently: 43% vs. 35%, p = 0.039). Patients with a history of solid cancer more frequently presented with acute HF with preserved ejection fraction (65% vs. 58%, p = 0.048) than reduced or mildly reduced. In-hospital and 6-month follow-up mortality was 31% (110/357) in patients with solid cancer vs. 26% (637/2466), p = 0.046. CONCLUSION: Our investigation demonstrates that in-hospital mortality and mortality during 6-month follow-up in patients with acute HF were higher in those subjects with a history of concomitant solid tumor cancer diagnosis.

Determinants of ultra-processed food consumption in Brazilian children and adolescents with type 1 diabetes mellitus: a cross-sectional study.

OBJECTIVES: To analyze the determinants of UPP consumption among children and adolescents with type 1 diabetes mellitus. METHODS: Cross-sectional study at a reference hospital for the treatment of diabetes in Rio de Janeiro, Brazil. The sociodemographic, anthropometric, dietary, and clinical factors associated with the percentage of total energy intake (TEI) consumed in the form of UPP were investigated. Food consumption was assessed by 24 h recall and the foods were classified according to the degree of processing as described in the NOVA classification, after which the TEI of each food group was calculated. Multiple linear regression was adopted in the analysis, and associations with p<0.05 were considered significant. RESULTS: The study included 120 children and adolescents with a mean age of 11.74 ± 2.88 years, 53.3% female. Body mass index z-score was 0.65 (± 0.89) and 31.7% (n=38) were overweight. The average total energy consumption was 1,756.38 kcal (± 518.38). The mean percentage of TEI from UPP was 24.2% ± 17.9, meaning that 425.59 kcal (± 380.15) of all calories ingested came from such foods. The independent variables associated with the percentage of ultra-processed foods (UPP) in TEI were: per capita household income up to one the minimum wage (ß: -22.03; CI 95% -35.24 to -8.82); and parents/guardians schooling of the up to nine years in formal education (ß: 19.86; CI 95% 8.27-31.45). CONCLUSIONS: Lower household income and fewer years in formal education seem to determine a preference for UPP over fresh and minimally processed foods.

Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A, a ubiquitin protein ligase E3A. Here, we study neurons derived from patients with AS and neurotypical individuals, and reciprocally modulate UBE3A using antisense oligonucleotides. Unbiased proteomics reveal proteins that are regulated by UBE3A in a disease-specific manner, including PEG10, a retrotransposon-derived GAG protein. PEG10 protein increase, but not RNA, is dependent on UBE3A and proteasome function. PEG10 binds to both RNA and ataxia-associated proteins (ATXN2 and ATXN10), localizes to stress granules, and is secreted in extracellular vesicles, modulating vesicle content. Rescue of AS patient-derived neurons by UBE3A reinstatement or PEG10 reduction reveals similarity in transcriptome changes. Overexpression of PEG10 during mouse brain development alters neuronal migration, suggesting that it can affect brain development. These findings imply that PEG10 is a secreted human UBE3A target involved in AS pathophysiology.

Oral midazolam as pre-anesthetic medication in children and teenagers with cerebral palsy. A comparative study on the variations of the bispectral index.

BACKGROUND AND OBJECTIVES: Midazolam is a benzodiazepine with hypnotic action widely used as pre-anesthetic medication in pediatric anesthesia. Children with cerebral palsy (CP) also benefit from the use of midazolam, but its effects on this group of patients, who present several particularities, including changes at the site of action of midazolam, are still unknown. The objective of this study was to evaluate the effects of midazolam, when used as pre-anesthetic medication, on the bispectral index (EEG-BIS) of patients with cerebral palsy. METHODS: Two groups of patients were evaluated: one group with the diagnosis of CP and the other without central and peripheral nervous system disorders. The EEG-BIS was recorded in the room, the day before the surgery and at the day of the surgery, 40 minutes after the administration of 0.6 mg.kg(-1) of oral midazolam. Patients with a history of paradoxal reaction to midazolam as well as patients in the control group who were using other medications were excluded. RESULTS: Seventy-seven patients of both genders, 4 to 18 years old, participated in this study. Differences in EEG-BIS between both groups were not detected. After the use of midazolam EEG-BIS decreased in both groups with a statistically significant difference in each group. Statistically significant intergroup differences were not observed. CONCLUSIONS: Midazolam, used as pre-anesthetic medication, at a dose of 0.6 mg.kg(-1), reduced basal EEG-BIS without characterizing hypnosis and without statistically significant differences between the study groups.

A Service-Oriented Platform for Approximate Bayesian Computation in Population Genetics.

Approximate Bayesian computation (ABC) is a useful technique developed for solving Bayesian inference without explicitly requiring a likelihood function. In population genetics, it is widely used to extract part of the information about the evolutionary history of genetic data. The ABC compares the summary statistics computed on simulated and observed data sets. Typically, a forward-in-time approach is used to simulate the genetic material of a population starting from an initial ancestral population and following the evolution of the individuals by advancing generation by generation under various demographic and genetic forces. This approach is computationally expensive and requires a large number of computations making the use of high-performance computing crucial for decreasing the overall response times. In this work, we propose a fully distributed web service-oriented platform for ABC that is based on forward-in-time simulations. Our proposal is based on a client-server approach. The client enables users to define simulation scenarios. The server enables efficient and scalable population simulations and can be deployed on a distributed cluster of processors or even in the cloud. It is composed of four services: a workload generator, a simulation controller, a simulation results analyzer, and a result builder. The server performs multithread simulations by executing a simulation kernel encapsulated in a proposed libgdrift library. We present and evaluate three different libgdrift library approaches whose algorithms aim to reduce execution times and memory consumption.

Patients with sequelae of poliomyelitis. Does the anesthetic technique impose risks?

BACKGROUND AND OBJECTIVES: Several questions arise before performing neuro-axis block in patients with sequelae of poliomyelitis. Reports in the literature are scarce. The objective of this study was to describe the anesthetic techniques used in patients undergoing surgeries and possible complications. METHODS: We undertook a retrospective study of patients with sequelae of poliomyelitis who underwent surgeries during a five-year period. Demographic data, physical status (ASA), onset of the disease, body part affected, diagnosis of post-poliomyelitis syndrome, surgeries and type anesthesia used, postoperative analgesia, intra- and postoperative complications, outpatient follow-up, and development of neurological changes were evaluated. RESULTS: One-hundred and twenty-three patients who underwent 162 surgical procedures were evaluated. Most patients (n = 82; 66.6%) had neurological sequela in a lower limb. Patients developed acute poliomyelitis at approximately 28 months of age. Orthopedic surgery was performed in 87.7% of patients. Neuro-axis block was used in 64.1% of the cases; epidural block was more frequent. Intraoperative complications reported included: accidental puncture of the dura-mater (n = 1; 0.61%), bradycardia (n = 1; 0.61%), hypotension (n = 2; 1.23%), and apnea and thoracic rigidity (n = 1; 0.61%). Postoperative complications included: vomiting (n = 2; 1.23%), urinary retention (n = 4; 2.64%), and complex regional pain syndrome type 1 (n = 2; 1.23%). Patients were followed for 22 months and worsening of the neurological disorder was not observed. CONCLUSIONS: Patients with sequelae of poliomyelitis who underwent neuro-axis block did not develop any postoperative complications or worsening of their neurological status that could be attributed to the anesthetic technique used.

Thoracic epidural block performed safely in anesthetized patients. A study of a series of cases.

BACKGROUND AND OBJECTIVES: The development of paraplegia following the insertion of epidural catheter in anesthetized patients raised questions by some authors about the procedure, even without the confirmation that the lesion occurred because the patient was anesthetized. For this reason, we designed this study, with the objective to evaluate the frequency of neurological complications and development of sequelae after thoracic epidural block in patients under general anesthesia. METHODS: Patients undergoing thoracic surgeries from 02/16/2004 to 05/30/2006 participated in the study. After monitoring vital signs and the installation of general anesthesia, patients were placed in lateral decubitus for simple or continuous thoracic epidural block. Intercurrences, complications, and technical difficulties were recorded on a special form. Patients were followed postoperatively to detect the development of any signs and symptoms of neurological dysfunction. RESULTS: One hundred and thirteen patients were evaluated and the thoracic epidural catheter was placed in 108 patients. The puncture was considered traumatic, i.e., bleeding at the puncture site and multiple punctures, in 45 patients. Accidental perforation of the dura-mater occurred in two patients. In the immediate postoperative period, a patient complained of tingling in the lower limbs, another patient developed numbness in an upper limb, which resolved after the catheter was removed. Both patients had a single puncture. The other patients did not develop any signs or symptoms of neurologic changes. CONCLUSIONS: The cases studied here did not develop any neurologic complications. When performed judiciously and with specific care, thoracic epidural block can be safely done in the anesthetized patient.

Postoperative urinary retention: evaluation of patients using opioids analgesic.

The study aimed to determine the occurrence of urinary retention in patients using opioid analgesic and to describe the method used for vesical relief. A prospective and consecutive series of 1,316 patients undergoing surgery from September 1999 to April 2003 and using opioids post surgery were studied. From the 1,136 patients, 594 did not use urinary catheters pre-surgery. From these 594 patients, 128 (22%) suffered post operative urinary retention. Urinary retention was significantly related to the use of continuous epidural analgesia (p=0.009). About 69% of patients experiencing urinary retention post surgery returned to spontaneous micturition following a single catheterization. The incidence found of urinary retention was similar to the literature, more frequent in men who received continuous epidural analgesia. The findings suggest orientation and careful nursing team observation of post operative micturition, emphasizing the intermittent aseptically catheterization for urinary retention in order to prevent potential complications of the urinary tract.

Serial interactome capture of the human cell nucleus.

Novel RNA-guided cellular functions are paralleled by an increasing number of RNA-binding proteins (RBPs). Here we present 'serial RNA interactome capture' (serIC), a multiple purification procedure of ultraviolet-crosslinked poly(A)-RNA-protein complexes that enables global RBP detection with high specificity. We apply serIC to the nuclei of proliferating K562 cells to obtain the first human nuclear RNA interactome. The domain composition of the 382 identified nuclear RBPs markedly differs from previous IC experiments, including few factors without known RNA-binding domains that are in good agreement with computationally predicted RNA binding. serIC extends the number of DNA-RNA-binding proteins (DRBPs), and reveals a network of RBPs involved in p53 signalling and double-strand break repair. serIC is an effective tool to couple global RBP capture with additional selection or labelling steps for specific detection of highly purified RBPs.

Overweight among children and adolescent with type I diabetes mellitus: prevalence and associated factors.

OBJECTIVES: Describe the overweight frequency (overweight and obesity) and identify the factors associated with this in children and adolescents with type 1 diabetes mellitus (T1DM) treated at a University Children's Hospital in Rio de Janeiro. METHODS: This is an analytical cross-sectional study, which included patients diagnosed with T1DM who had complete anthropometric data (weight and height) and excluded those using drugs with effect on weight gain, genetic syndromes, celiac disease, hypothyroidism, renal failure and other chronic diseases, and pregnant women. The data collection was referring to the last consultation, and with respect to laboratory tests, the most recent data was collected. The dependent variable was the overweight, defined as Z score ≥1. The independent variables were gender, age, insulin dose, duration of disease, lipid profile, glycated hemoglobin, type of prescribed food planning, and place of residence. A logistic regression model was built for each outcome studied, considering significant associations those with p < 0.05. RESULTS: The study included 195 patients with a mean age of 10.6 (±3.8) years, and 49.7 % (n = 97) aged less than 10 years. The overweight frequency was 40 % (n = 78). The age ≥10 years (OR 0.41; 95 % CI 0.20-0.86; p = 0.019) and the dose of insulin/kg ideal weight (OR 3.38; 95 % CI 1:55-7:39; p = 0.002) were considered the variables associated with overweight. CONCLUSIONS: There was a high prevalence of overweight, which explains strategies for promoting healthy eating habits and changing lifestyle with a focus on children and adolescents with diabetes.

AIDS in the meeting of the Tapajós and Amazon rivers: deaths in the period 2010-2018 in Santarém, Pará, Brazil / AIDS no encontro dos rios Tapajós e Amazonas: óbitos no período de 2010-2018 em Santarém, Pará, Brasil

INTRODUCTION: The city of Santarém, the regional healthcare center in the western Pará State, lacks studies on the epidemic of the human immunodeficiency virus (HIV), in particular, on the causes of death. OBJECTIVE: To characterize the sociodemographic and clinical profile related to the evolution of HIV infection to death. METHODS: The sample consisted of 94 medical records of patients from a reference center in the city of Santarém-PA, who died between 2010-2018. Data were collected on the sociodemographic profile, immunological and clinical characteristics of the patients. Data were analyzed using descriptive and inferential statistics, adopting p<0.05. RESULTS: Most deaths were male (67%), aged between 15-29 years (39%) and diagnosed between 30-44 years (41%), single (54%), mixed race (91.5%), from Santarém (77%) and with sexual intercourse being the main type of exposure (95.7%). Most patients were not being treated at the moment of death (56.4%), the main cause of death was respiratory failure (5%), in which, these individuals had, at the moment of death, TCD4+ lymphocytes <200 cell/mm3 (26%) and detectable viral load (29%). CONCLUSION: The lifetime from diagnosis to death was 48.45±50,30 months, and immunosuppression in the diagnosis was positively associated with the shortest survival time. However, sex was not associated with the immunological profile, age at the time of diagnosis, and death. There was only a tendency for women towards immunosuppression and detectable viral load.

INTRODUÇÃO: A cidade de Santarém, o polo assistencial da região oeste do Pará, carece de estudos sobre a epidemia do vírus da imunodeficiência humana (HIV), especialmente, sobre as causas de óbitos. OBJETIVO: Caracterizar o perfil sociodemográfico e clínico relacionado à evolução da infecção pelo HIV até a morte. MÉTODO: A amostra foi de 94 prontuários de pacientes de um centro de referência do município de Santarém-PA, que evoluíram a óbito entre os anos de 2010-2018. Foram levantados os dados sobre o perfil sociodemográfico, características imunológicas e clínicas dos pacientes. Os dados foram analisados por estatística descritiva e inferencial, adotando-se p<0,05. RESULTADOS: A maioria dos óbitos foi de indivíduos do sexo masculino (67%), com faixa etária do diagnóstico entre 15-29 anos (39%) e de falecimento entre 30-44 anos (41%), solteiros (54%), pardos (91,5%), procedentes de Santarém (77%) e com a relação sexual sendo o principal tipo de exposição (95,7%). A maioria dos pacientes não estava em tratamento no momento do óbito (56,4%), a principal causa de morte foi por insuficiência respiratória (5%), no qual, esses indivíduos apresentavam, no momento da morte, linfócitos TCD4+ <200 cél/mm3 (26%) e carga viral detectável (29%). CONCLUSÃO: O tempo de vida do diagnóstico ao óbito foi de 48,45±50,30 meses e a presença de imunossupressão no diagnóstico associou-se positivamente com o menor tempo de sobrevida. Contudo, o sexo não apresentou associação com o perfil imunológico, a idade no momento do diagnóstico e do óbito, apenas notou-se uma tendência das mulheres para a imunossupressão e carga viral detectável.

Association between social isolation, level of physical activity and sedentary behavior in pandemic times / Associação de isolamento social, nível de atividade física e comportamento sedentário em tempos pandêmicos / Asociación entre el aislamiento social, el nivel de actividad física y la conducta sedentaria en tiempos de pandemia

Objective: To analyze the association between social isolation (SI), physical activity level (PAL) and sedentary behavior in the university community in pandemic times. Methods: A cross-sectional epidemiological study was carried out from May 7 to June 4, 2020, with 194 participants linked to the Federal University of Jataí Universidade Federal de Jataí ­ UFJ), in Goiás, Brazil. Data were collected using a form created on Google Forms® and sent to the email addresses of the academic community of UFJ to assess socioeconomic characteristics, lifestyle, body composition, physical activity level, and sedentary behavior, taking into account the periods prior to and during SI. Data were analyzed using descriptive and inferential statistics, with p<0.05 considered significant. Results: The study participants were predominantly women (n=141; 72.6%), 18-27 years old (n=100; 71%), single(n=96; 68%), students (n=110; 78%), and had no pre-existing diseases (n=94; 67%). Increases in the body mass and body massindex (BMI) (p<0.05) were observed during SI, and physical activity downtime increased for all participants, regardless of sex(p<0.05). Conclusion: SI recommended by health managers due to the pandemic caused by COVID-19 was responsible for inducing an increase in body mass and BMI accompanied by an increase in screen time during the week, as well as a decrease in the PAL of individuals belonging to the community of university students of UFJ. Descriptors: Coronavirus Infections; Sedentary Behavior; Motor Activity.

Objetivo: Analisar a associação de isolamento social (IS), nível de atividade física (NAF) e comportamento sedentário na comunidade universitária em tempos pandêmicos. Métodos: Estudo epidemiológico transversal realizado no período de 7 de maio a 4 de junho de 2020 com 194 participantes vinculados à Universidade Federal de Jataí (UFJ), Goiás, Brasil. Para coleta de dados, foi enviado ao e-mail da comunidade acadêmica da UFJ um formulário criado no Google Forms® para avaliar as características socioeconômicas, os hábitos de vida, a composição corporal, o nível de atividade física e o comportamento sedentário, levando em consideração o período anterior e durante o IS. Os dados foram analisados por estatística descritiva e inferencial, com p<0,05. Resultados: Os participantes do estudo foram, predominantemente, mulheres (n=141; 72,6%), na faixa etária de 18-27 anos (n=100; 71%), solteiras (n=96; 68%), discentes (n=110; 78%), com ausência de doenças pré-existentes(n=94; 67%). Durante o IS ocorreu aumento da massa corporal e do índice de massa corporal (IMC) dos indivíduos (p<0,05). Além disso, o tempo de inatividade física aumentou para todos os indivíduos, independente do sexo (p<0,05). Conclusão: O IS proporcionado pelos gestores de saúde em decorrência da pandemia ocasionada pela COVID-19 foi responsável por induzir um aumento da massa corporal e do IMC, acompanhado pela elevação do tempo de tela durante a semana e a diminuição do NAF dos indivíduos pertencentes à comunidade universitária da UFJ.

Objetivo: Analizar la asociación entre el aislamiento social (AS), el nivel de actividad física (NAF) y la conducta sedentaria de la comunidad universitaria en tiempos de pandemia. Métodos: Estudio epidemiológico transversal realizado entre el 07 de mayo y el 4 de junio de 2020 con 194 participantes de la Universidad Federal de Jataí (UFJ), Goiás, Brazil. La recogida de datos se dio a través de un formulario del Google Forms® que ha sido enviado para el correo electrónico de la comunidad académica de la UFJ para la obtención de las características socioeconómicas, el estilo de vida, la composición corporal, el nivel de actividad física y la conducta sedentaria en el periodo antes y durante el AS. Se ha utilizado la estadística descriptiva e inferencial para el análisis de datos con p<0,05. Resultados: Los participantes del estudio eran predominantemente mujeres (n=141; 72.6%), entre 18 y 27 años de edad (n=100; 71%), solteras (n=96; 68%), estudiantes (n=110; 78%) sin enfermedades anteriores (n=94; 67%). Durante el AS ha sido observado el aumento en la masa corporal y en el Índice de Masa Corporal (IMC) (p<0.05) y la inactividad física ha aumentado para todos los participantes, independientemente del sexo (p<0.05). Conclusión: El AS proporcionado por los gestores de salud debido a la pandemia de la COVID-19 ha sido responsable por inducir el aumento en la masa corporal yen el IMC asociado con el aumento del tiempo de tela durante la semana así como la disminución del NAF de los individuos de la comunidad de estudiantes universitarios de la UFJ.

Genomic analysis of the molecular neuropathology of tuberous sclerosis using a human stem cell model.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign tumor growths in multiple organs and neurological symptoms induced by mTOR hyperfunction. Because the molecular pathology is highly complex and the etiology poorly understood, we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology and suggest new targets for treatment. METHODS: We investigate the disease phenotype of TSC by neural differentiation of a human stem cell model that had been deleted for TSC2 by genome editing. Comprehensive genomic analysis was performed by RNA sequencing and ribosome profiling to obtain a detailed genome-wide description of alterations on both the transcriptional and translational level. The molecular effect of mTOR inhibitors used in the clinic was monitored and comparison to published data from patient biopsies and mouse models highlights key pathogenic processes. RESULTS: TSC2-deficient neural stem cells showed severely reduced neuronal maturation and characteristics of astrogliosis instead. Transcriptome analysis indicated an active inflammatory response and increased metabolic activity, whereas at the level of translation ribosomal transcripts showed a 5'UTR motif-mediated increase in ribosome occupancy. Further, we observed enhanced protein synthesis rates of angiogenic growth factors. Treatment with mTOR inhibitors corrected translational alterations but transcriptional dysfunction persisted. CONCLUSIONS: Our results extend the understanding of the molecular pathophysiology of TSC brain lesions, and suggest phenotype-tailored pharmacological treatment strategies.

mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis.

Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD), including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2(+/-) and TSC2(-/-) neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis.

Characterization of a human pluripotent stem cell-derived model of neuronal development using multiplexed targeted proteomics.

PURPOSE: Human pluripotent stem cell (hPSC)-derived cellular models have great potential to enable drug discovery and improve translation of preclinical insights to the clinic. We have developed a hPSC-derived neural precursor cell model for studying early events in human brain development. We present protein-level characterization of this model, using a multiplexed SRM approach, to establish reproducibility and physiological relevance; essential prerequisites for utilization of the neuronal development model in phenotypic screening-based drug discovery. EXPERIMENTAL DESIGN: Profiles of 246 proteins across three key stages of in vitro neuron differentiation were analyzed by SRM. Three independently hPSC-derived isogenic neural stem cell (NSC) lines were analyzed across five to nine independent neuronal differentiations. RESULTS: One hundred seventy-five proteins were reliably quantified revealing a time-dependent pattern of protein regulation that reflected protein dynamics during in vivo brain development and that was conserved across replicate differentiations and multiple cell lines. CONCLUSIONS AND CLINICAL RELEVANCE: SRM-based protein profiling enabled establishment of the reproducibility and physiological relevance of the hPSC-derived neuronal model. Combined with the successful quantification of proteins relevant to neurodevelopmental diseases, this validates the platform for use as a model to enable neuroscience drug discovery.