Spontaneously hypertensive rats develop left ventricular hypertrophy, increased blood pressure and blood pressure variability, which are important determinants of heart damage, like the activation of renin-angiotensin system.

Tinnitus is characterized by the perception of sound in the absence of an external auditory stimulus. The network connectivity of auditory and non-auditory brain structures associated with emotion, memory and attention are functionally altered in debilitating tinnitus. Current studies suggest that tinnitus results from neuroplastic changes in the frontal and limbic temporal regions. The objective of this study was to use Single-Photon Emission Computed Tomography (SPECT) to evaluate changes in the cerebral blood flow in tinnitus patients with normal hearing compared with healthy controls.

Despite great advance in multiple myeloma (MM) treatment since 2000s, it is still an incurable disease and novel therapies are welcome. Therefore, the purpose of this study was to explore MM plasma cells' (MM-PC) proteome, in comparison with their normal counterparts (derived from palatine tonsils of normal donors, ND-PC), in order to find potential therapeutic targets expressed on the surface of these cells. We also aimed to evaluate the proteome of MM cell lines with different genetic alterations, to confirm findings obtained with primary tumor cells. Bone marrow (BM) samples from eight new cases of MM and palatine tonsils from seven unmatched controls were submitted to PC separation and, in addition to two MM cell lines (U266, RPMI-8226), were submitted to protein extraction for mass spectrometry analyses. A total of 81 proteins were differentially expressed between MM-PC and ND-PC - 72 upregulated and nine downregulated; U266 vs. RPMI 8226 cell lines presented 61 differentially expressed proteins - 51 upregulated and 10 downregulated. On primary tumors, bioinformatics analyses highlighted upregulation of protein biosynthesis machinery, as well as downregulation of immune response components, such as MHC class I and II, and complement receptors. We also provided comprehensive information about U266 and RPMI-8226 cell lines' proteome and could confirm some patients' findings.

Our study aimed to associate IL-1β and IL-1RN polymorphisms with AD disease in comparison with elderly control group from São Paulo - Brazil. We genotyped 199 Alzheimer's disease (AD) patients, 165 elderly control and 122 young control samples, concerning VNTR (IL-1RN) and -511C>T and -31T>C (IL-1β) polymorphisms. Our findings revealed that -511C/-31T/2-repetitions VNTR haplotype had a protective effect for AD when compared to EC (p=0.005), whereas -511C/-31C/1-repetition VNTR haplotype was associated as a risk factor for AD (p=0.021). Taken together, we may suggest that there is a relevant role of IL-1 genes cluster in AD pathogenesis in this Brazilian population.

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70-80%) or hereditary (20-30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3p = 0.01 and DLK1p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

Overactivation of the classical arm of the renin-angiotensin (Ang) system (RAS) occurs during inflammation, oxidative stress and obesity-induced cardiomyopathy. The activation of the protective arm of RAS may act to counterbalance the deleterious effects of the classical RAS. Although aerobic exercise training (AET) shifts the balance of the RAS towards the protective arm, little is known about the molecular adaptations to different volumes of AET. The aim of this study was to evaluate the impact of AET volume on the modulation of RAS, as well as on cardiac biomarkers of oxidative stress and inflammation, in a diet-induced obesity model. Male Wistar rats were fed either control (CON) or high fat (HF) diet for 32 weeks. At week 20, HF group was subdivided into sedentary, low (LEV, 150 min/week) or high (HEV, 300 min/week) exercise volume. After 12 weeks of exercise, body mass gain, systolic blood pressure and heart rate were evaluated, as well as RAS, oxidative stress and inflammation in the heart. Body mass gain, systolic blood pressure and heart rate were higher in HF group when compared with SC group. Both trained groups restored systolic blood pressure and heart rate, but only HEV reduced body mass gain. Regarding the cardiac RAS, the HF group exhibited favoring of the classical arm and both trained groups shifted the balance towards the counterregulatory protective arm. The HF group had higher B1R expression and lower B2R expression than the control group, and B2R expression was reverted in both trained groups. The HF group also presented oxidative stress. The LEV and HEV groups improved the cardiac redox status by reducing Nox 2 and nitrotyrosine expression, but only the LEV group was able to increase the antioxidant defense by increasing Nrf2 signaling. While the HF group presented higher TNF-α, IL-6 and NFκB expression, and lower IL-10 expression, than the SC group, both training protocols improved the inflammatory profile. Although both trained groups improved the deleterious changes related to obesity cardiomyopathy, it is clear that the molecular mechanisms differ between them. Our results suggest that different exercise volumes might reach different molecular targets, and this could be a relevant factor when using exercise to manage obesity.

Neuroimaging studies suggest that brain development mechanisms might explain at least some behavioural and cognitive attention-deficit/hyperactivity disorder (ADHD) symptoms. However, the putative mechanisms by which genetic susceptibility factors influence clinical features via alterations of brain development remain largely unknown. Here, we set out to integrate genomics and connectomics tools by investigating the associations between an ADHD polygenic risk score (ADHD-PRS) and functional segregation of large-scale brain networks. With this aim, ADHD symptoms score, genetic and rs-fMRI (resting-state functional magnetic resonance image) data obtained in a longitudinal community-based cohort of 227 children and adolescents were analysed. A follow-up was conducted approximately 3 years after the baseline, with rs-fMRI scanning and ADHD likelihood assessment in both stages. We hypothesised a negative correlation between probable ADHD and the segregation of networks involved in executive functions, and a positive correlation with the default-mode network (DMN). Our findings suggest that ADHD-PRS is correlated with ADHD at baseline, but not at follow-up. Despite not surviving for multiple comparison correction, we found significant correlations between ADHD-PRS and segregation of cingulo-opercular networks and DMN at baseline. ADHD-PRS was negatively correlated with the segregation level of cingulo-opercular networks but positively correlated with the DMN segregation. These directions of associations corroborate the proposed counter-balanced role of attentional networks and DMN in attentional processes. However, the association between ADHD-PRS and brain networks functional segregation was not found at follow-up. Our results provide evidence for specific influences of genetic factors on development of attentional networks and DMN. We found significant correlations between polygenic risk score for ADHD (ADHD-PRS) and segregation of cingulo-opercular networks and default-mode network (DMN) at baseline. ADHD-PRS was negatively correlated with the segregation level of cingulo-opercular networks but positively correlated with the DMN segregation.

Functional brain hubs are key integrative regions in brain networks. Recently, brain hubs identified through resting-state fMRI have emerged as interesting targets to increase understanding of the relationships between large-scale functional networks and psychopathology. However, few studies have directly addressed the replicability and consistency of the hub regions identified and their association with symptoms. Here, we used the eigenvector centrality (EVC) measure obtained from graph analysis of two large, independent population-based samples of children and adolescents (7-15 years old; total N=652; 341 subjects for site 1 and 311 for site 2) to evaluate the replicability of hub identification. Subsequently, we tested the association between replicable hub regions and psychiatric symptoms. We identified a set of hubs consisting of the anterior medial prefrontal cortex and inferior parietal lobule/intraparietal sulcus (IPL/IPS). Moreover, lower EVC values in the right IPS were associated with psychiatric symptoms in both samples. Thus, low centrality of the IPS was a replicable sign of potential vulnerability to mental disorders in children. The identification of critical and replicable hubs in functional cortical networks in children and adolescents can foster understanding of the mechanisms underlying mental disorders.

Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two "in silico" protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

We investigated the role of DGCR2, a corticogenesis-related gene, on schizophrenia (SZ) and its subphenotypes, including brain morphology. A total of 221 SZ patients, 263 controls and 70 antipsychotic-naïve first episode of psychosis (FEP) were genotyped for 17 DGCR2 polymorphisms. While no association between DGCR2 polymorphisms and SZ was found, the missense variant rs2072123 was associated to left rostral anterior cingulate thickness, showing that DGCR2 seems not to be associated directly with the SZ but might be influencing the brain morphology. We also showed a DGCR2 downregulation in SZ patients when compared to controls and FEP.

We investigated the effects of AET on myomiRs expression in the skeletal muscle and serum of colon cachectic (CT26) and breast non-cachectic (MMTV-PyMT) cancer mice models. Colon cancer decreased microRNA-486 expression, increasing PTEN in tibialis anterior muscle (TA), decreasing the PI3K/mTOR protein pathway, body and muscle wasting, fibers' cross-sectional area and muscle dysfunction, that were not preserved by AET. In contrast, breast cancer decreased those muscle functions, but were preserved by AET. In circulation, the downregulation of microRNA-486 and -206 in colon cancer, and the downregulation of microRNA-486 and upregulation of microRNA-206 expression in breast cancer might be good cancer serum biomarkers. Since the microRNA-206 is skeletal muscle specific, their expression was increased in the TA, serum and tumor in MMTV, suggesting a communication among these three compartments. The AET prevents these effects on microRNA-206, but not on microRNA-486 in MMTV. In conclusion, cancer induced a downregulation of microRNA-486 expression in TA and serum of CT26 and MMTV mice and these effects were not prevented by AET; however, to MMTV, the trained muscle function was preserved, probably sustained by the downregulation of microRNA-206 expression. Serum microRNA-206 is a potential biomarker for colon (decreased) and breast (increased) cancer to monitor the disease evolution and the effects promoted by the AET.

Recently, several studies have investigated the neurodevelopment of psychiatric disorders using brain data acquired via structural magnetic resonance imaging (sMRI). These analyses have shown the potential of sMRI data to provide a relatively precise characterization of brain structural biomarkers. Despite these advances, a relatively unexplored question is how reliable and consistent a model is when assessing subjects from other independent datasets. In this study, we investigate the performance and generalizability of the same model architecture trained from distinct datasets comprising youths in diverse stages of neurodevelopment and with different mental health conditions. We employed models with the same 3D convolutional neural network (CNN) architecture to assess autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), brain age, and a measure of dimensional psychopathology, the Child Behavior Checklist (CBCL) total score. The investigated datasets include the Autism Brain Imaging Data Exchange II (ABIDE-II, N = 580), Attention Deficit Hyperactivity Disorder (ADHD-200, N = 922), Brazilian High-Risk Cohort Study (BHRCS, N = 737), and Adolescent Brain Cognitive Development (ABCD, N = 11,031). Models' performance and interpretability were assessed within each dataset (for diagnosis tasks) and inter-datasets (for age estimation). Despite the demographic and phenotypic differences of the subjects, all models presented significant estimations for age (p value < 0.001) within and between datasets. In addition, most models showed a moderate to high correlation in age estimation. The results, including the models' brain regions of interest (ROI), were analyzed and discussed in light of the youth neurodevelopmental structural changes. Among other interesting discoveries, we found that less confounded training datasets produce models with higher generalization capacity.

Obesity and renin angiotensin system (RAS) hyperactivity are profoundly involved in cardiovascular diseases, however aerobic exercise training (EXT) can prevent obesity and cardiac RAS activation. The study hypothesis was to investigate whether obesity and its association with EXT alter the systemic and cardiac RAS components in an obese Zucker rat strain.

Impaired cardiomyocyte contractility and calcium handling are hallmarks of left ventricular contractile dysfunction. Exercise training has been used as a remarkable strategy in the treatment of heart disease. The microRNA-1, which targets sodium/calcium exchanger 1 (NCX), and microRNA-214, which targets sarcoplasmic reticulum calcium ATPase-2a (Serca2a), are involved in cardiac function regulation. Thus, the aim of this study was to evaluate the effect of exercise training on cardiac microRNA-1 and -214 expression after myocardial infarction.

Investigations of brain maturation processes are a key step to understand the cognitive and emotional changes of adolescence. Although structural imaging findings have delineated clear brain developmental trajectories for typically developing individuals, less is known about the functional changes of this sensitive development period. Developmental changes, such as abstract thought, complex reasoning, and emotional and inhibitory control, have been associated with more prominent cortical control. The aim of this study is to assess brain networks connectivity changes in a large sample of 7- to 15-year-old subjects, testing the hypothesis that cortical regions will present an increasing relevance in commanding the global network. Functional magnetic resonance imaging (fMRI) data were collected in a sample of 447 typically developing children from a Brazilian community sample who were submitted to a resting state acquisition protocol. The fMRI data were used to build a functional weighted graph from which eigenvector centrality (EVC) was extracted. For each brain region (a node of the graph), the age-dependent effect on EVC was statistically tested and the developmental trajectories were estimated using polynomial functions. Our findings show that angular gyrus become more central during this maturation period, while the caudate; cerebellar tonsils, pyramis, thalamus; fusiform, parahippocampal and inferior semilunar lobe become less central. In conclusion, we report a novel finding of an increasing centrality of the angular gyrus during the transition to adolescence, with a decreasing centrality of many subcortical and cerebellar regions.

Ketamine has a fast onset of action that may offer a paradigm change for depression management at the end of life. We aimed to synthesize evidence regarding the safety and efficacy of ketamine in depression treatment within a broad palliative care concept.

To investigate the role of physical activity in functional and molecular bladder alterations in an obese and insulin-resistant murine model.

A growing body of evidence suggests a key role of tumor microenvironment, especially for bone marrow mesenchymal stem cells (MSC), in the maintenance and progression of multiple myeloma (MM), through direct and indirect interactions with tumor plasma cells. Thus, this study aimed to investigate the gene expression and functional alterations of MSC from MM patients (MM-MSC) in comparison with their normal counterparts from normal donors (ND-MSC). Gene expression analysis (Affymetrix) was performed in MM-MSC and ND-MSC after in vitro expansion. To validate these findings, some genes were selected to be evaluated by quantitative real time PCR (RT-qPCR), and also functional in vitro analyses were performed. We demonstrated that MM-MSC have a distinct gene expression profile than ND-MSC, with 485 differentially expressed genes (DEG) - 280 upregulated and 205 downregulated. Bioinformatics analyses revealed that the main enriched functions among downregulated DEG were related to cell cycle progression, immune response activation and bone metabolism. Four genes were validated by qPCR - ZNF521 and SEMA3A, which are involved in bone metabolism, and HLA-DRA and CHIRL1, which are implicated in the activation of immune response. Taken together, our results suggest that MM-MSC have constitutive abnormalities that remain present even in the absence of tumors cells. The alterations found in cell cycle progression, immune system activation, and osteoblastogenesis suggest, respectively, that MM-MSC are permanently dependent of tumor cells, might contribute to immune evasion and play an essential role in bone lesions frequently found in MM patients.

Evidence suggests increased prevalence of cluster B personality disorders (PD) among patients with juvenile myoclonic epilepsy (JME), which has been associated with worse seizure control and more psychosocial dysfunctions. A preliminary voxel-based morphometry study demonstrated corpus callosum (CC) volume reduction in patients with JME and cluster B PD, particularly in the posterior midbody and isthmus. In this study we aimed to follow up these results with region of interest analysis. Sixteen JME patients with cluster B PD, 38 JME patients without any psychiatric disorder, and 30 demographically matched healthy controls submitted to a psychiatric evaluation and a magnetic resonance imaging scan. The total and regional callosal areas were obtained from the midsagittal slice using a semi-automated program. Psychiatric evaluation was performed through SCID-I and -II. Significant reductions in the posterior region of the CC were observed in the JME with PD group relative to the other groups. These data support previous findings of callosal reductions in cluster B PD, as well as a possible involvement of CC in patients with JME and such personality characteristics.

Slow wave oscillations in the electroencephalogram (EEG) during sleep may reflect both sleep need and intensity, which are implied in homeostatic regulation. Adenosine is strongly implicated in sleep homeostasis, and a single nucleotide polymorphism in the adenosine deaminase gene (ADA G22A) has been associated with deeper and more efficient sleep. The present study verified the association between the ADA G22A polymorphism and changes in sleep EEG spectral power (from C3-A2, C4-A1, O1-A2, and O2-A1 derivations) in the Epidemiologic Sleep Study (EPISONO) sample from São Paulo, Brazil. Eight-hundred individuals were subjected to full-night polysomnography and ADA G22A genotyping. Spectral analysis of the EEG was carried out in all individuals using fast Fourier transformation of the signals from each EEG electrode. The genotype groups were compared in the whole sample and in a subsample of 120 individuals matched according to ADA genotype for age, gender, body mass index, caffeine intake status, presence of sleep disturbance, and sleep-disturbing medication. When compared with homozygous GG genotype carriers, A allele carriers showed higher delta spectral power in Stage 1 and Stages 3+4 of sleep, and increased theta spectral power in Stages 1, 2 and REM sleep. These changes were seen both in the whole sample and in the matched subset. The higher EEG spectral power indicates that the sleep of individuals carrying the A allele may be more intense. Therefore, this polymorphism may be an important source of variation in sleep homeostasis in humans, through modulation of specific components of the sleep EEG.