👤 Rosemayre S Freire

To investigate the moderating role of physical activity intensity and sedentary break patterns on the association between sedentary time (ST) and cardiometabolic risk in older adults. This cross-sectional study included 248 community-dwelling older adults without major cardiovascular diseases (66.0 ± 4.6 years; 78% female). Physical activity and ST were measured using a hip-worn accelerometer over seven consecutive days. Cardiometabolic disease risk was assessed using a sex-specific continuous metabolic syndrome score (cMetS). ST was entered as the explanatory variable for cMetS, while moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and the number of short (1-5 min) and long (>5 min) sedentary breaks were tested as moderators. All analyses were adjusted for traditional cardiometabolic risk factors and accelerometer wear time. MVPA (β = -0.005, p = 0.046), LPA (β = -0.030, p = 0.050), short (β = -0.003, p = 0.070) and long (β = -0.010, p = 0.011) sedentary breaks moderated the association between ST and cMetS. The Johnson-Neyman technique revealed that the association between ST and cMetS became non-significant (p ≥ 0.05) at thresholds of MVPA ≥ 19 min/day, LPA ≥ 5.9 h/day, short breaks ≥ 87/day, and long breaks ≥ 10/day. Our findings suggest that specific thresholds of MVPA and LPA, as well as short and long sedentary breaks may offset the deleterious association between ST and cardiometabolic risk in older adults. Show less

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of Cln3 Show less

Many pharmacological treatments are considered effective in the treatment of panic disorder (PD), however, about 20 to 40% of the patients have treatment-resistant PD. Pharmacogenetics could explain why some patients are treatment-resistant. Our objective was to gather preliminary data on the clinical usefulness of pharmacogenetic testing in this disorder. Twenty patients with treatment-resistant PD were included in this observational study and submitted to commercial pharmacogenetic testing. Testing panel included gene polymorphisms related to CYP, genes In 30% of the patients, the tests indicated reduced chance of response to the prescribed drug, while they indicated very low serum levels of the prescribed drug in 20% of the subjects. The pharmacogenetic tests predicted reduction of MTHFR enzyme activity in 74% of the patients. ABCB1 gene alleles associated to drug resistance were found in 90% of the samples. Commercial pharmacogenetic testing failed to predict negative treatment outcome in most patients with PD. The association between treatment-resistance in PD and the genes CYP2C19, MTHFR and ABCB1 deserves further study. Show less

Progressive exercise intolerance is a hallmark of pulmonary hypertension (pH), severely impacting patients' independence and quality of life (QoL). Accumulating evidence over the last decade shows that combined abnormalities in peripheral reflexes and target organs contribute to disease progression and exercise intolerance. The aim of this study was to review the literature of the last decade on the contribution of the cardiovascular, respiratory, and musculoskeletal systems to pathophysiology and exercise intolerance in pH. A systematic literature search was conducted using specific terms in PubMed, SciELO, and the Cochrane Library databases for original pre-clinical or clinical studies published between 2013 and 2023. Studies followed randomized controlled/non-randomized controlled and pre-post designs. The systematic review identified 25 articles reporting functional or structural changes in the respiratory, cardiovascular, and musculoskeletal systems in pH. Moreover, altered biomarkers in these systems, lower cardiac baroreflex, and heightened peripheral chemoreflex activity seemed to contribute to functional changes associated with poor prognosis and exercise intolerance in pH. Potential therapeutic strategies acutely explored involved manipulating the baroreflex and peripheral chemoreflex, improving cardiovascular autonomic control via cardiac vagal control, and targeting specific pathways such as GPER1, GDF-15, miR-126, and the JMJD1C gene. Information published in the last 10 years advances the notion that pH pathophysiology involves functional and structural changes in the respiratory, cardiovascular, and musculoskeletal systems and their integration with peripheral reflexes. These findings suggest potential therapeutic targets, yet unexplored in clinical trials, that could assist in improving exercise tolerance and QoL in patients with pH. Show less

Hypertrophic cardiomyopathy (HCM) is an inherited disorder whose causal variants involve sarcomeric protein genes. One of these is myosin-binding protein C (MYBPC3), being previously associated with a favourable prognosis. Our objective is to describe the clinical characteristics and events of a molecularly homogeneous HCM cohort associated with truncating A cohort of patients and relatives with HCM diagnosis and carrying a truncating This is the first molecularly homogeneous, contemporary cohort, including HCM patients secondary to Show less

MicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling muscle phenotype. miR-155 has been related to muscular dystrophy and muscle cell atrophy. However, the function of miR-155 and its molecular targets in muscular dystrophies remain poorly understood. Through in silico and in vitro approaches, we identify distinct transcriptional profiles induced by miR-155-5p in muscle cells. The treated myotubes changed the expression of 359 genes (166 upregulated and 193 downregulated). We reanalyzed muscle transcriptomic data from dystrophin-deficient patients and detected overlap with gene expression patterns in miR-155-treated myotubes. Our analysis indicated that miR-155 regulates a set of transcripts, including Show less

The accumulation of amyloid-β (Aβ) is the main event related to Alzheimer's disease (AD) progression. Over the years, several disease-modulating approaches have been reported, but without clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau protein aggregation and modulation of β-secretase (β-site amyloid precursor protein cleaving enzyme 1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release the C99 fragment, giving rise to several Aβ peptide species during the subsequent γ-secretase cleavage. In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal chemistry, as it plays a crucial role in the rate of Aβ generation. In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives. Show less

The ABA-induced MA12 cDNA from maize, which encodes a set of highly phosphorylated embryo proteins, was used to isolate the corresponding genomic clone. This gene, called RAB-17 (responsive to ABA), encodes a basic, glycine-rich protein (mol. wt. 17,164) containing a cluster of 8 serine residues, seven of them contiguous. It is a homologue of the rice RAB-21 gene (Mundy J, Chua NH, EMBO J 7; 2279-2286, 1988). Phosphoamino acid analysis of the isolated protein indicates that only the serine residues are phosphorylated and a putative casein-type kinase phosphorylatable sequence was identified in the protein. The pattern of expression and in vivo phosphorylation of the RAB-17 protein was studied during maize embryo germination and in calli of both meristematic or embryonic origin. ABA treatment induced the synthesis of RAB-17 mRNA and protein in calli, however, the RAB-17 proteins were found to be highly phosphorylated only in embryos. Show less