Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuroprotective Effects of Choline and Other Methyl Donors

Recent evidence suggests that physical and mental health are influenced by an intricate interaction between genes and environment. Environmental factors have been shown to modulate neuronal gene expression and function by epigenetic mechanisms. Exposure to these factors including nutrients during sensitive periods of life could program brain development and have long-lasting effects on mental health. Studies have shown that early nutritional intervention that includes methyl-donors improves cognitive functions throughout life. Choline is a micronutrient and a methyl donor that is required for normal brain growth and development. It plays a pivotal role in maintaining structural and functional integrity of cellular membranes. It also regulates cholinergic signaling in the brain via the synthesis of acetylcholine. Via its metabolites, it participates in pathways that regulate methylation of genes related to memory and cognitive functions at different stages of development. Choline-related functions have been dysregulated in some neurodegenerative diseases suggesting choline role in influencing mental health across the lifespan.
Image-Guided Percutaneous ‎Microwave Ablation Versus Cryoablation For Hepatocellular Carcinoma In High-Risk Locations: Intermediate-Term Results

Objective The aims of this study were to compare the clinical outcomes between image-guided percutaneous microwave ablation (MWA) and cryoablation (CRA) in patients with hepatocellular carcinoma (HCC) in high-risk locations and to identify the prognostic factors associated with the two treatment methods. Methods This retrospective study was institutional review board approved. A total of 120 patients (88 men and 32 women) with one hundred and thirty-four HCC lesions in high-risk locations from April 2014 to March 2018 were reviewed. Sixty-four patients underwent MWA and 56 patients underwent CRA. Survival, recurrence and complications were compared between the two groups. Effect of changes in key outcomes (i.e., overall survival (OS), recurrence-free survival (RFS) and local tumor progression (LTP)) was statistically analyzed with the log rank test. Univariate and multivariate analysis were performed on clinicopathological variables to identify factors affecting intermediate-term outcomes. Results The OS and RFS after MWA were comparable to those of CRA (P =0.141, and P=0.469, respectively). The LTP and major complication in MWA group was higher than those in CRA group (P=0.003, and P=0.039). Univariate analysis showed that age (P=0.007), tumor size (P=0.001), and Child-Turcotte-Pugh (CTP) grade (P=0.003) were risk factors for OS, and multivariate analysis results showed that older age (≥65 years) (P=0.002, HR:3.338, 95% CI:1.928–5.281), 3.0–5.0 cm in size (P<0.001, HR: 3.312, 95% CI: 1.872–4.489) and CTP grade B (P=0.001, HR:3.382, 95% CI: 1.882–5.902) were independently associated with poor OS. Conclusion CRA had comparable oncologic outcomes with MWA and could be a safe and effective treatment for HCC in high-risk locations.
Active expiration and chronic intermittent hypoxia‐induced hypertension: A hypothesis that still breathes!

The main issue addressed here is the contribution of an enhancement of the expiratory modulation of sympathetic activity to the development of neurogenic hypertension in rats submitted to chronic intermittent hypoxia (CIH). Considering that active expiration associated with sympathetic overactivity was characterized in the in situ preparation of rats submitted to CIH, the specific question presented by O ́Connor, Lucking, and O ́Halloran (2019) in their recent Viewpoint was: is active expiration really contributing to sympathetic overactivity and hypertension in rats submitted to CIH? In previous studies using the in situ working heart–brainstem preparation of rats, we described how the 10 day CIH protocol induced active expiration and a simultaneous increase in sympathetic nerve activity (Moraes et al., 2013; Zoccal et al., 2008). We also described the presence of active expiration in conscious, freely moving rats, but in that study we were not aware of the incidence of active expiration in the different phases of the sleep–wake cycle (Moraes et al., 2013). In our recent study (Bazilio, Bonagamba, Moraes, & Machado, 2019), which was the focus of the Viewpoint by O ́Connor et al. (2019), we documented that the incidence of active expiration was higher in awake CIH-exposed hypertensive rats than in control animals (11 versus 3% of all respiratory cycles during wakefulness), but it was not observed in non-REM and REM sleep. It is also important to highlight some of our previous studies and concepts (Moraes et al., 2013) that are relevant in the context of this discussion: (i) sympathetic overactivity in rats exposed to CIH is not dependent on changes in the intrinsic electrophysiological properties of bulbospinal presympathetic neurons in the rostral ventrolateral medula (RVLM); (ii) CIH reduced the synaptic inhibition from ventral medullary respiratory neurons to the expiratory oscillator located in the parafacial respiratory group (pFRG); and (iii) pFRG expiratory neurons increase the frequency of discharge of RVLM presympathetic neurons and induce active expiration. Therefore, the question here is: to what extent does the occurrence of active expiration determine the development of sympathetic overactivity and neurogenic hypertension in CIH rats? In this context, the observed active expiration implies the presence of abdominal muscle activity and presumed expiratory-related sympathetic overactivity. However, we must consider the neuronal network involved in this respiratory–sympathetic coupling to draw a better picture of their interaction and its possible contribution to the development of neurogenic hypertension in rats exposed to CIH. It is
Characterizing and Avoiding Problematic Global Optima of Variational Autoencoders

Variational Auto-encoders (VAEs) are deep generative latent variable models consisting of two components: a generative model that captures a data distribution p(x) by transforming a distribution p(z) over latent space, and an inference model that infers likely latent codes for each data point (Kingma and Welling, 2013). Recent work shows that traditional training methods tend to yield solutions that violate modeling desiderata: (1) the learned generative model captures the observed data distribution but does so while ignoring the latent codes, resulting in codes that do not represent the data (e.g. van den Oord et al. (2017); Kim et al. (2018)); (2) the aggregate of the learned latent codes does not match the prior p(z). This mismatch means that the learned generative model will be unable to generate realistic data with samples from p(z)(e.g. Makhzani et al. (2015); Tomczak and Welling (2017)). In this paper, we demonstrate that both issues stem from the fact that the global optima of the VAE training objective often correspond to undesirable solutions. Our analysis builds on two observations: (1) the generative model is unidentifiable - there exist many generative models that explain the data equally well, each with different (and potentially unwanted) properties and (2) bias in the VAE objective - the VAE objective may prefer generative models that explain the data poorly but have posteriors that are easy to approximate. We present a novel inference method, LiBI, mitigating the problems identified in our analysis. On synthetic datasets, we show that LiBI can learn generative models that capture the data distribution and inference models that better satisfy modeling assumptions when traditional methods struggle to do so.
Proteome Alterations in Equine Osteochondrotic Chondrocytes

Osteochondrosis is a failure of the endochondral ossification that affects developing joints in humans and several animal species. It is a localized idiopathic joint disorder characterized by focal chondronecrosis and growing cartilage retention, which can lead to the formation of fissures, subchondral bone cysts, or intra-articular fragments. Osteochondrosis is a complex multifactorial disease associated with extracellular matrix alterations and failure in chondrocyte differentiation, mainly due to genetic, biochemical, and nutritional factors, as well as traumas. This study describes the main proteomic alterations occurring in chondrocytes isolated from osteochondrotic cartilage fragments. A comparative analysis performed on equine osteochondrotic and healthy chondrocytes showed 26 protein species as differentially represented. In particular, quantitative changes in the extracellular matrix, cytoskeletal and chaperone proteins, and in cell adhesion and signaling molecules were observed in osteochondrotic cells, compared to healthy controls. Functional group analysis annotated most of these proteins in “growth plate and cartilage development”, while others were included in “glycolysis and gluconeogenesis”, “positive regulation of protein import”, “cell–cell adhesion mediator activity”, and “mitochondrion nucleoid”. These results may help to clarify some chondrocyte functional alterations that may play a significant role in determining the onset and progression of equine osteochondrosis and, being related, of human juvenile osteochondrosis.
TILLING by Sequencing: A Successful Approach to Identify Rare Alleles in Soybean Populations

Soybean seeds produce valuable protein that is a major component of livestock feed. However, soybean seeds also contain the anti-nutritional raffinose family oligosaccharides (RFOs) raffinose and stachyose, which are not digestible by non-ruminant animals. This requires the proportion of soybean meal in the feed to be limited, or risk affecting animal growth rate or overall health. While reducing RFOs in soybean seed has been a goal of soybean breeding, efforts are constrained by low genetic variability for carbohydrate traits and the difficulty in identifying these within the soybean germplasm. We used reverse genetics Targeting Induced Local Lesions in Genomes (TILLING)-by-sequencing approach to identify a damaging polymorphism that results in a missense mutation in a conserved region of the RAFFINOSE SYNTHASE3 gene. We demonstrate that this mutation, when combined as a double mutant with a previously characterized mutation in the RAFFINOSE SYNTHASE2 gene, eliminates nearly 90% of the RFOs in soybean seed as a proportion of the total seeds carbohydrates, and results in increased levels of sucrose. This represents a proof of concept for TILLING by sequencing in soybean.
Building a Patient-Centered Weight Management Program: A Mixed Methods Project to Obtain Patients’ Information Needs and Ideas for Program Structure

Achieving and maintaining weight loss for large segments of the population remains elusive, despite evidence demonstrating the value of many weight management programs. This study aimed to gather patients’ perceptions on weight management education needs, and ideas for the structure of a weight management program to be delivered in community pharmacies. This was an exploratory mixed methods study combining qualitative focus group interviews with a cross-sectional survey. Three focus group interviews were conducted, along with a brief survey based on focus groups findings and sent to all eligible participants. The survey allowed for individual responses on the program components and narrowing down of focus group findings. Nearly half of the respondents (45.9%) wanted further education on limiting carbohydrate and sugar intake. Participants were most interested in identifying different exercises appropriate for those with physical limitations (48.6%). Most participants preferred 1 h meetings (70.3%) that contain a mix of one-on-one and group meeting formats (67.6%). The results of the study suggest a three-month weight management program, with a combination of group and individual in-person meetings occurring twice per month, would be of most interest to patients.
Efficacy of Commercial Sanitizers Used in Food Processing Facilities for Inactivation of Listeria monocytogenes, E. Coli O157:H7, and Salmonella Biofilms

Bacteria entrapped in biofilms are a source of recurring problems in food processing environments. We recently developed a robust, 7-day biofilm microplate protocol for creating biofilms with strongly adherent strains of Listeria monocytogenes, Escherichia coli O157:H7, and Salmonella serovars that could be used to examine the effectiveness of various commercial sanitizers. Listeria monocytogenes 99-38, E.coli O157:H7 F4546, and Salmonella Montevideo FSIS 051 were determined from prior studies to be good biofilm formers and could be recovered and enumerated from biofilms following treatment with trypsin. Extended biofilms were generated by cycles of growth and washing daily, for 7 days, to remove planktonic cells. We examined five different sanitizers (three used at two different concentrations) for efficacy against the three pathogenic biofilms. Quaternary ammonium chloride (QAC) and chlorine-based sanitizers were the least effective, showing partial inhibition of the various biofilms within 2 h (1–2 log reduction). The best performing sanitizer across all three pathogens was a combination of modified QAC, hydrogen peroxide, and diacetin which resulted in ~6–7 log reduction, reaching levels below our limit of detection (LOD) within 1–2.5 min. All treatments were performed in triplicate replication and analyzed by one way repeated measures analysis of variance (RM-ANOVA) to determine significant differences (p < 0.05) in the response to sanitizer treatment over time. Analysis of 7-day biofilms by scanning electron microscopy (SEM) suggests the involvement of extracellular polysaccharides with Salmonella and E. coli, which may make their biofilms more impervious to sanitizers than L. monocytogenes.
An Improved Normalized Mutual Information Variable Selection Algorithm for Neural Network-Based Soft Sensors

In this paper, normalized mutual information feature selection (NMIFS) and tabu search (TS) are integrated to develop a new variable selection algorithm for soft sensors. NMIFS is applied to select influential variables contributing to the output variable and avoids selecting redundant variables by calculating mutual information (MI). A TS based strategy is designed to prevent NMIFS from falling into a local optimal solution. The proposed algorithm performs the variable selection by combining the entropy information and MI and validating error information of artificial neural networks (ANNs); therefore, it has advantages over previous MI-based variable selection algorithms. Several simulation datasets with different scales, correlations and noise parameters are implemented to demonstrate the performance of the proposed algorithm. A set of actual production data from a power plant is also used to check the performance of these algorithms. The experiments showed that the developed variable selection algorithm presents better model accuracy with fewer selected variables, compared with other state-of-the-art methods. The application of this algorithm to soft sensors can achieve reliable results.
Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure–activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.
Progressive cardiac arrhythmias and ECG abnormalities in the Huntington's disease BACHD mouse model.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease. There is accumulating evidence that HD patients have increased prevalence of conduction abnormalities and compromised sinoatrial node (SAN) function which could lead to increased risk for arrhythmia. We used mutant Huntingtin (mHTT) expressing Bacterial Artificial Chromosome Huntington's disease (BACHD) mice to determine if they exhibit electrocardiogram (ECG) abnormalities involving cardiac conduction that are known to increase risk of sudden arrhythmic death in humans. We obtained surface ECGs and analyzed arrhythmia susceptibility; we observed prolonged QRS duration, increases in PVCs as well as PACs. Abnormal histological and structural changes that could lead to cardiac conduction system dysfunction were seen. Finally, we observed decreases in desmosomal proteins, PKP2 and DSG2, which have been reported to cause cardiac arrhythmias and reduced conduction. Our study indicates that mHTT could cause progressive cardiac conduction system pathology that could increase the susceptibility to arrhythmias and sudden cardiac death in HD patients.
Internal clock and the surgical ICU patient.

PURPOSE OF REVIEW The alteration of circadian rhythms in the postoperative period has been demonstrated to influence the outcomes. With this narrative review we would revise how anesthesia, surgery and intensive care can interfere with the circadian clock, how this could impact on the postsurgical period and how to limit the disruption of the internal clock. RECENT FINDINGS Anesthesia affects the clock in relation to the day-time administration and the type of anesthetics, N-methyl-D-aspartate receptor antagonists or gamma-aminobutyric acid receptors agonists. Surgery causes stress and trauma with consequent alteration in the circadian release of cortisol, cytokines and melatonin. ICU represents a further challenge for the patient internal clock because of sedation, immobility, mechanical ventilation and alarms noise. SUMMARY The synergic effect of anesthesia, surgery and postoperative intensive care on circadian rhythms require a careful approach to the patient considering a role for therapies and interventions aimed to re-establish the normal circadian rhythms. Over time, approach like the Awakening and Breathing Coordination, Delirium Monitoring and Management, Early Mobility and Family engagement and empowerment bundle can implement the clinical practice.
Chocolate, “Food of the Gods”: History, Science, and Human Health

Chocolate is well known for its fine flavor, and its history began in ancient times, when the Maya considered chocolate (a cocoa drink prepared with hot water) the “Food of the Gods”. The food industry produces many different types of chocolate: in recent years, dark chocolate, in particular, has gained great popularity. Interest in chocolate has grown, owing to its physiological and potential health effects, such as regulation of blood pressure, insulin levels, vascular functions, oxidation processes, prebiotic effects, glucose homeostasis, and lipid metabolism. However, further translational and epidemiologic studies are needed to confirm available results and to evaluate other possible effects related to the consumption of cocoa and chocolate, verifying in humans the effects hitherto demonstrated only in vitro, and suggesting how best to consume (in terms of dose, mode, and time) chocolate in the daily diet.
Stochastic Expansions Maintain the Clonal Stability of CD8+ T Cell Populations Undergoing Memory Inflation Driven by Murine Cytomegalovirus

Key Points Clonal stability is a feature of memory inflation. Stochastic expansions maintain clonal stability during memory inflation. Persistent clonotypes are often public in the context of memory inflation. CMV is an obligate and persistent intracellular pathogen that continually drives the production of highly differentiated virus-specific CD8+ T cells in an Ag-dependent manner, a phenomenon known as memory inflation. Extensive proliferation is required to generate and maintain inflationary CD8+ T cell populations, which are counterintuitively short-lived and typically exposed to limited amounts of Ag during the chronic phase of infection. An apparent discrepancy therefore exists between the magnitude of expansion and the requirement for ongoing immunogenic stimulation. To address this issue, we explored the clonal dynamics of memory inflation. First, we tracked congenically marked OT-I cell populations in recipient mice infected with murine CMV (MCMV) expressing the cognate Ag OVA. Irrespective of numerical dominance, stochastic expansions were observed in each population, such that dominant and subdominant OT-I cells were maintained at stable frequencies over time. Second, we characterized endogenous CD8+ T cell populations specific for two classic inflationary epitopes, M38 and IE3. Multiple clonotypes simultaneously underwent Ag-driven proliferation during latent infection with MCMV. In addition, the corresponding CD8+ T cell repertoires were stable over time and dominated by persistent clonotypes, many of which also occurred in more than one mouse. Collectively, these data suggest that stochastic encounters with Ag occur frequently enough to maintain oligoclonal populations of inflationary CD8+ T cells, despite intrinsic constraints on epitope display at individual sites of infection with MCMV.
The Impact Of Structured Exercise Programs On Metabolic Syndrome And Its Components: A Systematic Review

Background The metabolic syndrome (MetS) is highly prevalent and associated with higher risk of diabetes and cardiovascular events. Exercise programs have been shown to improve components of MetS, but the optimal design of a structured exercise program for treatment of the MetS remains unclear. Purpose To assess the impact of different exercise programs on the MetS and its components. Methods MEDLINE via PubMed and Embase was searched. Randomized controlled trials of supervised exercise alone and in combination with nutrition programs compared with usual care in adults with the MetS were selected. Two authors independently reviewed articles to select eligible studies and performed data abstraction. Eight studies representing 1218 patients were included. The participants had a median age of 51, median BMI of 29 kg/m2, and were 55% male. Mean weight loss increased with program duration. For combination programs, the mean weight loss was −2.6 kg, −3.7 kg, and −6.5 kg for 3, 6, and 12 months, respectively. The components of the MetS most frequently statistically significantly improved were waist circumference (6/6 studies), blood pressure (4/6 studies), and high-density lipoprotein cholesterol (3/6 studies). Limitations Studies did not include long-term follow-up post program completion to evaluate persistence of benefit. It is unknown whether the same results would be found in an older, more obese population. Conclusion Supervised exercise programs yield significant resolution of components of the MetS, particularly in reducing waist circumference. Longer program duration and frequent interval sessions appear to have highest benefit and thus may help reduce cardiovascular risk and diabetes associated with the MetS.