Miracle-dz/UniFAR-FTUs huggingface dataset:
miR-200b Mediates Endothelial-to-Mesenchymal Transition in Diabetic Cardiomyopathy

Hyperglycemia-induced endothelial injury is a key pathogenetic factor in diabetic cardiomyopathy. Endothelial injury may lead to a phenotypic change (i.e., endothelial-to-mesenchymal transition [EndMT]), causing cardiac fibrosis. Epigenetic mechanisms, through specific microRNA, may regulate such a process. We investigated the mechanisms for such changes in cardiac microvascular endothelial cells and in the heart of genetically engineered mice with chemically induced diabetes. Cardiac tissues and isolated mouse heart endothelial cells (MHECs) from animals with or without endothelial-specific overexpression of miR-200b, with or without streptozotocin-induced diabetes, were examined at the mRNA and protein levels for endothelial and mesenchymal markers. Expression of miR-200b and its targets was quantified. Cardiac functions and structures were analyzed. In the hearts of wild-type diabetic mice, EndMT was observed, which was prevented in the miR-200b transgenic diabetic mice. Expression of specific markers such as vascular endothelial growth factor, zinc finger E-box–binding homeobox, transforming growth factor-β1, and p300 were increased in the hearts of diabetic mice and were prevented following miR-200b overexpression. MHECs showed similar changes. miR-200b overexpression also prevented diabetes-induced cardiac functional and structural changes. These data indicate that glucose-induced EndMT in vivo and in vitro in the hearts of diabetic mice is possibly mediated by miR-200b and p300.
Sex-Specific Control of Fat Mass and Counterregulation by Hypothalamic Glucokinase

Glucokinase (Gck) is a critical regulator of glucose-induced insulin secretion by pancreatic β-cells. It has been suggested to also play an important role in glucose signaling in neurons of the ventromedial hypothalamic nucleus (VMN), a brain nucleus involved in the control of glucose homeostasis and feeding. To test the role of Gck in VMN glucose sensing and physiological regulation, we studied mice with genetic inactivation of the Gck gene in Sf1 neurons of the VMN (Sf1Gck−/− mice). Compared with control littermates, Sf1Gck−/− mice displayed increased white fat mass and adipocyte size, reduced lean mass, impaired hypoglycemia-induced glucagon secretion, and a lack of parasympathetic and sympathetic nerve activation by neuroglucopenia. However, these phenotypes were observed only in female mice. To determine whether Gck was required for glucose sensing by Sf1 neurons, we performed whole-cell patch clamp analysis of brain slices from control and Sf1Gck−/− mice. Absence of Gck expression did not prevent the glucose responsiveness of glucose-excited or glucose-inhibited Sf1 neurons in either sex. Thus Gck in the VMN plays a sex-specific role in the glucose-dependent control of autonomic nervous activity; this is, however, unrelated to the control of the firing activity of classical glucose-responsive neurons.
Risk Factors for Cardiovascular Disease in Type 1 Diabetes

Risk factors for cardiovascular disease (CVD) are well-established in type 2 but not type 1 diabetes (T1DM). We assessed risk factors in the long-term (mean 27 years) follow-up of the Diabetes Control and Complications Trial (DCCT) cohort with T1DM. Cox proportional hazards multivariate models assessed the association of traditional and novel risk factors, including HbA1c, with major atherosclerotic cardiovascular events (MACE) (fatal or nonfatal myocardial infarction [MI] or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Age and mean HbA1c were strongly associated with any-CVD and with MACE. For each percentage point increase in mean HbA1c, the risk for any-CVD and for MACE increased by 31 and 42%, respectively. CVD and MACE were associated with seven other conventional factors, such as blood pressure, lipids, and lack of ACE inhibitor use, but not with sex. The areas under the receiver operating characteristics curves for the association of age and HbA1c, taken together with any-CVD and for MACE, were 0.70 and 0.77, respectively, and for the final models, including all significant risk factors, were 0.75 and 0.82. Although many conventional CVD risk factors apply in T1DM, hyperglycemia is an important risk factor second only to age.
Repeat Sprint Ability

SUMMARY SPRINT SPEED IS RELATED TO THE ABILITY TO DEPLETE LARGE AMOUNTS OF HIGH-ENERGY PHOSPHATES AT A FAST RATE. TO SPRINT REPEATEDLY, THE AEROBIC SYSTEM MUST RESYNTHESIZE POLYMERASE CHAIN REACTION, REMOVE ACCUMULATED INTRACELLULAR INORGANIC PHOSPHATE, AND OXIDIZE LACTATE DURING REST PERIODS. WHETHER THIS CAN BE APPRECIABLY IMPROVED VIA A HIGH V[Combining Dot Above]O2MAX REMAINS CONTROVERSIAL. HOWEVER, IT IS LIKELY IMPROVED VIA ANAEROBIC QUALITIES SUCH AS STRENGTH, POWER, AND SPEED, ALONG WITH THE ATHLETE'S VELOCITY AT ONSET OF BLOOD LACTATE ACCUMULATION. WHEN REPORTING REPEAT SPRINT ABILITY TEST RESULTS, TOTAL OR MEAN TIME SHOULD BE USED.
Ire1α in Pomc Neurons Is Required for Thermogenesis and Glycemia

Whether neuronal inositol-requiring enzyme 1 (Ire1) is required for the proper regulation of energy balance and glucose homeostasis is unclear. We found that pro-opiomelanocortin (Pomc)–specific deficiency of Ire1α accelerated diet-induced obesity concomitant with a decrease in energy expenditure. This hypometabolic phenotype included deficits in thermogenic responses to diet and cold exposure as well as “beiging” of white adipose tissue. We also demonstrate that loss of Ire1α in Pomc neurons impaired whole-body glucose and insulin tolerance as well as hepatic insulin sensitivity. At the cellular level, deletion of Ire1α in Pomc neurons elevated hypothalamic endoplasmic reticulum (ER) stress and predisposed Pomc neurons to leptin and insulin resistance. Together, the current studies extend and confirm conclusions that Ire1α-Xbp1s and associated molecular targets link ER stress in arcuate Pomc neurons to aspects of normal energy and glucose homeostasis.
Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signaling Pathway Impairs β-Cell Function In Vivo

Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-I signaling. We therefore examined the effects of mutation of five “inhibitory” Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic β-cells, either wild-type (WT) or a mutated IRS2 protein (IRS25A). Islets size, number, and mRNA levels of catalase and superoxide dismutase were increased, whereas those of nitric oxide synthase were decreased, in 7- to 10-week-old IRS25A-β mice compared with IRS2WT-β mice. However, glucose homeostasis and insulin secretion in IRS25A-β mice were impaired when compared with IRS2WT-β mice or to nontransgenic mice. This was associated with reduced mRNA levels of Glut2 and islet β-cell transcription factors such as Nkx6.1 and MafA. Similarly, components mediating the unfolded protein response were decreased in islets of IRS25A-β mice in accordance with their decreased insulin secretion. The beneficial effects of IRS25A on β-cell proliferation and β-cell transcription factors were evident only in 5- to 8-day-old mice. These findings suggest that elimination of inhibitory Ser phosphorylation sites of IRS2 exerts short-term beneficial effects in vivo; however, their sustained elimination leads to impaired β-cell function.
Rac1 and AMPK Account for the Majority of Muscle Glucose Uptake Stimulated by Ex Vivo Contraction but Not In Vivo Exercise

Exercise bypasses insulin resistance to increase glucose uptake in skeletal muscle and therefore represents an important alternative to stimulate glucose uptake in insulin-resistant muscle. Both Rac1 and AMPK have been shown to partly regulate contraction-stimulated muscle glucose uptake, but whether those two signaling pathways jointly account for the entire signal to glucose transport is unknown. We therefore studied the ability of contraction and exercise to stimulate glucose transport in isolated muscles with AMPK loss of function combined with either pharmacological inhibition or genetic deletion of Rac1. Muscle-specific knockout (mKO) of Rac1, a kinase-dead α2 AMPK (α2KD), and double knockout (KO) of β1 and β2 AMPK subunits (β1β2 KO) each partially decreased contraction-stimulated glucose transport in mouse soleus and extensor digitorum longus (EDL) muscle. Interestingly, when pharmacological Rac1 inhibition was combined with either AMPK β1β2 KO or α2KD, contraction-stimulated glucose transport was almost completely inhibited. Importantly, α2KD+Rac1 mKO double-transgenic mice also displayed severely impaired contraction-stimulated glucose transport, whereas exercise-stimulated glucose uptake in vivo was only partially reduced by Rac1 mKO with no additive effect of α2KD. It is concluded that Rac1 and AMPK together account for almost the entire ex vivo contraction response in muscle glucose transport, whereas only Rac1, but not α2 AMPK, regulates muscle glucose uptake during submaximal exercise in vivo.
A Comparison of Adult Attitudes Toward Their Parents' Sexuality and Their Parents' Attitudes

ABSTRACT This study compared the attitudes of adult children toward the sexuality of their older parents with their parent's own attitudes toward sexuality. A 56-item questionnaire was given to 41 family pairs consisting of a parent over age 65 and his or her son or daughter. Questions were based upon previous studies and involved six point Likért ratings. In general, attitudes toward sexuality were positive among parents and their adult children. However, adult children had significantly more positive attitudes than their parents. This difference was primarily due to more positive attitudes toward physical aspects of sexual behaviours. Overall, the disapproval and negative attitudes of adult children reported in previous research were not found in this study. Adult children had positive attitudes, much more positive attitudes than their parents, possibly due to a cohort effect RÉSUMÉ Cette recherche compare les attitudes des enfants adultes concernant la sexualité de leurs parents âgés avec les attitudes de leurs parents concernant la sexualité. Quarante-et-un parents ayant plus de 65 ans et leurs fils ou filles ont répondu à un questionnaire de 56 items. Les questions découlent de recherches antérieures et les réponses devaient être indiquées selon une grille d'analyse de type «Likert» de six points. Les attitudes des parents concernant la sexualité ainsi que celles de leurs enfants d'âge adulte étaient généralement positives. Les attitudes des enfants adultes étaient significativement plus positives que celles de leurs parents. Cette différence est due principalement à une attitude plus positive chez les enfants concernant les aspects physiques des comportements sexuels. Cette recherche n'a pas démontré la présence d'attitudes négatives de la part des enfants adultes. Les attitudes des enfants adultes étaient positives et généralement plus positives que celles de leurs parents, possiblement à cause de différences de cohortes.
High-Intensity Exercise as a Dishabituating Stimulus Restores Counterregulatory Responses in Recurrently Hypoglycemic Rodents

Hypoglycemia is a major adverse effect of insulin therapy for people with type 1 diabetes (T1D). Profound defects in the normal counterregulatory response to hypoglycemia explain the frequency of hypoglycemia occurrence in T1D. Defective counterregulation results to a large extent from prior exposure to hypoglycemia per se, leading to a condition called impaired awareness of hypoglycemia (IAH), the cause of which is unknown. In the current study, we investigate the hypothesis that IAH develops through a special type of adaptive memory referred to as habituation. To test this hypothesis, we used a novel intense stimulus (high-intensity exercise) to demonstrate two classic features of a habituated response, namely dishabituation and response recovery. We demonstrate that after recurrent hypoglycemia the introduction of a novel dishabituating stimulus (a single burst of high-intensity exercise) in male Sprague-Dawley rats restores the defective hypoglycemia counterregulatory response. In addition, the rats showed an enhanced response to the novel stimulus (response recovery). We make the further observation using proteomic analysis of hypothalamic extracts that high-intensity exercise in recurrently hypoglycemic rats increases levels of a number of proteins linked with brain-derived neurotrophic factor signaling. These findings may lead to novel therapeutic approaches for individuals with T1D and IAH.
Heterogeneous Nuclear Ribonucleoprotein F Stimulates Sirtuin-1 Gene Expression and Attenuates Nephropathy Progression in Diabetic Mice

We investigated the mechanism of heterogeneous nuclear ribonucleoprotein F (hnRNP F) renoprotective action in a type 2 diabetes (T2D) mouse model (db/db). Immortalized rat renal proximal tubular cells (IRPTCs) and kidneys from humans with T2D were also studied. The db/db mice developed hyperglycemia, oxidative stress, and nephropathy at age 20 weeks compared with their db/m littermates. These abnormalities, with the exception of hyperglycemia, were attenuated in db/db hnRNP F–transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs. Sirtuin-1, Foxo3α, and catalase expression were significantly decreased in RPTCs from db/db mice and normalized in db/db hnRNP F–Tg mice. In vitro, hnRNP F overexpression stimulated Sirtuin-1 and Foxo3α with downregulation of acetylated p53 expression and prevented downregulation of Sirtuin-1 and Foxo3α expression in IRPTCs by high glucose plus palmitate. Transfection of Sirtuin-1 small interfering RNA prevented hnRNP F stimulation of Foxo3α and downregulation of acetylated p53 expression. hnRNP F stimulated Sirtuin-1 transcription via hnRNP F–responsive element in the Sirtuin-1 promoter. Human T2D kidneys exhibited more RPTC apoptosis and lower expression of hnRNP F, SIRTUIN-1, and FOXO3α than nondiabetic kidneys. Our results demonstrate that hnRNP F protects kidneys against oxidative stress and nephropathy via stimulation of Sirtuin-1 expression and signaling in diabetes.
Exosomes From Adipose-Derived Stem Cells Attenuate Adipose Inflammation and Obesity Through Polarizing M2 Macrophages and Beiging in White Adipose Tissue

Adipose-derived stem cells (ADSCs) play critical roles in controlling obesity-associated inflammation and metabolic disorders. Exosomes from ADSCs exert protective effects in several diseases, but their roles in obesity and related pathological conditions remain unclear. In this study, we showed that treatment of obese mice with ADSC-derived exosomes facilitated their metabolic homeostasis, including improved insulin sensitivity (27.8% improvement), reduced obesity, and alleviated hepatic steatosis. ADSC-derived exosomes drove alternatively activated M2 macrophage polarization, inflammation reduction, and beiging in white adipose tissue (WAT) of diet-induced obese mice. Mechanistically, exosomes from ADSCs transferred into macrophages to induce anti-inflammatory M2 phenotypes through the transactivation of arginase-1 by exosome-carried active STAT3. Moreover, M2 macrophages induced by ADSC-derived exosomes not only expressed high levels of tyrosine hydroxylase responsible for catecholamine release, but also promoted ADSC proliferation and lactate production, thereby favoring WAT beiging and homeostasis in response to high-fat challenge. These findings delineate a novel exosome-mediated mechanism for ADSC–macrophage cross talk that facilitates immune and metabolic homeostasis in WAT, thus providing potential therapy for obesity and diabetes.
Comportamiento de la trichomonosis vaginal en un grupo de adolescente

: 275 adolescents aged 10-19 receiving attention at the infantojuvenile department of pregnancy interruption and of sexually transmitted infections of "Ramon Gonzalez Coro" and "Eusebio Hernandez" Gynecoobstetric Teaching Hospitals, both in Havana City, were studied from August, 1999, to September, 2000, aimed at knowing the behavior of the infection caused by Trichomonas vaginalis in this population group. The results yielded 18.1 % of positivity to parasitosis. It was proved by the calculation of relative risk that the adolescents that had an active or past infection due to Trichomonas vaginalis have more possibilities of getting an infection produced by human Papilomavirus than those without this condition. It was demonstrated that 78 (28.3 %) of the total of patients examined had some type of lesion in the uterine cervix. Some risk factors as non using condon, having multiple sexual partners and the early beginning of sexual relations, which may facilitate the adquisition of this parasitosis in a population so vulnerable as the adolescents, were made known.
The effects of beetroot juice supplementation on exercise economy, rating of perceived exertion and running mechanics in elite distance runners: A double-blinded, randomized study

Purpose Nitrate-rich beetroot juice supplementation has been extensively used to increase exercise economy in different populations. However, its use in elite distance runners, and its potential effects on biomechanical aspects of running have not been properly investigated. This study aims to analyze the potential effects of 15 days of beetroot juice supplementation on physiological, psychological and biomechanical variables in elite runners. Methods Twelve elite middle and long-distance runners (age = 26.3 ± 5.1yrs, VO2Max = 71.8±5.2 ml*kg-1*min-1) completed an incremental running test to exhaustion on a treadmill before and after a 15-days supplementation period, in which half of the group (EG) consumed a daily nitrate-rich beetroot juice and the other group (PG) consumed a placebo drink. Time to exhaustion (TEx), running economy, vastus lateralis oxygen saturation (SmO2), leg stiffness and rate of perceived exertion (RPE) were measured at 15, 17.1 and 20 km/h during the incremental test. Results Likely to very likely improvements in EG were observed for the RPE (Standardized mean difference (SMD) = -2.17, 90%CI = -3.23, -1.1), SmO2 (SMD = 0.72, 90%CI = 0.03, 1.41) and TEx (SMD = 1.18, 90%CI = -0.14, 2.5) in comparison with PG. No other physiological or biomechanical variable showed substantial improvements after the supplementation period. Conclusions Fifteen days of nitrate-rich beetroot juice supplementation produced substantial improvements in the time to exhaustion in elite runners; however, it didn’t produce meaningful improvements in running economy, VO2Max or mechanical parameters.
The Eect of Deregionalization on Health Outcomes: Evidence from Neonatal Intensive Care

The number of neonatal intensive care units (NICUs) in smaller, community hospitals increased greatly during the 1980s and 1990s, attracting deliveries away from hospitals with the most sophisticated NICUs. The health care community has voiced concern over this pattern of deregionalization because previous estimates nd higher mortality rates for infants born in hospitals with less sophisticated NICUs relative to infants born in hospitals with the highest level of care, conditional on a host of observable characteristics. These estimates, however, may be biased by unobserved selection. In this paper I estimate the causal eect on mortality of the level of neonatal care available at the hospital in which a very low birth weight infant is born. To overcome potential selection bias, I use an instrumental variable strategy that exploits exogenous variation in distance from a mother’s residence to hospitals oering each level of care. My instrumental variable estimates are bounded well below ordinary least squares estimates and are not statistically dierent from zero. These results suggest that relocating patients from lower level facilities to hospitals with the highest level of care prior to delivery may not lead to improved mortality outcomes, because the infants born in lower level facilities have higher unobserved mortality risk. I provide suggestive evidence that inter-hospital transfer after birth is one mechanism by which infants born at the lowest levels of care achieve similar outcomes to those born at higher level hospitals.
Uncertainty in malaria simulations in the highlands of Kenya: Relative contributions of model parameter setting, driving climate and initial condition errors

In this study, experiments are conducted to gauge the relative importance of model, initial condition, and driving climate uncertainty for simulations of malaria transmission at a highland plantation in Kericho, Kenya. A genetic algorithm calibrates each of these three factors within their assessed prior uncertainty in turn to see which allows the best fit to a timeseries of confirmed cases. It is shown that for high altitude locations close to the threshold for transmission, the spatial representativeness uncertainty for climate, in particular temperature, dominates the uncertainty due to model parameter settings. Initial condition uncertainty plays little role after the first two years, and is thus important in the early warning system context, but negligible for decadal and climate change investigations. Thus, while reducing uncertainty in the model parameters would improve the quality of the simulations, the uncertainty in the temperature driving data is critical. It is emphasized that this result is a function of the mean climate of the location itself, and it is shown that model uncertainty would be relatively more important at warmer, lower altitude locations.
Virtual screening using covalent docking to find activators for G245S mutant p53

TP53 is the most mutated gene in all cancers. The mutant protein also accumulates in cells. The high frequency of p53 mutations makes the protein a promising target for anti-cancer therapy. Only a few molecules have been found, using in vitro screening, to reactivate the mutant protein. APR-246 is currently the most successful mutant p53 activator, which reactivates the transcriptional activity of p53 by covalently binding to C124 of the protein. We have recently created in silico models of G245S-mp53 in its apo and DNA-bound forms. In this paper we further report on our in silico screening for potential activators of G245S-mp53. We filtered the ZINC15 database (13 million compounds) to only include drug-like molecules with moderate to standard reactivity. Our filtered database of 130,000 compounds was screened using the DOCKTITE protocol in the Molecular Operating Environment software. We performed covalent docking at C124 of G245S-mp53 to identify potential activators of the mutant protein. The docked compounds were ranked using a consensus scoring approach. We also used ADMET Predictor™ to predict pharmacokinetics and the possible toxicities of the compounds. Our screening procedure has identified compounds, mostly thiosemicarbazones and halo-carbonyls, with the best potential as G245S-mp53 activators, which are described in this work. Based on its binding scores and ADMET risk score, compound 2 is likely to have the best potential as a G245S-mp53 activator compared to the other top hits.