Miracle-dz/UniFAR-FTUs huggingface dataset:
Incorrect DNA methylation of the DAZL promoter CpG island associates with defective human sperm†

BACKGROUND Successful gametogenesis requires the establishment of an appropriate epigenetic state in developing germ cells. Nevertheless, an association between abnormal spermatogenesis and epigenetic disturbances in germline-specific genes remains to be demonstrated. METHODS In this study, the DNA methylation pattern of the promoter CpG island (CGI) of two germline regulator genes—DAZL and DAZ, was characterized by bisulphite genomic sequencing in quality-fractioned ejaculated sperm populations from normozoospermic (NZ) and oligoasthenoteratozoospermic (OAT) men. RESULTS OAT patients display increased methylation defects in the DAZL promoter CGI when compared with NZ controls. Such differences are recorded when analyzing sperm fractions enriched either in normal or defective germ cells (P< 0.001 in both cases). Significant differences in DNA methylation profiles are also observable when comparing the qualitatively distinct germ cell fractions inside the NZ and OAT groups (P= 0.003 and P= 0.007, respectively). Contrastingly, the unmethylation pattern of the DAZ promoter CGI remains correctly established in all experimental groups. CONCLUSIONS An association between disrupted DNA methylation of a key spermatogenesis gene and abnormal human sperm is described here for the first time. These results suggest that incorrect epigenetic marks in germline genes may be correlated with male gametogenic defects.
A meta-analysis of HLA peptidome composition in different hematological entities: entity-specific dividing lines and “pan-leukemia” antigens

Hematological malignancies (HM) are highly amenable targets for immunotherapeutic intervention and may be effectively treated by antigen-specific T-cell based treatment. Recent studies demonstrate that physiologically occurring anti-cancer T-cell responses in certain HM entities target broadly presented non-mutated epitopes. HLA ligands are thus implied as prime targets for broadly applicable and antigen-specific off-the-shelf compounds. With the aim of assessing the presence of common targets shared among different HM which may enable addressing a larger patient collective we conducted a meta-analysis of 83 mass spectrometry-based HLA peptidome datasets (comprising 40,361 unique peptide identifications) across four major HM (19 AML, 16 CML, 35 CLL, and 13 MM/MCL samples) and investigated similarities and differences within the HLA presented antigenic landscape. We found the cancer HLA peptidome datasets to cluster specifically along entity and lineage lines, suggesting that the immunopeptidome directly reflects the differences in the underlying (tumor-)biology. In line with these findings, we only detected a small set of entity-spanning antigens, which were predominantly characterized by low presentation frequencies within the different patient cohorts. These findings suggest that design of T-cell immunotherapies for the treatment of HM should ideally be conducted in an entity-specific fashion.
Energy metabolism in weight-stable postobese individuals.

A low metabolic rate for a given body size and body composition and a low ratio of fat to carbohydrate oxidation predict body weight gain. Such metabolic traits could also explain, in part, the propensity of previously obese (postobese) individuals to regain weight after dieting. We studied 11 postobese volunteers (4 males, 7 females; aged 43 +/- 13 y, weighing 80.6 +/- 10.2 kg, with 30 +/- 7% body fat; x +/- SD) who lost 57 +/- 38 kg (23-139 kg) over 14 +/- 12 mo (6-48 mo) on various diet programs and had maintained this weight loss for > or = 2 mo (2-72 mo; 21 +/- 27 mo). After > or = 2 d of a weight-maintenance diet on a metabolic ward, 24-h energy expenditure and ratio of fat to carbohydrate oxidation were measured in a respiratory chamber. Compared with a control group (n = 110) with similar physical characteristics (aged 43 +/- 14 y, weighing 79.5 +/- 11.4 kg, with 30 +/- 12% body fat), [sequence: see text] postobese individuals had similar energy expenditures adjusted for fat-free mass, fat mass, age, and sex, but significantly higher respiratory quotients over 24 h (0.883 +/- 0.026 compared with 0.863 +/- 0.024, P < 0.01) and during sleep, 10 h after the last meal (0.894 +/- 0.063 compared with 0.845 +/- 0.055). These results suggest that postobese individuals have low rates of fat oxidation that may explain their propensity to regain weight. (ABSTRACT TRUNCATED AT 250 WORDS)
Home gardens focusing on the production of yellow and dark-green leafy vegetables increase the serum retinol concentrations of 2-5-y-old children in South Africa.

BACKGROUND Production of yellow and dark-green leafy vegetables at the household level may provide economically deprived households with direct access to provitamin A-rich foods. OBJECTIVE The aim of the study was to determine whether the dietary intake of yellow and dark-green leafy vegetables and the serum retinol concentrations of children improve with a home-gardening program. DESIGN A home-gardening program was integrated with a community-based growth-monitoring system in a rural village. Cross-sectional data were collected at baseline and 20 mo after implementation of the program. The dietary intake, serum retinol concentrations, and growth of 2-5-y-old children and maternal knowledge regarding vitamin A were determined. A neighboring village served as a control village. RESULTS In the experimental village, 126 home gardens were established, representing approximately one-third of the households. Serum retinol concentrations in the experimental village increased significantly (P = 0.0078), whereas those in the control village decreased significantly (P = 0.0148). At follow-up, children from the experimental village consumed yellow and dark-green leafy vegetables more often and had significantly higher (P = 0.005) serum retinol concentrations (0.81 +/- 0.22 micro mol/L; n = 110) than did children from the control village (0.73 +/- 0.19 micro mol/L; n = 111). Maternal knowledge regarding vitamin A improved significantly in the experimental village (P = 0.001). CONCLUSION A home-gardening program that was integrated with a primary health care activity, linked to nutrition education, and focused on the production of yellow and dark-green leafy vegetables significantly improved the vitamin A status of 2-5-y-old children in a rural village in South Africa.
Prediction of Drug-Induced Hepatotoxicity Using Long-Term Stable Primary Hepatic 3D Spheroid Cultures in Chemically Defined Conditions

Abstract High failure rates of drug candidates in the clinics, restricted-use warnings as well as withdrawals of drugs in postmarketing stages are of substantial concern for the pharmaceutical industry and drug-induced liver injury (DILI) constitutes one of the most frequent reasons for such safety failures. Importantly, as DILI cannot be accurately predicted using animal models, animal safety tests are commonly complemented with assessments in human in vitro systems. 3D spheroid cultures of primary human hepatocytes in chemically defined conditions, hereafter termed CD-spheroids, have recently emerged as a microphysiological model system in which hepatocytes retain their molecular phenotypes and hepatic functions for multiple weeks in culture. However, their predictive power for the detection of hepatotoxic liabilities has not been systematically assessed. Therefore, we here evaluated the hepatotoxicity of 123 drugs with or without direct implication in clinical DILI events. Importantly, using ATP quantifications as the single endpoint, the model accurately distinguished between hepatotoxic and nontoxic structural analogues and exceeded both sensitivity and specificity of all previously published in vitro assays at substantially lower exposure levels, successfully detecting 69% of all hepatotoxic compounds without producing any false positive results (100% specificity). Furthermore, the platform supports the culture of spheroids of primary hepatocytes from preclinical animal models, thereby allowing the identification of animal-specific toxicity events. We anticipate that CD-spheroids represent a powerful and versatile tool in drug discovery and preclinical drug development that can reliably flag hepatotoxic drug candidates and provide guidance for the selection of the most suitable animal models.
Role of cyclic ADP-ribose in the regulation of [Ca2+]i in porcine tracheal smooth muscle.

The purpose of the present study was to determine whether cyclic ADP-ribose (cADPR) acts as a second messenger for Ca2+ release through ryanodine receptor (RyR) channels in tracheal smooth muscle (TSM). Freshly dissociated porcine TSM cells were permeabilized with β-escin, and real-time confocal microscopy was used to examine changes in intracellular Ca2+ concentration ([Ca2+]i). cADPR (10 nM-10 μM) induced a dose-dependent increase in [Ca2+]i, which was blocked by the cADPR receptor antagonist 8-amino-cADPR (20 μM) and by the RyR blockers ruthenium red (10 μM) and ryanodine (10 μM), but not by the inositol 1,4,5-trisphosphate receptor blocker heparin (0.5 mg/ml). During steady-state [Ca2+]ioscillations induced by acetylcholine (ACh), addition of 100 nM and 1 μM cADPR increased oscillation frequency and decreased peak-to-trough amplitude. ACh-induced [Ca2+]ioscillations were blocked by 8-amino-cADPR; however, 8-amino-cADPR did not block the [Ca2+]iresponse to a subsequent exposure to caffeine. These results indicate that cADPR acts as a second messenger for Ca2+ release through RyR channels in TSM cells and may be necessary for initiating ACh-induced [Ca2+]ioscillations.
Protein nutritional status and function are associated with type 2 diabetes in Hispanic elders.

BACKGROUND Hispanic elders have a high prevalence of diabetes and poor glycemic control, leading to inadequate nutritional status, muscle wasting, and impaired function. OBJECTIVE We examined the association of type 2 diabetes with nutritional status measured by serum albumin concentrations and midupper arm muscle area (MAM) and with function measured by difficulty with at least one activity of daily living. DESIGN : Health history and disability were assessed by self report in 556 Hispanics with a mean (+/- SD) age of 69 +/- 7 y and 158 non-Hispanic whites (NHW; aged 71 +/- 7 y) from the Massachusetts Hispanic Elders Survey. Energy intake (in MJ/d) and protein intake (in g/d) were estimated with use of a food-frequency questionnaire. Body mass index (BMI; in kg/m(2)) and C-reactive protein concentrations (in mg/L) were also measured. Multiple logistic regression models by ethnic group were used. RESULTS There were no significant differences between Hispanics and NHWs in the proportion of those with low albumin concentrations or low MAM. Hispanic diabetic women had the lowest proportion of low MAM. The risk of low serum albumin concentration was twice as high in Hispanics taking insulin as in their NHW counterparts. Among Hispanics, low albumin concentration and low BMI were associated with low MAM; female sex, low albumin concentration, high BMI, and insulin use were significantly associated with risk of functional impairment. CONCLUSION Type 2 diabetes is associated with poor nutritional status, muscle loss, and functional impairment among Hispanic elders.
Differential effects of rat pregnancy on uterine and lung atrial natriuretic factor receptors.

We investigated if the refractoriness to the tocolytic effects of atrial natriuretic factor (ANF) during rat pregnancy is due to a downregulation of one or both guanylyl cyclase (GC)-coupled GC-A and GC-B ANF receptors; lungs were used as controls. Uteri and lungs of virgin, pregnant ( days 7, 16, and 21), and day 2postpartum rats expressed mRNAs for GC-A and GC-B as well as GC-uncoupled ANF-C receptors. GC-B receptor protein was more abundant than GC-A in uteri; the reverse was the case in lungs. Pregnancy decreased uterine mRNAs and proteins for GC-A and GC-B receptors as well as the effects of ANF and C-type natriuretic peptide (CNP) on uterine GC activity; lung ANF receptors and effects of ANF and CNP on lung GC activity were not modulated by pregnancy. It is concluded that pregnancy induces organ-specific modulation of ANF receptors and a downregulation of ANF-GC receptors would minimize interference with uterine motility during pregnancy.
Ractopamine in particulate matter emitted from beef cattle feedyards and playa wetlands in the Central Plains

Beef cattle in the United States are routinely administered ractopamine, a β‐adrenergic receptor agonist, to enhance growth. The present study is the first to quantify ractopamine in feedyard‐emitted particulate matter and playa wetlands near feedyards. Ractopamine was present in 92% of particulate matter samples, 16% of playa sediment samples, and 3% of playa water samples, at maximum concentrations of 4.7 μg/g, 5.2 ng/g (dry wt), and 271 ng/L, respectively. These data suggest that aerial transmission and deposition of particulate matter is a transport mechanism for ractopamine between feedyards and aquatic systems in the region. Environ Toxicol Chem 2018;37:970–974. © 2017 SETAC
Digestion and absorption of carbohydrates in fowl and events through perinatal development.

Starch is the main carbohydrate in the food of poultry. Starch granules are digested by pancreatic alpha-amylase in the small intestine. Intestinal villi have enterocytes that project microvilli with a fibrous glycocalyx from the surface. These fine structures are envisaged to entrap water that is mixed with mucin from nearby goblet cells to form the "unstirred water layer. " Maltose, maltotriose and alpha-limit dextrins must diffuse across this first barrier to absorption to be hydrolyzed by maltase and sucrase-isomaltase immobilized at the membrane; however, the resultant glucose, once formed, accrues at the surface to provide a concentration advantage. Fowl adjust to changes in dietary starch by altering the amount of amylase released, intestinal surface area and enterocyte carbohydrase concentration. Enterocytes arising during embryonic development have no carbohydrases and are not involved with glucose absorption, but they appear to be specialized for maternal immunoglobin transfer in ovo. Embryonic villi are stimulated by transfer activity, and their growth depends on enterocytes arising from the crypt. Mature crypt cells are capable of digestion-absorptive activities and dominate the villus shortly after the chick hatches when yolk sac reserves are depleted.
Biochemical hypothyroidism secondary to iodine deficiency is associated with poor school achievement and cognition in Bangladeshi children.

Iodine deficiency in pregnancy leads to poor cognitive function in the offspring; however, the effect of concurrent iodine deficiency on school-aged children is not clear. Several studies have shown that school children in iodine-deficient villages have poorer cognitive function than children in iodine-sufficient villages. However, villages differ in many factors that may also detrimentally affect children's development. In addition, the children's nutritional and health status has not usually been taken into account. In this study, we compared the cognitive function and school achievement levels of 170 children who had recently had low thyroxine (T4) levels [T4 </= 45 nmol/L (hypothyroid)] with children who had not had low T4 levels [T4 >/=70 nmol/L (euthyroid)]. The children were matched for school and grade level and came from the same iodine-deficient regions in rural Bangladesh. They were given a battery of cognitive, motor and school achievement tests. We also measured their nutritional status, examined their stools for geohelminths and assessed their home environments. A factor analysis of cognitive and motor function tests yielded two factors, a general cognitive factor and a fine motor factor. The children's height and arm circumference, experience of hunger, parental characteristics and stimulation in the home made independent contributions to their test scores. Controlling for these variables, the hypothyroid children performed worse than the euthyroid children on reading and spelling and the general cognitive factor. These findings indicate that a large number of disadvantages including hypothyroidism are related to the poor development of these children.
Mechanisms for the acute effect of fructose on postprandial lipemia.

BACKGROUND A high fructose intake can lead to postprandial hypertriacylglycerolemia. The underlying mechanism is unclear. OBJECTIVE The objective of the study was to investigate the mechanisms involved in fructose-induced hypertriacylglycerolemia and the contribution of de novo lipogenesis in an acute setting. DESIGN In a randomized, crossover study, 14 subjects were given a fructose or glucose test meal after an overnight fast. [(2)H2]Palmitate and [U(13)C]d-fructose or [U(13)C]d-glucose were added to trace the handling of dietary fats and the fate of dietary sugars in the body. Blood samples were taken before and after the meal. Respiratory exchange ratio was measured by using indirect calorimetry, and breath samples were collected. RESULTS Plasma triacylglycerol and VLDL-triacylglycerol concentrations were significantly higher (P = 0.001 for both), whereas the concentrations of insulin and [(2)H2]palmitate in nonesterified fatty acids were significantly lower after fructose than after glucose (P = 0.002 and 0.03, respectively). The respiratory exchange ratio was higher after fructose (P = 0.04); significantly (P = 0.003) more carbon from sugars was recovered in breath carbon dioxide over 6 h after fructose (30.5%) than after glucose (24.5%). At 240 min, newly synthesized fatty acids from fructose made up approximately 0.4% of circulating VLDL-triacylglycerol, whereas newly synthesized triacylglycerol-glycerol made up 38%. Newly synthesized fatty acids and triacylglycerol-glycerol from glucose contributed almost none of VLDL-triacylglycerol (P = 0.002 and 0.007 for glucose and fructose, respectively). CONCLUSIONS The lower insulin excursion after fructose may result in less activation of adipose tissue lipoprotein lipase, which led to impaired triacylglycerol clearance. The contribution of de novo lipogenesis to fructose-induced hypertriacylglycerolemia is small, but its effect on altering the partitioning of fatty acids toward esterification may be considerable.
Metabolism of skin and muscle protein is regulated differently in response to nutrition.

We have measured skin and muscle protein kinetics and amino acid (AA) transport in anesthetized rabbits during 1) 64-h fast, 2) AA infusion, 3) AA plus fat emulsion infusion, and 4) AA plus hyperinsulinemia.l-[ ring-13C6]phenylalanine was infused as the tracer, and the ear and hindlimb were used as arteriovenous units to reflect skin and muscle protein kinetics, respectively. Skin protein net balance was not different from zero in all groups, indicating a maintenance of protein mass. In contrast, the muscle net balance differed over a range from -1.6 ± 0.6 after fasting to 0.2 ± 0.2 μmol ⋅ 100 g-1 ⋅ h-1during hyperinsulinemia. In the skin, 59-66% of intracellular free phenylalanine came from proteolysis, and phenylalanine availability from proteolysis was positively correlated to the protein synthesis rate. In conclusion, normal skin maintains its constant protein mass by efficient reutilization of AAs from proteolysis. In contrast to muscle, skin protein is relatively insensitive to control by nutritional and hormonal factors. Because of the metabolic differences, when limb models are used for muscle protein metabolism, the potential contribution by limb skin should be considered.
Evaluation of the Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients Bleeding Score for Predicting the Long-term Out-of-hospital Bleeding Risk in Chinese Patients after Percutaneous Coronary Intervention

Background: The Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients (PARIS) bleeding score is a novel score for predicting the out-of-hospital bleeding risk after percutaneous coronary intervention (PCI). However, whether this score has the same value in non-European and American populations is unclear. This study aimed to assess the PARIS bleeding score's predictive value of bleeding in patients after PCI in the Chinese population. Methods: We performed a prospective, observational study of 10,724 patients who underwent PCI from January to December 2013, in Fuwai Hospital, China. We defined the primary end point as major bleeding (MB) according to Bleeding Academic Research Consortium definition criteria including Type 2, 3, or 5. The predictive value of the PARIS bleeding score was assessed with the area under the receiver operating characteristic (AUROC) curve. Results: Of 9782 patients, 245 (2.50%) MB events occurred during the 2 years of follow-up. The PARIS bleeding score was significantly higher in the MB group than that of non-MB group (4.00 [3.00, 5.00] vs. 3.00 [2.00, 5.00], Z = 3.71, P < 0.001). According to risk stratification of the PARIS bleeding score, the bleeding risk in the intermediate- and high-risk groups was 1.50 times (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.160–1.950; P = 0.002) and 2.27 times higher (HR: 2.27; 95% CI: 1.320–3.900; P = 0.003) than that in the low-risk group. The PARIS bleeding score showed a moderate predictive value for MB in the overall population (AUROC: 0.568, 95% CI: 0.532–0.605; P < 0.001) and acute coronary syndrome (ACS) subgroup (AUROC: 0.578, 95% CI: 0.530–0.626; P = 0.001) and tended to be predictive in the non-ACS subgroup (AUROC: 0.556, 95% CI: 0.501–0.611; P = 0.054). Conclusion: The PARIS bleeding score shows good clinical value for risk stratification and has a significant, but relatively limited, prognostic value for out-of-hospital bleeding in the Chinese population after PCI.
Diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction.

BACKGROUND Endothelial dysfunction is one of the mechanisms linked to an increased risk of cardiovascular disease. OBJECTIVE We assessed the association between several diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction. DESIGN Diet-quality scores on the Healthy Eating Index (HEI), Alternate Healthy Eating Index (AHEI), Diet Quality Index Revised (DQI-R), Recommended Food Score (RFS), and the alternate Mediterranean Diet Index (aMED) were calculated by using a food-frequency questionnaire that was administered in 1990 to 690 women in the Nurses' Health Study (ages 43-69 y, no cardiovascular disease or diabetes). Blood collection was completed in the same year. We used regression analysis to assess the associations between these diet-quality scores and plasma concentrations of C-reactive protein, interleukin 6, E-selectin, soluble intercellular cell adhesion molecule 1, and soluble vascular cell adhesion molecule 1. RESULTS The various diet-quality scores were significantly correlated with each other; correlation coefficients ranged from 0.56 to 0.80 (all P values < 0.0001). After adjustment for age, body mass index, alcohol intake, physical activity, smoking status, and energy intake, the HEI and DQI-R were not significantly associated with any of the biomarkers, whereas the AHEI and aMED scores were associated with significantly lower concentrations of most biomarkers. The RFS was significantly associated with a lower concentration of E-selectin only. C-reactive protein concentrations were 30% (P < 0.05) and 24% (P < 0.05) lower in the top than in the bottom quintile of the AHEI and of the aMED, respectively CONCLUSION Higher AHEI and aMED scores were associated with lower concentrations of biomarkers of inflammation and endothelial dysfunction and therefore may be useful as guidelines for reducing the risk of diseases involving such biological pathways.