Miracle-dz/UniFAR-FTUs huggingface dataset:
Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans[S]

Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog eprotirome. Both hyperthyroidism and eprotirome treatment reduced circulating PCSK9, lipoprotein cholesterol, apoB and AI, and lipoprotein(a), while cholesterol synthesis was stable. Hyperthyroidism, but not eprotirome treatment, markedly increased bile acid synthesis and reduced fibroblast growth factor (FGF) 19 and dietary cholesterol absorption. Eprotirome treatment, but not hyperthyroidism, reduced plasma triglycerides. Neither hyperthyroidism nor eprotirome treatment altered insulin, glucose, or FGF21 levels. TH reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism. TH also stimulates bile acid synthesis, although this response is not critical for its LDL-lowering effect.
An unsupervised feature learning approach to improve automatic incident detection

Sophisticated automatic incident detection (AID) technology plays a key role in contemporary transportation systems. Though many papers were devoted to study incident classification algorithms, few study investigated how to enhance feature representation of incidents to improve AID performance. In this paper, we propose to use an unsupervised feature learning algorithm to generate higher level features to represent incidents. We used real incident data in the experiments and found that effective feature mapping function can be learnt from the data crosses the test sites. With the enhanced features, detection rate (DR), false alarm rate (FAR) and mean time to detect (MTTD) are significantly improved in all of the three representative cases. This approach also provides an alternative way to reduce the amount of labeled data, which is expensive to obtain, required in training better incident classifiers since the feature learning is unsupervised.
Llama oviductal sperm reservoirs: involvement of bulbourethral glands

The aim of this study was to elucidate the role of llama seminal plasma in the formation of oviductal sperm reservoirs. Female llamas with follicles in the mature phase were mated with a bulbourethral glands‐removed male. Females mated with nonbulbourethral glands‐removed males were used as control. Oviducts were obtained by surgery 24 h after mating. The uterotubal junction and isthmus were examined by scanning electron microscopy, and mucopolysaccharides were identified by Alcian blue staining. To know the proteins probably involved in sperm reservoir formation, SDS‐PAGE of seminal plasma (8% and 18% resolving gel) was made. Spermatozoa only adhered to the oviductal mucosa surface of uterotubal junction of females mated with nonbulbourethral glands‐removed males confirming that seminal plasma and, in particular, bulbourethral secretions are related with the oviductal sperm reservoir formation. Histological sections showed sperm in the lumen, immersed in substance, positive for acid mucopolysaccharides. Alcian blue staining of seminal plasma proteins SDS‐PAGE showed a band of high molecular weight containing mucopolysaccharides, only present in nonbulbourethral glands‐removed males. Bulbourethral glands would secrete at least eight different proteins that most likely participate in the process of sperm storage in the oviduct.
PGC-1α-mediated changes in phospholipid profiles of exercise-trained skeletal muscle[S]

Exercise training influences phospholipid fatty acid composition in skeletal muscle and these changes are associated with physiological phenotypes; however, the molecular mechanism of this influence on compositional changes is poorly understood. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a nuclear receptor coactivator, promotes mitochondrial biogenesis, the fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training induces these adaptations, together with increased PGC-1α, PGC-1α may contribute to the exercise-mediated change in phospholipid fatty acid composition. To determine the role of PGC-1α, we performed lipidomic analyses of skeletal muscle from genetically modified mice that overexpress PGC-1α in skeletal muscle or that carry KO alleles of PGC-1α. We found that PGC-1α affected lipid profiles in skeletal muscle and increased several phospholipid species in glycolytic muscle, namely phosphatidylcholine (PC) (18:0/22:6) and phosphatidylethanolamine (PE) (18:0/22:6). We also found that exercise training increased PC (18:0/22:6) and PE (18:0/22:6) in glycolytic muscle and that PGC-1α was required for these alterations. Because phospholipid fatty acid composition influences cell permeability and receptor stability at the cell membrane, these phospholipids may contribute to exercise training-mediated functional changes in the skeletal muscle.
Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study[S]

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.
Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice

Low-grade chronic inflammation plays an important role in the pathogenesis of obesity-induced insulin resistance. ABCA1 is essential for reverse cholesterol transport and HDL synthesis, and protects against macrophage inflammation. In the present study, the effects of ABCA1 deficiency in hematopoietic cells on diet-induced inflammation and insulin resistance were tested in vivo using bone marrow transplanted (BMT)-WT and BMT-ABCA1−/− mice. When challenged with a high-fat high-carbohydrate diabetogenic diet with added cholesterol (HFHSC), BMT-ABCA1−/− mice displayed enhanced insulin resistance and impaired glucose tolerance as compared with BMT-WT mice. The worsened insulin resistance and impaired glucose tolerance in BMT-ABCA1−/− mice were accompanied by increased macrophage accumulation and inflammation in adipose tissue and liver. Moreover, BMT-ABCA1−/− mice had significantly higher hematopoietic stem cell proliferation, myeloid cell expansion, and monocytosis when challenged with the HFHSC diet. In vitro studies indicated that macrophages from ABCA1−/− mice showed significantly increased inflammatory responses induced by saturated fatty acids. Taken together, these studies point to an important role for hematopoietic ABCA1 in modulating a feed-forward mechanism in obesity such that inflamed tissue macrophages stimulate the production of more monocytes, leading to an exacerbation of inflammation and associated disease processes.
Testicular morphology in spontaneously hypertensive rat model: oxidant status and stereological implications

Studies by researchers suggest that reductions in blood flow to the testis could play an important role in the pathogenesis of male infertility. As this oxygen‐dependent organ functions in a state of near anoxia, such a decrease in blood flow may very likely have profound effects on the tissue morphology that ultimately would predispose to various forms of hypo‐spermatogenesis with consequent compromise in reproductive capability. With varying opinions expressed by experts as to the actual culprit or potential pathway and/or effects of pathophysiology of testicular haemodynamics, it still remains debatable whether the observed degenerative changes in testicular tissue are the result of major or minor reductions in flow or the consequence of other vascular pathologies or even extraneous factors. Again, increasing age and male gender have been identified as the single independent risk factors for the occurrence of cardiovascular pathologies with sexual dimorphism highly debated. The investigation of these factors occurring under hypertensive states using the spontaneously hypertensive rat (SHR) as an experimental model has attracted substantial attention in recent past. This review examines the relationships and potential morphologic changes in the testicular tissue under conditions of perturbations in blood flow as seen in the SHR with a view to the proper understanding of the role(s) of various factors that contributes to male subfertility. A suggestion to the use of stereological methods for quantitating various measurements in a highly active and dynamic structure like the testis with its arterial system has been added as this may facilitate a better understanding of the mechanisms implicated under hypertensive conditions.
Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway[S]

The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic β-cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D.
Lipids regulate the hydrolysis of membrane bound glucosylceramide by lysosomal β-glucocerebrosidase

Glucosylceramide (GlcCer) is the primary storage lipid in the lysosomes of Gaucher patients and a secondary one in Niemann-Pick disease types A, B, and C. The regulatory roles of lipids on the hydrolysis of membrane bound GlcCer by lysosomal β-glucocerebrosidase (GBA1) was probed using a detergent-free liposomal assay. The degradation rarely occurs at uncharged liposomal surfaces in the absence of saposin (Sap) C. However, anionic lipids stimulate GlcCer hydrolysis at low pH by up to 1,000-fold depending on the nature and position of the negative charges in their head groups while cationic lipids inhibit the degradation, thus showing the importance of electrostatic interactions between the polycationic GBA1 and the negatively charged vesicle surfaces at low pH. Ceramide, fatty acids, monoacylglycerol, and diacylglycerol also stimulate GlcCer hydrolysis while SM, sphingosine, and sphinganine play strong inhibitory roles, thereby explaining the secondary storage of GlcCer in Niemann-Pick diseases. Surprisingly, cholesterol stimulates GlcCer degradation in the presence of bis(monoacylglycero)phosphate (BMP). Sap C strongly stimulates GlcCer hydrolysis even in the absence of BMP and the regulatory roles of the intraendolysosomal lipids on its activity is discussed. Our data suggest that these strong modifiers of GlcCer hydrolysis affect the genotype-phenotype correlation in several cases of Gaucher patients independent of the types.
Male hypogonadism and metabolic syndrome

The role of androgens in cardiovascular disease is still controversial in men. In this study, we investigated metabolic disorders in Tunisian hypogonadal men compared with healthy controls. Forty hypogonadal men and 80 control subjects were enrolled. Patients with a history of pre‐existing panhypopituitarism, thyroid dysfunction or inflammatory disease were excluded. Glycaemia, glycated haemoglobin (HbA1c), high‐sensitive C‐reactive protein (hsCRP), lipid profile, insulin, testosterone and gonadotrophins were measured. Insulin resistance was assessed by homoeostasis model assessment of insulin resistance (Homa IR). Waist circumference, body mass index and blood pressure were significantly higher in patients compared with controls. Glycemia, HbA1c, fasting serum insulin and Homa IR were significantly increased among hypogonadal men. In univariate analysis, testosterone levels were inversely correlated with body mass index, waist circumference, blood pressure, glycaemia, HbA1C, insulin, Homa IR and hsCRP. In multivariate analysis including all significant variables, initial testosterone level was the only independent risk factor for developing dyslipidaemia. With logistic regression, male hypogonadism was an independent risk factor for MS (P < 0.001). We conclude that low testosterone level plays a central role in the development of metabolic syndrome. Further prospective data are required to establish the causative link.
Effect of cryoprotectant and equilibration temperature on cryopreservation of Lama glama spermatozoa

The aim of this study was to determine the effect of two equilibration temperatures (5 °C and room temperature) and two cryoprotectants (glycerol and dimethylformamide, both at 7%) on llama sperm cryopreservation. Llama ejaculates were divided into four aliquots. A lactose‐EDTA‐egg yolk (LEEY) extender with either 7% glycerol (LEEY‐G) or 7% dimethylformamide (LEEY‐DMF) was added to two of the aliquots, which were equilibrated for 20 min at room temperature and subsequently frozen. The other two aliquots were extended in LEEY, cooled to 5 °C, then LEEY‐G or LEEY‐DMF was added, equilibrated for 20 min at 5 °C and frozen. No significant differences (P > 0.05) were observed in membrane function and chromatin condensation between any of the freeze–thawing protocols. Post‐thaw motility was greater (P < 0.05) in LEEY‐DMF than LEEY‐G. DNA fragmentation was not different between raw and frozen semen with LEEY‐DMF but was high in all samples with glycerol. Our results indicate that 7% glycerol would be detrimental for llama spermatozoa, but further studies are needed to evaluate effectiveness if used at lower concentrations. Dimethylformamide preserved motility and DNA integrity of frozen–thawed llama spermatozoa and could be used to replace glycerol at the concentrations used in this study.
Effects of smoking on fatty acid composition of phospholipid sperm membrane and the malondialdehyde levels in human seminal plasma

The aim of this study was to investigate fatty acids composition of sperm phospholipids, level of lipoperoxidation represented by malondialdehyde and to examine differences between recent smokers and nonsmokers. The levels of malondialdehyde were in the group of all patients 1.51 ± 0.56 μmol l−1, in smokers 1.36 ± 0.59 μmol l−1 and in nonsmokers 1.53 ± 0.55 μmol l−1. Total sperm membrane phospholipid fatty acids were profiled into several groups, saturated acids (in smokers 61.86 ± 9.02%, in nonsmokers 61.20 ± 11.66%), polyunsaturated acids n‐3 (in smokers 12.62 ± 8.18%, in nonsmokers 14.28 ± 13.65%), polyunsaturated acids n‐6 (in smokers 9.13 ± 4.37%, in nonsmokers 10.10 ± 3.79%) and other acids (in smokers 14.36 ± 3.94%, in nonsmokers 13.88 ± 2.31%). Significant correlations were found between the level of malondialdehyde (MDA) and total sperm motility in all patients (r = −0.358, P = 0.013), between both the level of MDA and progressive motility (r = −0.465, P = 0.001) and between the level of MDA and total motility (r = −0.382, P = 0.037) in nonsmokers. There were no statistically significant differences between composition of sperm phospholipid important fatty acids in smokers and nonsmokers. Significant correlations between selected sperm fatty acids and sperm motility and morphology in smokers and nonsmokers were not observed.
Prevention of renal apoB retention is protective against diabetic nephropathy: role of TGF-β inhibition[S]

Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr−/− mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-β (TGF-β), in some experiments mice were injected with either the TGF-β-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect on renal apoB accumulation, but led to modest attenuation of DN with ∼30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF-β. Use of 1D11 led to sustained suppression of TGF-β for approximately 8 weeks at a time. The 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy, and improved survival, compared with the 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of DN. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-β inhibition is nephroprotective.
The role of selected risk factors for development of oesophageal cancer

A hospital-based analytical observational case-control study of 88 oesophageal cancer cases and 200 controls was conducted in the University Hospital Olomouc. A standardized questionnaire was used. The adjusted odds ratio (OR) are calculated by logistic regression. The adjusted odds ratios for tobacco smoking were 6.20 (95% CI 2.78–13.83), 10.64 (95% CI 3.46–32.72) and 3.53 (95% CI 1.26–9.88) for oesophageal cancer, for oesophageal squamous cell carcinoma, and oesophageal adenocarcinoma, respectively. An inverse association with overweight and obesity was found in both histological types. In adenocarcinoma, there was a relatively strong positive association with a statistically significant result for alcohol consumption only in a group consuming more than 300 g of alcohol weekly; the OR was 5.81 (95% CI 1.17–28.84). The strong, statistically significant association was found in alcohol consumption regardless of histological type: the OR was 4.41 (95% CI 1.09–17.84). In a group with 20 or more X-ray exposures, there was a very strong statistically significant positive association. In vegetable consumption, an inverse association was found that was statistically significant only if more than 8 portions of vegetables were eaten weekly, ORs were 0.02–0.11.
The Multiple Risk Factor Intervention Trial

To the Editor. — The Journalis to be commended for its publication of the MRFIT mortality report. How many studies that do not show positive results are ever published? The Journalis also to be commended for the call to "responsible debate on controversial issues" contained in the accompanying editorial by Dr Lundberg. As to the MRFIT report itself, the reason for the striking failure of the trial lies in its erroneous basic assumption that reductions in CHD mortality would result from reductions in the three so-called major risk factors—cigarette smoking, high levels of BP, and serum cholesterol (SC). The MRFIT program failed to achieve an anticipated greater reduction in the overall CHD mortality rate in the special intervention (SI) group than in the control group receiving usual care (UC), despite the fact that the risk factor-reduction goals were essentially met. During the follow-up period, the SI group showed a
Effects and Tolerability of n-6 Essential Fatty Acid Supplementation in Patients with Recurrent Breast Cysts—a Randomized Double-blind Placebo-controlled Trial

Two hundred women with breast cysts proven by aspiration were entered into a randomized double-blind trial of evening primrose oil (Efamol) at a dose of 3 g daily by mouth or placebo for a year. Neither the number of patients developing recurrent cysts nor the total numbers of recurrent cysts were significantly reduced in the Efamol treated group compared with the placebo treated group. Efamol treatment was well-tolerated as only six women dropped out because of side effects, three in both the Efamol and placebo treated groups. There was no difference in the numbers of patients in each group who complained of side effects, and no haematological suppression or alteration of renal or hepatic function during the treatment period.
Duration of priapism is associated with increased corporal oxidative stress and antioxidant enzymes in a rat model

Ischaemic priapism is characterised by hypoxia, hypercapnia and acidosis with resultant corporal fibrosis. Studies reported decreased erectile recovery after treatment of priapism longer than 36 h. However, a recent study revealed that half of patients with 3 days of priapism achieved recovery after T‐shunt, although mechanism remains unclear. We aimed to investigate the effect of priapism duration on oxidative stress and antioxidant enzymes. Twenty‐four male rats were divided into four groups. Group 1 served as control. Groups 2, 3 and 4 represented 1, 2 and 4 h, respectively, of priapism induced by vacuum device and rubber band placed at base of erect penis. After 30 min of reperfusion, penectomy and blood withdrawal were performed to investigate levels of malondialdehyde (MDA), protein carbonyl (PC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx). Corporal MDA progressively increased with priapism duration (P = 0.01). Corporal SOD significantly differed between groups 1, 2 and 4. Also, there were significant differences in corporal GPx in groups 1 and 4 (P = 0.004) and groups 2 and 4 (P = 0.01). Corporal CAT was higher in group 4, but multivariable analysis revealed insignificant differences. Plasma MDA of the experimental groups was significantly higher than that of controls. There were no differences among groups in terms of other parameters. Increased antioxidant enzymes according to duration of priapism suggest that immediate treatment to relieve oxidative stress should be initiated in prolonged cases. However, further studies should be conducted to determine resistance mechanisms of the corpora to prolonged ischaemia.