Miracle-dz/UniFAR-FTUs huggingface dataset:
Compositional Influence of Movement Behaviours on Bone Health during Ageing.

INTRODUCTION AND PURPOSE Physical activity (PA) is considered the best non-pharmacological treatment for the decrease in bone mass (BM) produced during ageing. Therefore, it is essential to assess how the time spent in PA is distributed in order to control further changes. This work examines the relationship between movement behaviours and BM during ageing, using compositional data analysis. METHODS We studied 227 older people aged 65 to 94 (102 men and 125 women) divided by sex and bone status, over a period of 4 years. Time spent in sedentary behaviour (SB), light PA (LPA) and moderate-to-vigorous PA (MVPA), was assessed using accelerometry. BM was determined by dual-energy X-ray absorptiometry. RESULTS The changes in MVPA was positively associated with the rate of BM decay at spine and leg in the whole sample and men's subgroup (p≤0.05). In women, the rate of BM decay at spine and Ward's triangle were negatively associated with SB changes and BM decay at femoral neck and Ward's was positively associated with LPA (p≤0.05). CONCLUSION Increasing MVPA related to other movement behaviours produces improvements in the rate of bone change in older men; while to increase LPA and maintain MVPA would be the best approach to enhance bone mass in older women.
TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development, lead to altered DNA methylation landscapes and to an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed Acute Myeloid Leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we demonstrate that loss of TET2 leads to enzymatic activity-dependent attenuation of chromatin binding of the hematopoietic TF CDX4. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provide a compelling example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.
Recombinant Human Superoxide Dismutase and N-Acetylcysteine Addition to Exogenous Surfactant in the Treatment of Meconium Aspiration Syndrome

This study aimed to evaluate the molecular background of N-acetylcysteine (NAC) and recombinant human superoxide dismutase (rhSOD) antioxidant action when combined with exogenous surfactant in the treatment of meconium aspiration syndrome (MAS), considering redox signalling a principal part of cell response to meconium. Young New Zealand rabbits were instilled with meconium suspension (Mec) and treated by surfactant alone (Surf) or surfactant in combination with i.v. NAC (Surf + NAC) or i.t. rhSOD (Surf + SOD), and oxygen-ventilated for 5 h. Dynamic lung-thorax compliance, mean airway pressure, PaO2/FiO2 and ventilation efficiency index were evaluated every hour; post mortem, inflammatory and oxidative markers (advanced oxidation protein products, total antioxidant capacity, hydroxynonenal (HNE), p38 mitogen activated protein kinase, caspase 3, thromboxane, endothelin-1 and secretory phospholipase A2) were assessed in pulmonary tissue homogenates. rhSOD addition to surfactant improved significantly, but transiently, gas exchange and reduced levels of inflammatory and oxidative molecules with higher impact; Surf + NAC had stronger effect only on HNE formation, and duration of treatment efficacy in respiratory parameters. In both antioxidants, it seems that targeting reactive oxygen species may be strong supporting factor in surfactant treatment of MAS due to redox sensitivity of many intracellular pathways triggered by meconium.
Extracellular microRNAs exhibit sequence-dependent stability and cellular release kinetics

ABSTRACT Multiple studies have described extracellular microRNAs (ex-miRNAs) as being remarkably stable despite the hostile extracellular environment, when stored at 4ºC or lower. Here we show that many ex-miRNAs are rapidly degraded when incubated at 37ºC in the presence of serum (thereby simulating physiologically relevant conditions). Stability varied widely between miRNAs, with half-lives ranging from ~1.5 hours to more than 13 hours. Notably, ex-miRNA half-lives calculated in two different biofluids (murine serum and C2C12 mouse myotube conditioned medium) were highly similar, suggesting that intrinsic sequence properties are a determining factor in miRNA stability. By contrast, ex-miRNAs associated with extracellular vesicles (isolated by size exclusion chromatography) were highly stable. The release of ex-miRNAs from C2C12 myotubes was measured over time, and mathematical modelling revealed miRNA-specific release kinetics. While some ex-miRNAs reached the steady state in cell culture medium within 24 hours, the extracellular level of miR-16 did not reach equilibrium, even after 3 days in culture. These findings are indicative of miRNA-specific release and degradation kinetics with implications for the utility of ex-miRNAs as biomarkers, and for the potential of ex-miRNAs to transfer gene regulatory information between cells.
The French National Alzheimer Database: A Fast Growing Database for Researchers and Clinicians

Background: Alzheimer's disease (AD) is a major public health issue. The French National Alzheimer database (BNA) registers all medical acts performed by memory units and independent specialists throughout France. This article describes the national coverage, the registered patient characteristics and illustrates research possibilities. Methods: All data transmitted up to December 2012 were analyzed. The following patient characteristics were studied: age, sex, educational level, place of living, diagnosis, Mini-Mental State Examination score and existence of pharmacological or psychosocial interventions. Results: At the end of 2012, the BNA included 84% (n = 357) of all French memory units, contained 341,498 patients and more than 800,000 medical acts. AD accounted for 26.4% of all registered diagnoses, related disorders for 21.7% and mild cognitive impairment for 8.7%. Conclusion: The BNA offers a multitude of research possibilities. In the coming years, the BNA will play a major role in monitoring trends and related risk factors in AD.
Cardiac‐specific overexpression of caveolin‐3 preserves t‐tubular I Ca during heart failure in mice

What is the central question of this study? What is the cellular basis of the protection conferred on the heart by overexpression of caveolin‐3 (Cav‐3 OE) against many of the features of heart failure normally observed in vivo? What is the main finding and its importance? Cav‐3 overexpression has little effect in normal ventricular myocytes but reduces cellular hypertrophy and preserves t‐tubular ICa, but not local t‐tubular Ca2+ release, in heart failure induced by pressure overload in mice. Thus Cav‐3 overexpression provides specific but limited protection following induction of heart failure, although other factors disrupt Ca2+ release.
Surveillance of transmitted drug resistance to integrase inhibitors in Spain: implications for clinical practice.

BACKGROUND Integrase strand-transfer inhibitors (INSTIs) constitute at present one of the pillars of first-line ART. OBJECTIVES To study the prevalence of and the trend in transmitted drug resistance (TDR) to INSTIs in ART-naive patients in Spain. METHODS During the period 2012-17, 1109 patients from CoRIS were analysed. The Stanford algorithm v8.7 was used to evaluate TDR and transmission of clinically relevant resistance. To describe individual mutations/polymorphisms, the most recent IAS list (for INSTIs) and the 2009 WHO list update (for the backbone NRTIs used in combination with INSTIs in first-line treatment) were used. RESULTS Clinically relevant resistance to the INSTI class was 0.2%: T66I, 0.1%, resistance to elvitegravir and intermediate resistance to raltegravir; and G163K, 0.1%, intermediate resistance to raltegravir and elvitegravir. No clinical resistance to dolutegravir or bictegravir was observed. The prevalence of INSTI TDR following the IAS-USA INSTI mutation list was 2.6%, with no trend towards changes in the prevalence throughout the study period. The overall prevalence of NRTI WHO mutations was 4.3%, whereas clinically relevant resistance to tenofovir, abacavir and emtricitabine/lamivudine was 1.7%, 1.9% and 0.7%, respectively. CONCLUSIONS Given the low prevalence of clinically relevant resistance to INSTIs and first-line NRTIs in Spain, it is very unlikely that a newly diagnosed patient will present with clinical resistance to a first-line INSTI-based regimen. These patients may not benefit from INSTI and NRTI baseline resistance testing.
New approaches for metagenome assembly with short reads

Abstract In recent years, the use of longer range read data combined with advances in assembly algorithms has stimulated big improvements in the contiguity and quality of genome assemblies. However, these advances have not directly transferred to metagenomic data sets, as assumptions made by the single genome assembly algorithms do not apply when assembling multiple genomes at varying levels of abundance. The development of dedicated assemblers for metagenomic data was a relatively late innovation and for many years, researchers had to make do using tools designed for single genomes. This has changed in the last few years and we have seen the emergence of a new type of tool built using different principles. In this review, we describe the challenges inherent in metagenomic assemblies and compare the different approaches taken by these novel assembly tools.
Vitamin D deficiency predicts severe acute pancreatitis

Background The ability to predict the severity of disease is important to reduce morbidity and mortality in patients with acute pancreatitis (AP). Vitamin D deficiency has been associated with severity in various diseases. Objective This study was conducted to assess vitamin D as a predictor of disease severity in patients with AP. Methods Patients with AP were prospectively enrolled at Yonsei University Wonju College of Medicine from March 2015 to September 2017. Serum vitamin D was analyzed as soon as AP was diagnosed. The level of vitamin D was classified as normal (>20 ng/ml), insufficient (>10 and ≤20 ng/ml) or deficient (≤10 ng/ml). Results Among 242 patients with AP, the prevalence of vitamin D deficiency was 56.2%, and 28.5% of patients had vitamin D insufficiency. Serum vitamin D level was negatively correlated with severity indexes, such as the Atlanta classification, Computed Tomography Severity Index, Bedside Index for Severity of Acute Pancreatitis, and Ranson score. The prevalence of vitamin D deficiency increased with severity of AP according to the Atlanta classification. Vitamin D deficiency was the independent factor for predicting severe AP (OR 5.37, 95% CI 1.13–25.57, p = 0.015) and intensive care unit admission (OR 3.09, 95% CI 1.24–7.69, p = 0.035). Conclusion Vitamin D deficiency is associated with increased severity of AP and is a predictor for intensive care unit admission.
International Divergence in Gene Patenting.

This review explores the recent divergence in international patent law relating to the patenting of genes and related subject matter. This divergence stems primarily from decisions of the highest courts in the United States and Australia on the eligibility of patent claims relating to the BRCA gene sequences. Patent offices, courts, and policy makers have struggled for many years to clearly articulate the bounds of patent claims on isolated and synthetic DNA and related products and processes, including methods for their use in genetic diagnostics. This review provides context to the current divergence by mapping key events in the gene patent journey from the early 1980s onward in five key jurisdictions: the United States, the member states of the European Patent Convention, Australia, Canada, and China. Early approaches to gene patenting had some commonalities across jurisdictions, which makes exploration of the recent divergence all the more interesting. There is insufficient empirical evidence to date to confidently predict the consequences of this recent divergence. However, it could potentially have a significant effect on local industry and on consumer access. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 30, 2019. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Long-Term Outcome of Stents Versus Bypass Surgery in Diabetic and Nondiabetic Patients With Multivessel or Left Main Coronary Artery Disease: A Pooled Analysis of 5775 Individual Patient Data

Background— Coronary artery bypass grafting and percutaneous coronary intervention (PCI) are alternative treatments for complex multivessel or left main disease. However, the relative treatment effects in diabetic and nondiabetic patients remain uncertain. Methods and Results— We performed a pooled analysis of 5775 patients from 3 clinical studies comparing PCI and coronary artery bypass grafting for multivessel or left main disease and compared adverse outcomes (death; a composite outcome of death, Q-wave myocardial infarction, or stroke; and repeat revascularization) according to the diabetic status. Over a median follow-up of 5.5 years, risk-adjusted mortality after PCI relative to coronary artery bypass grafting was not different in diabetic (hazard ratio [HR], 1.15; 95% CI, 0.88–1.51) and nondiabetic (HR, 1.15; 95% CI, 0.88–1.50) patients. The adjusted risks of the composite outcome of death, Q-wave myocardial infarction, or stroke were also not different in diabetic (HR, 1.00; 95% CI, 0.79–1.26) and nondiabetic (HR, 0.99; 95% CI, 0.78–1.26) patients. However, PCI was significantly associated with higher risk of repeat revascularization both in diabetic (HR, 3.56; 95% CI, 2.62–4.83) and in nondiabetic (HR, 3.55; 95% CI, 2.61–4.83) patients. Significant interactions were absent between diabetic status and revascularization strategies for death (P=0.27), composite outcome of death, Q-wave myocardial infarction, or stroke (P=0.97), and repeat revascularization (P=0.08). Conclusions— For multivessel or left main disease, the long-term risks of mortality and composite serious outcomes were not different between PCI and coronary artery bypass grafting in diabetic and nondiabetic patients, but PCI was associated with higher risk of repeat revascularization. These relative treatment effects were not modified by diabetic status. These results are hypothesis generating and should be addressed in a randomized trial.
Intelligence as a predictor of social mobility in Estonia.

The purpose of this study was to explore how individual and environmental predictors of intergenerational social mobility intersect in rarely studied post-communist developing society of Estonia. We used a contemporary cross-sectional dataset (n = 759) to assess the influence of cognitive ability and parental socioeconomic status to the participants' educational and occupational attainment. Our results indicated that cognitive ability and one's own educational level mediated the association of parental socioeconomic status with one's own occupational success. Analysis of separate components of cognitive ability indicated that verbal ability had the highest influence on occupational status. We concluded that both individual-level and environmental factors have a predictive effect on educational and occupational attainment.
Loss of growth hormone–mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity

Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5 via the GHR (Ghr‐391−/−) as for GHR‐null (GHR−/−) mice. These changes were associated with a striking inhibition of hepatic glucose output associated with altered glycogen metabolism and elevated hepatic glycogen content during unfed state. The enhanced hepatic insulin sensitivity was associated with increased insulin receptor β and insulin receptor substrate 1 activation along with activated downstream protein kinase B signaling cascades. Although phosphoenolpyruvate carboxykinase (Pck)‐1 expression was unchanged, its inhibitory acetylation was elevated because of decreased sirtuin‐2 expression, thereby promoting loss of PCK1. Loss of STAT5 signaling to defined chromatin immunoprecipitation targets would further increase lipogenesis, supporting hepatosteatosis while lowering glucose output. Finally, up‐regulation of IL‐15 expression in muscle, with increased secretion of adiponectin and fibroblast growth factor 1 from adipose tissue, is expected to promote insulin sensitivity. —Chhabra, Y. , Nelson, C. N. , Plescher, M. , Barclay, J. L. , Smith, A. G. , Andrikopoulos, S. , Mangiafico, S. , Waxman, D. J., Brooks, A. J., Waters, M. J. Loss of growth hormone‐mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity. FASEB J. 33, 6412–6430 (2019). www.fasebj. org
Sex Chromosome Evolution in Cotton Stainers of the Genus Dysdercus (Heteroptera: Pyrrhocoridae)

The neo-X and neo-Y sex chromosomes of Dysdercus albofasciatus represent a unique model for the study of early stages of sex chromosome evolution since they retained the ability to pair and recombine, in contrast to sex chromosomes in most Heteroptera. Here we examined structure, molecular differentiation, and meiotic behaviour of the D. albofasciatus neo-sex chromosomes. Two related species with the ancestral X0 system, D. chaquensis and D. ruficollis, were used for a comparison. In D. albofasciatus, 2 nucleolar organizer regions (NORs) were identified on the neo-X chromosome using fluorescence in situ hybridization (FISH) with an rDNA probe, whereas a single NOR was found on an autosomal pair in the other 2 species. Genomic in situ hybridization (GISH) differentiated a part of the original X in the neo-X chromosome but not the neo-Y chromosome. The same segment of the neo-X chromosome was identified by Zoo-FISH with a chromosome painting probe derived from the X chromosome of D. ruficollis, indicating that this part is conserved between the species. Immunostaining against the cohesin subunit SMC3 revealed that only terminal regions of the D. albofasciatus neo-Xneo-Y bivalent pair and form a synaptonemal complex, which is in keeping with the occurrence of terminal chiasmata, whereas the interstitial region forms a large loop indicating the absence of homology. These results support the hypothesis that the neo-X chromosome evolved by insertion of the original X chromosome into 1 NOR-bearing autosome in an ancestor carrying the X0 system. As a consequence, the homologue of this NOR-autosome became the neo-Y chromosome. A subsequent inversion followed by transposition of the NOR located on the neo-Y onto the neo-X chromosome resulted in the present neo-sex chromosome system in D. albofasciatus.
Width of Patulous Eustachian Tube: Comparison of Assessment by Sonotubometry and Tubo-tympano-aerography.

OBJECTIVE To assess the accuracy of tubo-tympano-aerodynamic-graphy (TTAG) in the estimation of morphological severity of patulous Eustachian tube (PET), and to compare the results with that of sonotubometry in clinical cases and in model experiments. STUDY DESIGN Retrospective chart review and model experiment. SETTING Tertiary referral center. SUBJECTS A retrospective survey of medical records in Sen-En Rifu Hospital identified 26 patients (12 men and 14 women subjects aged 14-78 yr, average 49.4 ± 20.9 yr), comprising of 35 ears with PET. A definite diagnosis of PET was made for all patients based on the diagnostic criteria proposed by the Japan Otological Society. MAIN OUTCOME MEASURES Commercial equipment for sonotubometry and TTAG (JK-05A; RION Co., Ltd., Kokubunji, Tokyo, Japan) were used in the following investigations. Model Experiment: The ET model was made using two truncated syringes with silicone barrels and a narrow connecting tube (0.2, 0.4, 0.58, 0.8, 1.00, 2.00, and 3.00 mm). Clinical Investigation: Morphological evaluation of ET patency was performed by a three-dimensional (3-D) CT (3D Accuitomo; Morita MFG. Corp., Kyoto, Japan) and analyzed by software (Integrated Information System i-VIEW; Morita MFG. Corp.). RESULTS: The transmitted sound pressure level gradually increased as the tube caliber was widened up to 3 mm diameter. On the other hand, pressure transmission was suddenly elevated and reached a plateau at 0.58 mm in diameter. The cross-sectional area at the narrowest portion of the ET was significantly correlated with the sound attenuation from nostril to external auditory canal (EAC) (Spearman rank correlation test: r = -0.521, p < 0.001). In contrast, the cross-sectional area at the narrowest portion of the ET was not correlated with the pressure changes of TTAG (Spearman rank correlation test: r = 0.317, p = 0.64). CONCLUSION Sound transmission assessed by sonotubometry could be more useful than pressure transmission assessed by TTAG to predict the morphological severity of PET.
Venlafaxine Abuse in a Patient With a History of Methylphenidate Abuse: A Case Report.

To the Editors: T he abuse of antidepressants is rare in comparison with other prescription drugs such as opioids or benzodiazepines. However, misuse or abuse of antidepressants (mainly bupropion, amineptine, tianeptine) to achieve psychostimulant-like effects has been reported. We present here the first case of abuse of venlafaxine in a patient with a history of methylphenidate abuse, leading to rhabdomyolysis with acute renal failure. The author obtained verbal permission from the patient to publish this case report.