julilili42/papers huggingface dataset:
ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy
2020-03-27

Objective Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient‐derived fibroblasts. Results Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype‐modifier variants. All the DOA‐associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28‐associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA‐associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28‐associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission‐inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18–32
Spirals inside the millimeter cavity of transition disk SR 21
2020-03-27

Context. Hydrodynamical simulations of planet-disk interactions suggest that planets may be responsible for a number of the substructures frequently observed in disks in both scattered light and dust thermal emission. Despite the ubiquity of these features, direct evidence of planets embedded in disks and of the specific interaction features like spiral arms within planetary gaps are still rare. Aims. In this study we discuss recent observational results in the context of hydrodynamical simulations in order to infer the properties of a putative embedded planet in the cavity of a transition disk. Methods. We imaged the transition disk SR 21 in H -band in scattered light with SPHERE/IRDIS and in thermal dust emission with ALMA band 3 (3 mm) observations at a spatial resolution of 0.1′′. We combine these datasets with existing Band 9 (430 μ m) and Band 7 (870 μ m) ALMA continuum data. Results. The Band 3 continuum data reveals a large cavity and a bright ring peaking at 53 au strongly suggestive of dust trapping. The ring shows a pronounced azimuthal asymmetry, with a bright region in the northwest that we interpret as a dust overdensity. A similarly asymmetric ring is revealed at the same location in polarized scattered light, in addition to a set of bright spirals inside the millimeter cavity and a fainter spiral bridging the gap to the outer ring. These features are consistent with a number of previous hydrodynamical models of planet-disk interactions, and suggest the presence of a ∼1 M Jup planet at 44 au and PA = 11 deg. This makes SR21 the first disk showing spiral arms inside the millimeter cavity, and the first disk for which the location of a putative planet can be precisely inferred. Conclusions. The main features of SR 21 in both scattered light and thermal emission are consistent with hydrodynamical predictions of planet-disk interactions. With the location of a possible planet being well constrained by observations, it is an ideal candidate for follow-up observations to search for direct evidence of a planetary companion still embedded in its disk.
Temporal variations in rockfall and rock-wall retreat rates in a deglaciated valley over the past 11 k.y.
2020-03-27

Abstract This study addresses the temporal variations in rockfall activity in the 5.2 km2 calcareous cliffs of the deglaciated Lauterbrunnen Valley, Switzerland. We did this using 19 campaigns of repeated terrestrial laser scans (TLS) over 5.2 yr, power-law predicted behavior from extrapolation of the TLS-derived frequency-magnitude relationship, and estimates of long-time-scale (∼11 k.y.) activity based on the volume of preserved postglacial rockfall talus. Results from the short-time-scale observations indicate no statistically significant difference between TLS observations averaging over 1.5 versus 5.2 yr. Rock-wall retreat rates in both cases are 0.03–0.08 mm/yr. In contrast, the power-law predicted rock-wall retreat rates are 0.14–0.22 mm/yr, and long-term rates from talus volumes are 0.27–0.38 mm/yr. These results suggest (1) short (1.5 yr) TLS inventories of rockfalls provide (within uncertainties) similar frequency-magnitude relationships as longer (5.2 yr) inventories, thereby suggesting short observation periods may be sufficient for hazard characterization from TLS, and (2) higher rock-wall retreat rates over long time scales (Holocene averaged) may reflect debuttressing and stress relaxation effects after glacial retreat, and/or enhanced rockfall activity under periglacial (climatic) conditions.
Cycling Performance in Short-term Efforts: Laboratory and Field-Based Data in XCO Athletes
2020-03-27

Abstract Mountain bike cross-country Olympic has an intermittent performance profile, underlining the importance of short-term but high cycling power output. Previous findings indicate that power output during sprint tests differs between laboratory and field-based conditions and that cycling cadence rises with increasing workload. The aim was therefore to examine power output and cadence in short-term efforts under laboratory and field conditions. Twenty-three competitive athletes (17.9±3.7 years) performed a laboratory power profile test and a simulated race within one week. Power output and cadence during the power profile test were compared to corresponding short-term efforts during the race over durations of 10–300s (TT10–300). Differences were TT10+8%, TT30+7%, TT60–15% and TT300–12% for power output and+10%,+8%,+19%,+21% for cadence respectively. Compared to the race, we found higher power output during the power profile test for the shorter efforts but lower for TT60 and TT300. Confirming previous results, cadence was higher during the power profile test compared to the respective intervals of the race and increased with increasing workload or shorter time trial duration. Future research should take into account that compared to the field, a higher cadence is used in laboratory settings to produce similar power output.
Improving the Spatial Prediction of Soil Organic Carbon Content in Two Contrasting Climatic Regions by Stacking Machine Learning Models and Rescanning Covariate Space
2020-03-29

Understanding the spatial distribution of soil organic carbon (SOC) content over different climatic regions will enhance our knowledge of carbon gains and losses due to climatic change. However, little is known about the SOC content in the contrasting arid and sub-humid regions of Iran, whose complex SOC–landscape relationships pose a challenge to spatial analysis. Machine learning (ML) models with a digital soil mapping framework can solve such complex relationships. Current research focusses on ensemble ML models to increase the accuracy of prediction. The usual ensemble method is boosting or weighted averaging. This study proposes a novel ensemble technique: the stacking of multiple ML models through a meta-learning model. In addition, we tested the ensemble through rescanning the covariate space to maximize the prediction accuracy. We first applied six state-of-the-art ML models (i.e., Cubist, random forests (RF), extreme gradient boosting (XGBoost), classical artificial neural network models (ANN), neural network ensemble based on model averaging (AvNNet), and deep learning neural networks (DNN)) to predict and map the spatial distribution of SOC content at six soil depth intervals for both regions. In addition, the stacking of multiple ML models through a meta-learning model with/without rescanning the covariate space were tested and applied to maximize the prediction accuracy. Out of six ML models, the DNN resulted in the best modeling accuracies, followed by RF, XGBoost, AvNNet, ANN, and Cubist. Importantly, the stacking of models indicated a significant improvement in the prediction of SOC content, especially when combined with rescanning the covariate space. For instance, the RMSE values for SOC content prediction of the upper 0–5 cm of the soil profiles of the arid site and the sub-humid site by the proposed stacking approaches were 17% and 9% respectively, less than that obtained by the DNN models—the best individual model. This indicates that rescanning the original covariate space by a meta-learning model can extract more information and improve the SOC content prediction accuracy. Overall, our results suggest that the stacking of diverse sets of models could be used to more accurately estimate the spatial distribution of SOC content in different climatic regions.
Quality, availability and storage conditions of oxytocin and misoprostol in Malawi
2020-03-29

Abstract Background Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low- and middle-income countries (LMICs). Oxytocin and misoprostol are used for the prevention and treatment of PPH. However, both medicines are chemically unstable and sensitive to environmental conditions. Previous studies reported a high prevalence of substandard oxytocin and misoprostol preparations in LMICs. Methods In randomly selected health facilities of four districts of Malawi, the availability of oxytocin and misoprostol was determined, and the knowledge of health workers on storage requirements and use of oxytocics was assessed. Temperature loggers were used to record the storage temperature of oxytocics. Samples of oxytocin injections and misoprostol tablets were collected from the health facilities and from wholesalers. Oxytocin samples were analysed for identity, assay (= quantity of oxytocin) and for pH value according to United States Pharmacopeia 40. Misoprostol samples were analysed for identity, assay, dissolution and related substances according to the International Pharmacopeia 2017. Results All visited hospitals and health centers had oxytocin available. At non-refrigerated storage sites, the recorded mean kinetic temperature exceeded the oxytocic’s storage temperature stated on the labels in 42% of the sites. At refrigerated storage sites, the required temperature of 2–8 °C was exceeded in 33% of the sites. Out of 65 oxytocin samples, 7 (11%) showed moderate deviations from specification, containing 82.2–86.8% of the declared amount of oxytocin. Out of 30 misoprostol samples, 5 (17%) showed extreme deviations, containing only 12.7–30.2% of the declared amount. The extremely substandard misoprostol was reported to the national authorities and to WHO, leading to an immediate recall of the respective brand in Malawi. The UK-based distributor of this brand closed its business shortly thereafter. Conclusion Availability of oxytocin was excellent in Malawi, and its quality was better than reported in previous studies in other LMICs. However, storage conditions at the health facilities often did not meet the requirements. Extremely substandard misoprostol tablets were found, representing a serious risk to maternal health. This shows the need for continued efforts for quality assurance in medicine procurement and registration, as well as for post-marketing surveillance.
Development of entrepreneurial competences in mini-companies at schools
2020-03-29

Purpose Entrepreneurship is not only seen as an important factor for economic growth and welfare but also as a vehicle of societal development and change, both at the regional, national and international level. Thus, entrepreneurship education at schools plays an increasingly important role, linking policy, businesses, education and science. However, research on entrepreneurship education programmes, especially on mini-companies which rely on an experiential learning setting, is still a young field and shared frameworks concerning entrepreneurial competences and longitudinal research designs are missing. This paper addresses to this research gap by analysing whether students who participate in a mini-company develop entrepreneurial competences. Design/methodology/approach The study is conducted in a quasi-experimental design, building upon a validated and psychometrically sound research instrument that is based on a newly designed entrepreneurial competence framework. In total, 100 pupils from grammar schools in Baden-Wuerttemberg, Germany, participated in the experimental and control group at both time points. Findings The results show that students expand their entrepreneurial competences on an economic level. In comparison, they show only limited developments on the personal and team level. The findings have important implications for the further development of entrepreneurship education programmes as well as on the interaction between schools and (regional) entrepreneurs, business partners and enterprises. Originality/value This study examines pupils' development of entrepreneurial competences in a quasi-experimental design. It highlights that participating pupils develop economic competences when participating in mini-companies in comparison to pupils participating in regular economics classes. This study sheds further light on the effects of mini-companies, and thus contributes to the discussion of entrepreneurship education at schools.
Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling
2020-03-30

Abstract Aims Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients. Methods and results Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1β-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated β cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro. Conclusions Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.
Oral Supplementation of Sodium Butyrate Attenuates the Progression of Non-Alcoholic Steatohepatitis
2020-03-30

Sodium butyrate (SoB) supplementation has been suggested to attenuate the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined the therapeutic potential of SoB on NAFLD progression and molecular mechanism involved. Eight-week old C57BL/6J mice were pair-fed a fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C). After 8 weeks, some mice received 0.6g SoB/kg bw in their respective diets (C+SoB; FFC+SoB) or were maintained on C or FFC for the next 5 weeks of feeding. Liver damage, markers of glucose metabolism, inflammation, intestinal barrier function and melatonin metabolism were determined. FFC-fed mice progressed from simple steatosis to early non-alcoholic steatohepatitis, along with significantly higher TNFα and IL-6 protein levels in the liver and impaired glucose tolerance. In FFC+SoB-fed mice, disease was limited to steatosis associated with protection against the induction of Tlr4 mRNA and iNOS protein levels in livers. SoB supplementation had no effect on FFC-induced loss of tight junction proteins in the small intestine but was associated with protection against alterations in melatonin synthesis and receptor expression in the small intestine and livers of FFC-fed animals. Our results suggest that the oral supplementation of SoB may attenuate the progression of simple steatosis to steatohepatitis.
Inhibition of effector B cells by ibrutinib in systemic sclerosis
2020-03-30

Abstract Objective Systemic sclerosis (SSc) is a connective tissue disease with a significant morbidity and reduced survival of patients. Effective treatment and clinical control of the disease remain challenging. In particular, the development of pulmonary and cardiac fibrosis and pulmonary hypertension are severe complications responsible for excessive mortality. Currently available treatment strategies only alleviate symptoms and slow disease progression. Here, we investigated the therapeutic potential of ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor used in B cell malignancies, to alter B cell pathology in SSc in an in vitro model of autoimmunity. Methods PBMCs and sorted B cells of 24 patients with SSc were used for functional testing after stimulation with hypomethylated DNA fragments (CpG) to induce an innate immune response. The effects of ibrutinib on cytokine production, autoantibody release, and activation of the transcription factor NFκB were evaluated. Results Ibrutinib was able to reduce the production of the profibrotic hallmark cytokines IL-6 and TNF-α mainly from the effector B cell population in patients with SSc. Importantly, small doses of ibrutinib (0.1 μM) preserved the production of immunoregulatory IL-10 while effectively inhibiting hyperactivated, profibrotic effector B cells. In a flow cytometry analysis of phosphorylated NFκB, an important transcription factor in the induction of innate immune responses in B cells, significantly less activation was observed with ibrutinib treatment. Conclusion Our data could pave the avenue for a clinical application of ibrutinib for patients with SSc as a novel treatment option for the underlying pathogenetic immune imbalance contributing to disease onset and progression.
Consensus on definition and severity grading of lymphatic complications after kidney transplantation
2020-03-30

Abstract Background The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy. Methods Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres. Results Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention. Conclusion A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.
Visualization of the Borazine Core of B3N3-Doped Nanographene by STM
2020-03-30

Electronic interface properties and the initial growth of hexa-<i>peri</i>-hexabenzocoronene with a borazine core (BN-HBC) on Au(111) have been studied by using X-ray photoelectron spectroscopy (XPS), low-energy electron diffraction (LEED), and scanning tunneling microscopy (STM). A weak, but non-negligible, interaction between BN-HBC and Au(111) was found at the interface. Both hexa-<i>peri</i>-hexabenzocoronene (HBC) and BN-HBC molecules form well-defined monolayers. The different contrast in STM images of HBC and BN-HBC at different tunneling voltages with submolecular resolution can be ascribed to differences in the local density of states (LDOS). At positive and negative tunneling voltages, STM images reproduce the distribution of the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO) as determined by density functional theory (DFT) calculations very well.
Preoccupied with the body: mild stress amplifies the relation between rumination and interoception
2020-03-30

Classic and modern emotion theories suggest that the perception of bodily sensations, or interoception, is foundational to emotion processing. The present research examined whether interoception is enhanced among people high in ruminative tendencies, especially under stress. To test this notion, the present research examined the effects of a mild stressor on subjective and objective measures of interoception among people varying in ruminative tendencies. Under conditions of mild stress, rumination was positively associated with self-reported private body consciousness -a marker of interoceptive sensibility- in Study 1 (<i>N</i> = 312) and with heartbeat detection accuracy (especially in the presence of auditory interference) in Study 2 (<i>N</i> = 180). In both studies, rumination was not significantly associated with interoceptive sensibility or accuracy in the absence of stress. These findings suggest that stress-induced amplification of bodily sensations may be important in explaining emotional dysregulation among chronic ruminators.