Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial.

Importance Few studies have assessed the effects of daily vitamin D doses at or above the tolerable upper intake level for 12 months or greater, yet 3% of US adults report vitamin D intakes of at least 4000 IU per day. Objective To assess the dose-dependent effect of vitamin D supplementation on volumetric bone mineral density (BMD) and strength. Design, Setting, and Participants Three-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017, including 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L. Interventions Daily doses of vitamin D3 for 3 years at 400 IU (n = 109), 4000 IU (n = 100), or 10 000 IU (n = 102). Calcium supplementation was provided to participants with dietary intake of less than 1200 mg per day. Main Outcomes and Measures Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis. Results Of 311 participants who were randomized (53% men; mean [SD] age, 62.2 [4.2] years), 287 (92%) completed the study. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10 000-IU group. There were significant group × time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (-3.9 mg HA/cm3 [95% CI, -6.5 to -1.3]) and 10 000 IU group (-7.5 mg HA/cm3 [95% CI, -10.1 to -5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of -1.2% (400 IU group), -2.4% (4000 IU group), and -3.5% (10 000 IU group). Tibial volumetric BMD differences from the 400 IU group were -1.8 mg HA/cm3 (95% CI, -3.7 to 0.1) in the 4000 IU group and -4.1 mg HA/cm3 in the 10 000 IU group (95% CI, -6.0 to -2.2), with mean percent change values of -0.4% (400 IU), -1.0% (4000 IU), and -1.7% (10 000 IU). There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12). Conclusions and Relevance Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful. Trial Registration ClinicalTrials.gov Identifier: NCT01900860.
Genistein Decreases APP/tau Phosphorylation and Ameliorates Aβ Over- production Through Inhibiting CIP2A.

Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role in disease- related phosphorylation of tau/APP and tau pathology/Aβ overproduction through inhibiting PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment research. In this study, the inhibitory effect of Genistein on tau/APP phosphorylation and Aβ overproduction in AD cell models have been explored. The results showed that Genistein effectively reduced CIP2A expression, and restored PP2A activities both in CIP2A/APP and CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and inhibited Aβ production. In the meantime, Genistein ameliorated tau hyperphosphorylation by repressing the inhibitory effect of CIP2A on PP2A. Thus, Genistein has the potential to be used in AD treatment by targeting CIP2A-PP2A signaling in AD therapy.
SAND 2011-8310 Unlimited Release Printed November 2011 Uncertainty Assessment in Atmospheric Component of Climate Models

This report summarizes the work focusing on uncertainty analysis in atmosphere models from JulyOctober 2011 under the Climate Science for a Sustainable Energy Future (CSSEF) project. The work had several objectives: the development of surrogate models (including kriging and stochastic expansion), sensitivity analysis and the identification of important input parameters, uncertainty quantification, and some initial calibration. This report documents the progress to date.
Beyond the Scavenging of Reactive Oxygen Species (ROS): Direct Effect of Cerium Oxide Nanoparticles in Reducing Fatty Acids Content in an In Vitro Model of Hepatocellular Steatosis

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipids. Antisteatotic effects of cerium oxide nanoparticles (CeO2NPs) have recently been shown in animal models of liver disease. However, it is unclear whether the activity of CeO2NPs is related solely to the decrease in oxidative stress or, in addition, they directly decrease liver fatty acid accumulation. To address this question, in this work, we used an in vitro model of hepatocellular steatosis, exposing HepG2 cells to oleic and palmitic acid. Cell uptake of CeO2NPs and their effect on oxidative stress and viability of hepatic cells cultured with H2O2 were also evaluated. Results show that CeO2NPs were uptaken by HepG2 cells and reduced oxidative stress and improved cell viability. Treatment with oleic and palmitic acid increased lipogenesis and the content of different fatty acids. CeO2NPs reduced palmitic and stearic acid and most fatty acids consisting of more than 18 carbon atoms. These effects were associated with significant changes in elongase and desaturase activity. In conclusion, CeO2NPs directly protected HepG2 cells from cell injury in oxidative stress conditions and reduced fatty acid content in steatotic conditions by inducing specific changes in fatty acid metabolism, thus showing potential in the treatment of NAFLD.
Synovial Cytokines Significantly Correlate with Osteoarthritis-Related Knee Pain and Disability: Inflammatory Mediators of Potential Clinical Relevance

The aim of this study was to identify inflammatory mediators of potential clinical relevance in synovial fluid (SF) samples of patients with knee osteoarthritis (OA). Therefore, radiographic OA severity, knee pain and function of 34 OA patients undergoing unicompartmental (UC) and bicompartmental (BC) knee arthroplasty were assessed prior to surgery and SF samples were analyzed for a broad variety of inflammatory mediators, including interleukins (ILs), interferons (IFNs), C-X-C motif ligand chemokines (CXCLs), and growth factors (nerve growth factor; NGF, vascular endothelial growth factor; VEGF, and stem cell growth factor β; SCGF-β) using multiplex assay. Significant differences were observed between the SF levels of different inflammatory markers. When compared to UC OA, significantly higher concentrations of IL-7, IL-8, IL-10, IL-12, IL-13, IFN-γ, VEGF and CXCL1 were detected in BC OA. Correlation analyses revealed significant associations between OA severity and IL-6, IL-8, IFN-γ, SCGF-β, VEGF, CXCL1. Interestingly, increases in both anti- (IL-10, IL-13) and pro-inflammatory (IL-7, IL-12, IFN-γ) cytokines, as well as growth factors (SCGF-β, VEGF), correlated significantly with the level of knee pain. Poorer knee function was associated with higher IL-6, IL-10, IL-12, IL-13, IL-18, βNGF, SCGF-β, VEGF and CXCL9 levels. In conclusion, this study provides an extensive profile of synovial inflammatory mediators in knee OA and identifies cytokines of potential clinical relevance. In fact, five of the mediators examined (IL-10, IL-12, IL-13, SCGF-β, VEGF) significantly correlate with both knee pain and function.
Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. Some ligands that bind to GPCRs activate different downstream signaling pathways. G protein activation, or β-arrestin biased signaling, involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. β-arrestin biased signaling has become a hot target for structure-based drug discovery. However, challenges include that there are few crystal structures available in the Protein Data Bank and that GPCRs are highly dynamic. Hence, molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators’ interactions with receptors and ligands. Here, we highlight recent MD simulation studies and enhanced sampling methods used to study biased G protein-coupled receptor signaling and their conformational dynamics as well as applications to drug discovery.
Assessing aggression following Acquired Brain Injury (ABI): a systematic review of assessment measures

ABSTRACT Objective: To conduct a systematic review to identify and examine the reliability and validity of standardized measures used to assess aggression in people with ABI. Data sources: Systematic searches of PsychInfo, Medline, Embase, PubMed and CINAHL databases along with hand searching of gray literature and review articles. Study selection: Studies were included if the sample had an ABI, and the measure included assessment of aggression. Data extraction: Sample and measure characteristics and psychometric properties were extracted. Measure quality was assessed using the COSMIN checklist. Data synthesis: Of 5,100 abstracts screened, 78 were reviewed in full against the inclusion and exclusion criteria, and 25 articles met the criteria for analysis. Included articles assessed the psychometric properties of 17 different measures of aggression in adults with ABI. Quality of evidence was often low. Four measures (MBPC-1990R, NFI, SASNOS and KSMS) demonstrated positive evidence of at least one psychometric property with good quality evidence. Conclusions: Although a large number of general measures were available, there are few measures that only assess post-ABI aggression, and many are not well-validated. Future research should assess the psychometric properties of these measures.
A 3‐D Shear Velocity Model of the Crust and Uppermost Mantle Beneath Alaska Including Apparent Radial Anisotropy

This paper presents a model of the 3‐D shear velocity structure of the crust and uppermost mantle beneath Alaska and its surroundings on a ~50‐km grid, including crustal and mantle radial anisotropy, based on seismic data recorded at more than 500 broadband stations. The model derives from a Bayesian Monte Carlo inversion of Rayleigh wave group and phase speeds and Love wave phase speeds determined from ambient noise and earthquake data. Prominent features resolved in the model include the following: (1) Apparent crustal radial anisotropy is strongest across the parts of central and northern Alaska that were subjected to significant extension during the Cretaceous. This is consistent with crustal anisotropy being caused by deformationally aligned middle to lower crustal sheet silicates (micas) with shallowly dipping foliation planes beneath extensional domains. (2) Crustal thickness estimates are similar to those from receiver functions by Miller and Moresi (2018, https://doi.org/10.1785/0220180222). (3) Very thick lithosphere underlies Arctic‐Alaska, with high shear wave speeds that extend at least to 120‐km depth, which may challenge rotational transport models for the evolution of the region. (4) Subducting lithosphere beneath Alaska is resolved, including what we call the “Barren Islands slab anomaly,” an “aseismic slab edge” north of the Denali Volcanic Gap, the “Wrangellia slab anomaly,” and Yakutat lithosphere subducting seaward of the Wrangell volcanic field. (5) The geometry of the Alaskan subduction zone generally agrees with the slab model Alaska_3D 1.0 of Jadamec and Billen (2010, https://doi.org/10.1038/nature09053) except for the Yakutat “slab shoulder region,” which is newly imaged in our model.
The first evidence of Acidithiobacillus albertensis in weathered ore samples from active gold mine Hodruša-Hámre (Slovakia)

Abstract Sulphur-oxidising autotrophic bacterial communities in deep biosphere from weathered ore samples from active gold mine Hodruša-Hámre, Slovakia were analysed using cultivation approach followed by DNA extraction, PCR amplification and 16S rRNA gene analyses. Indirect measurement of pH changes in cultivation media evidenced the presence of acidophilic bacteria with active production of acids. The decrease of pH was observed at the beginning of isolation and later pH in range of 1.5 – 2 was maintained in both, sulphuric acid and thiosulphate, media. The presence of homogenous population of gram-negative rods was proved by Gram staining. Molecular analyses have revealed that the population of sulphur-oxidising bacteria in gold mine is dominated by a single species of Aciditiobacillus genus, identified as A. albertensis, suggesting the low level of autotrophic bacteria diversity in deep deposits. For the first time this species was isolated from weathered rocks of a gold mine subsurface environment.
3 Internal Dynamics of the Ferroelectric ( C 3 N 2 H 5 ) 5 Bi 2 Cl 11 Studied by 1 H NMR and IINS Methods

Ferroelectric properties of materials of the general formula RaMbX(3b+a) (R-organic cation, M=Sb, Bi, X=Cl, Br, I) have been studied during the last twenty years (Gagor, 2011; Sobczyk, 1997; Piecha, 2005; Jakubas, 2005). The family of halogenobismuthates (III) and halogenoantimonates (III) is characterized by a rich diversity of the anionic forms. It has been shown that ferroelectricity is restricted to compounds characterized by two types of the anionic substructure: two-dimensional anionic layers (M2X93-)∝ and discrete bioctahedral units Bi2X115-. Especially, the latter type compounds evoke much interest because all connections crystallizing with the R5M2X11 composition, reported to date, were found to exhibit ferroelectric properties. Within this subclass there are known three imidazolium ferroelectrics which appeared to be isomorphous in their paraelectric phase. One of these compounds, namely imidazolium undecachlorodibismuthate III of chemical formula (C3N2H5)5Bi2Cl11 (abbreviated as ICB) undergoes the following sequence of phase transitions (Sobczyk, 1997; Piecha, 2005; Jakubas, 2005) :
The Spirocyclic Imine from a Marine Benthic Dinoflagellate, Portimine, Is a Potent Anti-Human Immunodeficiency Virus Type 1 Therapeutic Lead Compound

In this study, we aimed to find chemicals from lower sea animals with defensive effects against human immunodeficiency virus type 1 (HIV-1). A library of marine natural products consisting of 80 compounds was screened for activity against HIV-1 infection using a luciferase-encoding HIV-1 vector. We identified five compounds that decreased luciferase activity in the vector-inoculated cells. In particular, portimine, isolated from the benthic dinoflagellate Vulcanodinium rugosum, exhibited significant anti-HIV-1 activity. Portimine inhibited viral infection with an 50% inhibitory concentration (IC50) value of 4.1 nM and had no cytotoxic effect on the host cells at concentrations less than 200 nM. Portimine also inhibited vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped HIV-1 vector infection. This result suggested that portimine mainly targeted HIV-1 Gag or Pol protein. To analyse which replication steps portimine affects, luciferase sequences were amplified by semi-quantitative PCR in total DNA. This analysis revealed that portimine inhibits HIV-1 vector infection before or at the reverse transcription step. Portimine has also been shown to have a direct effect on reverse transcriptase using an in vitro reverse transcriptase assay. Portimine efficiently inhibited HIV-1 replication and is a potent lead compound for developing novel therapeutic drugs against HIV-1-induced diseases.
Perivascular adipose tissue–derived extracellular vesicle miR‐221‐3p mediates vascular remodeling

Adipose tissue–secreted extracellular vesicles (EVs) containing microRNAs (miRNAs) convey intercellular message signaling. The biogenesis of EV‐miRNAs from perivascular adipose tissue (PVAT) and their roles in intercellular communication in response to obesity‐associated inflammation have not yet been fully explored. By feeding mice a high‐fat diet for 16 wk, we established obesity‐associated, chronic low‐grade inflammation in PVAT, characterized as hypertrophy of perivascular adipocytes, decreased adipogenesis, and proinflammatory macrophage infiltration. We show that PVAT‐derived EVs and their encapsulated miRNAs can be taken up into vascular smooth muscle cells (VSMCs) in vivo and in vitro. miR‐221‐3p is one of the highly enriched miRNAs in obese PVAT and PVAT‐derived EVs. Transfer and direct overexpression of miR‐221‐3p dramatically enhances VSMC proliferation and migration. Peroxisome proliferator–activated receptor γ coactivator 1α is identified as a miR‐221‐3p target in VSMC phenotypic modulation. Obese mice secrete abundant miRNA‐containing EVs, evoking inflammatory responses in PVAT and vascular phenotypic switching in abdominal aorta of lean mice. Local delivery of miR‐221‐3p mimic in femoral artery causes vascular dysfunction by suppressing the contractile genes in the arterial wall. Our findings provide an EV–miR‐221‐3p–mediated mechanism by which PVAT triggers an early‐stage vascular remodeling in the context of obesity‐associated inflammation. —Li, X. , Ballantyne, L. L. , Yu, Y. , Funk, C. D. Perivascular adipose tissue–derived extracellular vesicle miR‐221‐3p mediates vascular remodeling. FASEB J. 33, 12704–12722 (2019). www.fasebj. org
Racial/ethnic variations in gestational weight gain: a population-based study in Ontario

To explore inadequate and excessive gestational weight gain (GWG) among pregnant women of different racial/ethnic backgrounds in Ontario, Canada. A population-based retrospective cohort study was conducted among women who had prenatal screening and had a singleton birth in an Ontario hospital between April 2016 and March 2017. We estimated adjusted risk ratios (aRR) of racial/ethnic differences for inadequate or excessive GWG using multinomial logistic regression models. Interaction effects were examined to determine whether racial/ethnic difference in GWG varied by pre-pregnancy body mass index (BMI). Among 74,424 women, the prevalence of inadequate GWG in White, Asian, and Black women was 15.7%, 25.8%, and 25.0%, and excessive GWG was 62.8%, 45.5%, and 54.7%, respectively. There were significant interaction effects between race/ethnicity and pre-pregnancy BMI for inadequate GWG (Wald p < 0.01) and excessive GWG (Wald p < 0.01). Compared with White women, Asian women had higher risk of inadequate GWG and lower risk of excessive GWG in all weight classes, and Black women had higher risk of inadequate GWG and lower risk of excessive GWG if their BMI was normal, overweight, or obese. Variations in unhealthy GWG by pre-pregnancy weight classes among Ontario White, Asian and Black women were observed. Individualized counseling regarding appropriate GWG is universally recommended. Additional consideration of racial/ethnic variations by maternal weight classes may help to promote healthy GWG in Canada.
Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin

A longstanding question is how influenza evolves to escape human immunity, which is polyclonal and can target many distinct epitopes on the virus. Here we map how all amino-acid mutations to influenza’s major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations is not present among ferrets, which are frequently used as a model in influenza studies. Our results show how different single mutations help influenza escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.
Self-trapped holes (small polarons) in ferroelectric KH2PO4 crystals

Density functional theory is used to establish the ground-state structure of the self-trapped hole (STH) in KH2PO4 crystals. The STHs in this nonlinear optical material are free small polarons, a fundamental intrinsic point defect. They are produced with ionizing radiation in the low-temperature orthorhombic structure of KH2PO4 and are only stable (i.e. long-lived) below approximately 70 K. A large 129-atom cluster, K19H40P14O56, is constructed to model the STH. The ωB97XD functional with the 6−31+G* basis set is used and geometry optimization is performed. Our results show that two of the oxygen ions in a PO4 unit relax toward each other and equally share the hole. These two oxygen ions do not initially have close hydrogen neighbors. This equal sharing of the hole is related to the presence of isolated, slightly distorted, PO4 units and is significantly different from the small-polaron behavior often observed in other oxide crystals where the hole is localized on only one oxygen ion. The computational results provide a detailed description of the lattice relaxation occurring during formation of the STH. Characteristic spectral features of this defect are a larger hyperfine interaction with one 31P nucleus and equal, but smaller, hyperfine interactions with two 1H nuclei. The computed values for these isotropic and anisotropic hyperfine coupling constants are in excellent agreement with results obtained from electron paramagnetic resonance experiments.
Stretch growth of motor axons in custom mechanobioreactors to generate long‐projecting axonal constructs

The central feature of peripheral motor axons is their remarkable lengths as they project from a motor neuron residing in the spinal cord to distant target muscle. However, current in vitro models have not replicated this feature owing to challenges in generating motor axon tracts beyond a few millimeters in length. To address this, we have developed a novel combination of microtissue engineering and mechanically assisted growth techniques to create long‐projecting centimeter‐scale motor axon tracts. Here, primary motor neurons were isolated from rat spinal cords and induced to form engineered microspheres via forced aggregation in custom microwells. This technique yielded healthy motor neurons projecting dense, fasciculated axonal tracts. Within our custom‐built mechanobioreactors, motor neuron culture conditions, neuronal/axonal architecture, and mechanical growth conditions were optimized to generate parameters for robust and efficient stretch growth of motor axons. We found that axons projecting from motor neuron aggregates were able to tolerate displacement rates at least 10 times greater than those by axons projecting from dissociated motor neurons. The growth and structural characteristics of these stretch‐grown motor axons were compared with that of benchmark stretch‐grown sensory axons, revealing increased motor axon fasciculation. Finally, motor axons were integrated with myocytes and stretch grown to create novel long‐projecting axonal‐myocyte constructs that recreate characteristic dimensions of native nerve‐muscle anatomy. This is the first demonstration of mechanical elongation of spinal motor axons and may have applications as anatomically inspired in vitro testbeds or as tissue‐engineered living scaffolds for targeted axon tract reconstruction following nervous system injury or disease.