Miracle-dz/UniFAR-FTUs huggingface dataset:
Folic acid supplementation lowers blood arsenic 2

, Abstract Background— Chronic arsenic exposure currently affects >100 million persons worldwide. Methylation of ingested inorganic arsenic (InAs) to monomethylarsonic (MMAs) and dimethylarsinic (DMAs) acids relies on folate-dependent one-carbon metabolism and facilitates urinary arsenic elimination. Objective— We hypothesized that folic acid supplementation to arsenic-exposed Bangladeshi adults would increase arsenic methylation and thereby lower total blood arsenic. Design— In this randomized, double-blind, placebo-controlled trial, we evaluated blood concentrations of total arsenic, InAs, MMAs, and DMAs in 130 participants with low plasma folate (<9 nmol/L) before and after 12 wk of supplementation with folic acid (400 μ g/d) or placebo. Results— MMAs in blood was reduced by a mean ± SE of 22.24 ± 2.86% in the folic acid supplementation group and by 1.24 ± 3.59% in the placebe group ( P < 0.0001). There was no change in DMAs in blood; DMAs is rapidly excreted in urine as evidenced by an increase in urinary DMAs ( P = 0.0099). Total blood arsenic was reduced by 13.62% in the folic acid supplementation group and by 2.49% in the placebo group ( P = 0.0199). Conclusions— Folic acid supplementation to participants with low plasma concentrations of folate lowered blood arsenic concentrations, primarily by decreasing blood MMAs and increasing urinary DMAs. Therapeutic strategies to facilitate arsenic methylation, particularly in populations with folate deficiency or hyperhomocysteinemia or both, may lower blood arsenic concentrations and thereby contribute to the prevention of arsenic-induced illnesses.
Bidirectional Resonant Converter with Half-Bridge Circuits: Analysis, Design, and Implementation

A soft-switching dc–dc converter with bidirectional power flow capability is studied in this paper for energy storage units or electric vehicle applications. The circuit topology of the studied converter is constructed using a dual half-bridge circuit with split capacitors. A series resonant tank with frequency control modulation is employed in the proposed circuit to realize the soft switching characteristics of active devices. Synchronous-rectifier-based Metal-Oxide-Semiconductor Field-Effect Transistor (MOSFETs) are used on the low-voltage side to lessen conduction loss on the power semiconductors. The benefits of the studied circuit are bidirectional power flow capability, high efficiency, low switching loss, and simple circuit structure. The achievability of the developed converter is demonstrated from test results with a scaled-down laboratory prototype.
Functionally Active HIV-specific T cells that Target gag and nef can be expanded from Virus-naive Donors and Target a Range of Viral Epitopes: Implications for a Cure Strategy after Allogeneic HSCT

Allogeneic HSCT can potentially cure HIV by eliminating infected recipient cells, particularly in the context of technologies that may confer HIV resistance to these stem cells. But to date, the Berlin patient remains the only case of HIV cure despite multiple attempts to eradicate infection with HSCT. One approach to improve this is to administer virus-specific T cells, a strategy that has proven success in preventing other infections post-transplant. While we have reported that broadly-HIV-specific T cells can be expanded from HIV+ patients, allogeneic transplants only contain virus-naïve T cells. Modifying this approach for the allogeneic setting thus required a robust, reproducible platform that can expand HIV-specific cells from the naïve pool. Hence, we hypothesized that HIV-specific T cells could be primed ex vivo from seronegative individuals to effectively target HIV. Here, we show that ex vivo primed and expanded HIV specific T cells released IFN γ in response to HIV antigens, and that these cells have enhanced ability to suppress replication in vitro. This is the first demonstration of ex vivo priming and expansion of functional, multi-HIV antigen specific T-cells from HIV negative donors, which has implications for use of allogeneic HSCT as a functional HIV cure.
Simulated Online Adaptive MR-Guided SBRT for the Treatment of Oligometastatic Disease of the Abdomen and Central Thorax: Characterization of Potential Advantages

Purpose/Objectives— Stereotactic body radiotherapy (SBRT) is increasingly used to treat oligometastatic or unresectable primary malignancy, although proximity of organs-at-risk (OAR) may limit delivery of sufficiently ablative dose. Magnetic resonance (MR)-based online-adaptive radiotherapy (ART) has potential to improve SBRT’s therapeutic ratio. This study characterizes potential advantages of online-adaptive MR-guided SBRT to treat oligometastatic disease of the non-liver abdomen and central thorax. Materials/Methods— Ten patients treated with RT for unresectable primary or oligometastatic disease of the non-liver abdomen (n=5) or central thorax (n=5) underwent imaging throughout treatment on a clinical MR-IGRT system. SBRT plans were created based on tumor/OAR anatomy at initial CT simulation (P I ) and simulated adaptive plans were created based on observed MR-image set tumor/OAR “anatomy-of-the-day” (P A ). Each P A was planned under workflow constraints to simulate online-ART. Prescribed dose was 50Gy/5fractions with goal coverage of 95% PTV by 95% of the prescription, subject to hard OAR constraints. P I was applied to each MR dataset and compared to P A to evaluate changes in dose delivered to tumor/OARs, with dose escalation when possible. Results— Hard OAR constraints were met for all P I based on anatomy from initial CT simulation, and all P A based on anatomy from each daily MR-image set. Application of the P I to anatomy-of-the-day caused OAR constraint violation in 19/30 cases. Adaptive planning increased PTV coverage in 21/30 cases, including 14 cases where hard OAR constraints were violated by the non-adaptive plan. For 9 P A cases, decreased PTV coverage was required to meet hard OAR constraints that would have been violated in a non-adaptive setting. Conclusions— Online-adaptive MRI-guided SBRT may allow PTV dose escalation and/or simultaneous OAR sparing compared to non-adaptive SBRT. A prospective clinical trial is underway at our institution to evaluate clinical outcomes of this technique. In this study, potential dosimetric gains from daily online adaptive SBRT for central thoracic and abdominal applications were characterized. Initial CT-simulation plans were applied to MR localization images, with evaluation and reoptimization based on variable anatomy. We found a significant incidence of OAR constraint violation by application of the initial plan to localization images. Online adaptive planning resolved all potential OAR violations, and allowed dose escalation in a majority of patients and fractions. Our findings suggest that this method could improve the therapeutic ratio for SBRT of central thoracic and abdominal malignancies.
Vulnerability for Alcohol Use Disorder is Associated with Rate of Alcohol Consumption

Objective— Although several risk factors have been identified for alcohol use disorder, many individuals with these factors do not go on to develop the disorder. Identifying early phenotypic differences between vulnerable individuals and healthy controls could help identify those at higher risk. Binge drinking, defined as reaching a blood alcohol level of 80 mg%, carries a risk of negative legal and health outcomes and may be an early marker of vulnerability. Using a carefully controlled experimental paradigm, we tested the hypothesis that risk factors for alcohol use disorder, including family history of alcoholism, male sex, impulsivity, and low level of response to alcohol, would predict rate of binging during an individual alcohol consumption session. Method— This cross-sectional study included 159 young social drinkers who completed a laboratory session in which they self-administered alcohol intravenously. Cox proportional hazards models were used to determine whether risk factors for alcohol use disorder were associated with the rate of achieving a binge-level exposure. Results— A greater percentage of relatives with alcoholism (hazard ratio 1.04, 95% CI 1.02 to 1.07), male sex (hazard ratio 1.74, 95% CI 1.03 to 2.93), and higher impulsivity (hazard ratio 1.17, 95% CI 1.00 to 1.37), were associated with a higher rate of binging throughout the session. Participants with all 3 risk factors had the highest rate of binging throughout the session compared to the lowest risk group (hazard ratio 5.27, 95% CI 1.81 to 15.30). Conclusions— Binge drinking may be an early indicator of vulnerability to alcohol use disorder and should be carefully assessed as part of a thorough clinical evaluation.
Medicare Postacute Care Payment Reforms Have Potential to Improve Efficiency, but May Need Changes to Cut Costs

The Affordable Care Act mandates changes in payment policies for Medicare postacute care services intended to contain spending in the long run and help ensure the program’s financial sustainability. In addition to reducing annual payment increases to providers under the existing prospective payment systems, the act calls for demonstration projects of bundled payment, accountable care organizations, and other strategies to promote care coordination and reduce spending. Experience with the adoption of Medicare prospective payment systems in postacute care settings approximately a decade ago suggests that current reforms could, but need not necessarily, produce such undesirable effects as decreased access for less profitable patients, poorer patient outcomes, and only short-lived curbs on spending. Policy makers will need to be vigilant in monitoring the impact of the Affordable Care Act reforms and be prepared to amend policies as necessary to ensure that the reforms exert persistent controls on spending without compromising the delivery of patient-appropriate postacute services. Each year, more than ten million Medicare beneficiaries are discharged from acute care hospitals into postacute care settings. These settings are long-term care hospitals, inpatient rehabilitation facilities, skilled nursing facilities, and patients’ homes with services from home health agencies. Medicare beneficiaries receiving postacute services are some of the frailest and most vulnerable elders. Medicare’s spending on them has more than doubled in the decade, increasing from $26.6 billion 2001 $58 billion The Affordable Care Act implemented changes to Medicare payment policy to curtail this growth in spending. The act establishes demonstration projects such as bundled payment and accountable care organizations to promote care coordination and reduce unnecessary spending. It also mandates reductions in payment increases for providers from fiscal years 2010–19.
MOLECULAR BASIS FOR THE RECOGNITION OF PHOSPHORYLATED STAT1 BY IMPORTIN α 5

Interferon- γ (IFN- γ ) stimulation triggers tyrosine-phosphorylation of transcription factor STAT1 at position 701, which is associated with the switching from carrier-independent nucleocytoplasmic shuttling to carrier-mediated nuclear import. Unlike most substrates that carry a classical Nuclear Localization Signal (cNLS) and bind to importin α 1, STAT1 possesses a nonclassical NLS recognized by the isoform importin α 5. In the present study, we have analyzed the mechanisms by which importin α 5 binds phosphorylated STAT1 (pSTAT1). We found that a homodimer of pSTAT1 is recognized by one equivalent of importin α 5 with K d = 191 ± 20 nM. Whereas tyrosine-phosphorylation at position 701 is essential to assemble a pSTAT1:importin α 5 complex, the phosphate moiety is not a direct binding determinant for importin α 5. In contrast to classical NLS substrates, pSTAT1 binding to importin α 5 is not displaced by the N-terminal importin β binding (IBB)-domain, and requires the importin α 5 C-terminal acidic tail (505-EEDD-508). A local unfolding of importin α 5 ARM repeat 10 accompanies high affinity binding to pSTAT1. This unfolding is mediated by a single conserved tyrosine at position 476 of importin α 5, which is inserted in between Armadillo (ARM) repeat 10 helices H1-H2-H3, thereby preventing the intramolecular helical stacking essential to stabilize the folding conformation of ARM 10. Introducing a glycine at this position, as in importin α 1, disrupts high-affinity binding to pSTAT1, suggesting pSTAT1 recognition is dependent on the intrinsic flexibility of ARM 10. Using the quantitative stoichiometry and binding data presented in this paper together with mutational information available in the literature, we propose importin α 5 binds in between two STAT1 monomers, with two major binding determinants in the SH2- and DNA-binding domains. In vitro this model is supported by the observation that a 38mer DNA oligonucleotide containing two tandem cfos M67-promoters can displace importin α 5 from pSTAT1, suggesting a possible role for DNA in releasing activated STAT1 in the cell nucleus.
A wideband polarization reconfigurable isosceles trapezoidal monopole antenna

In this article, a polarization reconfigurable isosceles trapezoidal monopole antenna for the circular polarization (CP) is presented. A trapezoidal monopole and the ground plane are on the same side of the dielectric substrate. The monopole is excited by a reconfigurable T‐shaped 50 Ω microstrip feed line and reconfigurable vertical slots are incorporated in the ground plane to realize switchable wideband CP. For the different switching states of the p‐i‐n diodes, linear polarization, left‐handed and right handed CP can be achieved in the boresight direction (+z direction). The antenna prototype is fabricated and tested. The measured reflection coefficient bandwidth (|S11| < −10 dB) is 31.2% (2.13 ‐ 2.91 GHz) and axial ratio bandwidth (axial ratio < 3 dB) is 22% (2.18 ‐ 2.72 GHz) for the CP. The measured reflection coefficient bandwidth is 18.56% (2.15 ‐ 2.59 GHz) for linear polarization.
The Gordon Wilson lecture. Adrenergic receptors: regulation at the biochemical, physiological and clinical levels.

Of the numerous biologically active agents that have their primary interaction at the cell surface, few elicit more diverse and ubiquitous effects than the catecholamines such as epinephrine and norepinephrine. Several major types of receptors for the catecholamines exist and, in recent years, have been studied by direct radioligand-binding techniques, as well as by assays of linked enzymatic activities (1). Currently, most available information is about the 83-adrenergic receptors that generally stimulate the enzyme adenylate cyclase, thus activating the cyclic AMP (cAMP) cascade of reactions (2, 3, 4). Because of their widespread occurrence and important role in mediating the physiological effects of the catecholamines on such diverse processes as cardiac contractility, lipolysis, glycogenolysis, smooth muscle relaxation, and many others, the adenylate cyclase-coupled /8-adrenergic receptors have been intensively studied. They are currently viewed as providing perhaps the best model of a hormone receptor coupled to a well-defined effector enzyme within the plasma membrane of the cell. Two subtypes of f8-adrenergic receptors termed 381 and 82 have also been defined based on physiological studies (5). These differ in that ,81 receptors display approximately equal affinity for epinephrine and norepinephrine, whereas at 32 receptors epinephrine is considerably more potent than norepinephrine. Two subtypes of a-adrenergic receptors are also known, termed a, and a2 receptors (6, 7). Alpha, receptors are generally postsynaptic and display quite high affinity for the a, selective antagonist prazosin. Alpha2 receptors may be either presynaptic, where they mediate feedback inhibition of noradrenaline release from sympathetic nerve terminals, or postsynaptic where they have a variety of effects. Alpha2 receptors have high affinity for the antagonist yohimbine and, in some systems, appear to be coupled in an inhibitory fashion to the enzyme adenylate cyclase (8). Alpha, receptors appear to change calcium fluxes across cell membranes with consequent changes in intracellular calcium concentrations (9). The first successful direct ligand binding studies of adrenergic receptors
Tower construction of a wind turbine and method for stabilizing a tower construction of a wind turbine

The invention relates to a tower construction for a wind turbine, said tower construction enabling very large hub heights due to a combination of inner prestress, guying, and a torsion-resistant tower shaft. The tower construction has a tower shaft, a foundation, and a transition piece in the area of the upper end of the tower shaft, guying elements being provided which are angled in relation to a longitudinal axis (A) of the tower shaft and which extend radially outside of the exterior shell defined by the tower shaft, by means of which guying elements the tower shaft is guyed at least in some sections, characterized in that tension members are provided radially inside the exterior shell, by means of which tension members the tower shaft is vertically prestressed at least in some sections, the tower shaft being made of concrete, in particular prestressed concrete, in the area between the transition piece and the foundation. In order to better control the resonance behavior of this structure, the invention additionally proposes prestressing elements and guying elements that can be loaded with a variable tensile stress, the natural frequencies of the tower construction thus being varied and influenced to the effect that no interferences between excitation frequencies, in particular of the rotor unit of the wind generator, and the natural frequencies in particular of the tower construction occur and at the same time aerodynamic damping becomes possible.
Estrous cycle regulates activation of hippocampal Akt, LIMK, and neurotrophin receptors in C57BL6 mice

Estradiol modulates dendritic spine morphology and synaptic protein expression in the rodent hippocampus, as well as hippocampal-dependent learning and memory. In the rat, these effects may be mediated through nongenomic steroid signaling such as estradiol activation of Akt and LIMK pathways, in addition to genomic signaling involving estradiol upregulation of brain-derived neurotrophic factor expression (BDNF). Due to the many species differences between mice and rats, including differences in the hippocampal response to estradiol, it is unclear whether estradiol modulates these pathways in the mouse hippocampus. Therefore, we investigated whether endogenous fluctuations of gonadal steroids modulate hippocampal activation of Akt, LIMK, and the BDNF receptor TrkB in conjunction with spatial memory in female mice. We found that Akt, LIMK, and TrkB were activated throughout the dorsal hippocampal formation during the high-estradiol phase of proestrus compared to diestrus. Cycle phase also modulated expression of the pre-and post-synaptic markers synaptophysin and PSD-95. However, cycle phase did not influence performance on an object placement test of spatial memory, although this task is known to be sensitive to the complete absence of ovarian hormones. The findings suggest that endogenous estradiol and progesterone produced by the ovaries modulate specific signaling pathways governing actin remodeling, cell excitability, synapse formation. and hilus and SGZ of the dentate. Two-way ANOVA demonstrated a significant effect of brain region (F(4,633.5)=45.0, p<0.0001) and cycle phase (F(2,460.4)=32.7, p<0.0001), but no interaction (F(8,17.2)=1.2, p=0.30). Post-hoc tests revealed that pTrkB IR was highest in the SGZ, and higher in the stratum lucidum and dentate hilus than in the stratum radiatum. pTrkB IR was significantly higher in proestrus than in estrus and diestrus (p<0.0001). This indicates that TrkB activation in the dorsal hippocampus is high during the high-estradiol phase of the cycle, proestrus, and low during the low-estradiol phases of estrus and diestrus. steroid hormone signaling and synaptic protein expression in female C57BL6 mice. The findings suggest that the endogenous surge in estradiol during proestrus may directly activate the PI3K pathway (with downstream targets Akt, LIMK, and PSD-95) and the BDNF/TrkB system in this cycle phase. Future work using gonadectomy and hormone treatment and mice with different genotypes will clarify the direct role of ovarian steroids in these findings. Because the hippocampal formation plays an important role in both cognitive function and normal or disordered mood, this study marks an important step in elucidating the mechanism of cycle- and ovarian steroid-associated neurologic and psychiatric disorders.
Electrophysiological characterization of neurons in the dorsolateral pontine REM sleep induction zone of the rat: intrinsic membrane properties and responses to carbachol and orexins

Pharmacological, lesion and single-unit recording techniques in several animal species have identified a region of the pontine reticular formation (Subcoeruleus, SubC) just ventral to the locus coeruleus as critically involved in the generation of rapid-eye-movement (REM) sleep. However, the intrinsic membrane properties and responses of SubC neurons to neurotransmitters important in REM sleep control, such as acetylcholine and orexins/hypocretins, have not previously been examined in any animal species and thus were targeted in this study. We obtained whole-cell patch-clamp recordings from visually identified SubC neurons in rat brain slices in vitro. Two groups of large neurons (mean diameter 30 and 27 μ m) were tentatively identified as cholinergic (rostral SubC) and noradrenergic (caudal SubC) neurons. SubC reticular neurons (non-cholinergic, non-noradrenergic) showed a medium-sized depolarizing sag during hyperpolarizing current pulses and often had a rebound depolarization (low-threshold spike, LTS). During depolarizing current pulses they exhibited little adaptation and fired maximally at 30–90 Hz. Those SubC reticular neurons excited by carbachol (n=27) fired spontaneously at 6 Hz, often exhibited a moderately sized LTS, and varied widely in size (17–42 μ m). Carbachol-inhibited SubC reticular neurons were medium-sized (15–25 μ m) and constituted two groups. The larger group (n=22) was silent at rest and possessed a prominent LTS and associated 1–4 action potentials. The second, smaller group (n=8) had a delayed return to baseline at the offset of hyperpolarizing pulses. Orexins excited both carbachol excited and carbachol inhibited SubC reticular neurons. SubC reticular neurons had intrinsic membrane properties and responses to carbachol similar to those described for other reticular neurons but a larger number of carbachol inhibited neurons were found (> 50 %), the majority of which demonstrated a prominent LTS and may correspond to PGO-on neurons. Some or all carbachol-excited neurons are presumably REM-on neurons. Carbachol; CARB-E Carbachol CARB-I Carbachol coupled Choline acetyltransferase; DAB Diaminobenzidine; DC Direct GABA Gamma-amino-butyric acid; GAD67 glutamic acid decarboxylase 67 kDa isoform; HCN Hyperpolarization cyclic nucleotide gated cation channels; IACUC Animal Care and Use IR-DIC Infra-red differential interference contrast; LC locus LDT laterodorsal LTS