Miracle-dz/UniFAR-FTUs huggingface dataset:
Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction: The GEOSTAT-1 Study

Background—Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results—The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). Conclusion—The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration—URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.
Midlevel Student Affairs Leaders' Intentions to Leave: Examining the Quality of Their Professional and Institutional Work Life

This national study examines those demographic characteristics and work life issues that may have an impact on the morale and satisfaction of midlevel student affairs leaders and their intentions to leave their positions. Using structural equation modeling, this study proposes to demonstrate the roles job satisfaction and employee morale play in student affairs leaders' intentions to leave a career in student affairs.
Augmented quantal release of acetylcholine at the vertebrate neuromuscular junction following tdp-43 depletion

TAR DNA binding protein (TDP-43) is a 43 kD, predominately nuclear, protein involved in RNA metabolism. Of clinical significance is that the majority of amyotrophic lateral sclerosis (ALS) patients display abnormal accumulation of misfolded TDP-43 in the cytoplasm, which is coincident with a loss of nuclear localization in the afflicted regions of the central nervous system. Little is known about defects that arise in loss-of-function models, in particular synaptic defects that arise at the neuromuscular junction (NMJ). In this report, we examined abnormalities arising at the NMJ following depletion of tdp-43 using a previously characterized mutant tardbp (encoding tdp-43) zebrafish line containing a premature stop codon (Y220X) that results in an unstable and degraded protein. Homozygous tardbpY220X/Y220X zebrafish do not produce tdp-43 but develop normally due to expression of an alternative splice variant of tardbpl (tardbp paralog). Using an antisense morpholino oligonucleotide to knockdown expression of the tardbpl in tardbpY220X/Y220X embryos, we examined locomotor defects, NMJ structural abnormalities and release of quantal synaptic vesicles at the NMJ. As in previous reports, larvae depleted of tdp-43 display reduced survival, gross morphological defects and severely impaired locomotor activity. These larvae also displayed an increased number of orphaned pre- and postsynaptic NMJ markers but surprisingly, we observed a significant increase (3.5 times) in the frequency of quantal acetylcholine release at the NMJ in larvae depleted of tdp-43. These results indicate that reduced TDP-43 levels alter quantal vesicle release at the NMJ during vertebrate development and may be relevant for understanding synaptic dysfunction in ALS.
Wolbachia Lipoprotein Stimulates Innate and Adaptive Immunity through Toll-like Receptors 2 and 6 to Induce Disease Manifestations of Filariasis*

Wolbachia endosymbiotic bacteria have been implicated in the inflammatory pathogenesis of filariasis. Inflammation induced by Brugia malayi female worm extract (BMFE) is dependent on Toll-like receptors 2 and 6 (TLR2/6) with only a partial requirement for TLR1. Removal of Wolbachia, lipids, or proteins eliminates all inflammatory activity. Wolbachia bacteria contain the lipoprotein biosynthesis genes Ltg and LspA but not Lnt, suggesting Wolbachia proteins cannot be triacylated, accounting for recognition by TLR2/6. Lipoprotein databases revealed 3–11 potential lipoproteins from Wolbachia. Peptidoglycan-associated lipoprotein (PAL) and Type IV secretion system-VirB6 were consistently predicted, and B. malayi Wolbachia PAL (wBmPAL) was selected for functional characterization. Diacylated 20-mer peptides of wBmPAL (Diacyl Wolbachia lipopeptide (Diacyl WoLP)) showed a near identical TLR2/6 and TLR2/1 usage compared with BMFE and bound directly to TLR2. Diacyl WoLP induced systemic tumor necrosis factor-α and neutrophil-mediated keratitis in mice. Diacyl WoLP activated monocytes induce up-regulation of gp38 on human lymphatic endothelial cells and induced dendritic cell maturation and activation. Dendritic cells primed with BMFE generated a non-polarized Th1/Th2 CD4+ T cell profile, whereas priming with Wolbachia depleted extracts (following tetracycline treatment; BMFEtet) polarized to a Th2 profile that could be reversed by reconstitution with Diacyl WoLP. BMFE generated IgG1 and IgG2c antibody responses, whereas BMFEtet or inoculation of TLR2 or MyD88−/− mice produced defective IgG2c responses. Thus, in addition to innate inflammatory activation, Wolbachia lipoproteins drive interferon-γ-dependent CD4+ T cell polarization and antibody switching.
Streptococcus gordonii Modulates Candida albicans Biofilm Formation through Intergeneric Communication

ABSTRACT The fungus Candida albicans colonizes human oral cavity surfaces in conjunction with a complex microflora. C. albicans SC5314 formed biofilms on saliva-coated surfaces that in early stages of development consisted of ∼30% hyphal forms. In mixed biofilms with the oral bacterium Streptococcus gordonii DL1, hyphal development by C. albicans was enhanced so that biofilms consisted of ∼60% hyphal forms. Cell-cell contact between S. gordonii and C. albicans involved Streptococcus cell wall-anchored proteins SspA and SspB (antigen I/II family polypeptides). Repression of C. albicans hyphal filament and biofilm production by the quorum-sensing molecule farnesol was relieved by S. gordonii. The ability of a luxS mutant of S. gordonii deficient in production of autoinducer 2 to induce C. albicans hyphal formation was reduced, and this mutant suppressed farnesol inhibition of hyphal formation less effectively. Coincubation of the two microbial species led to activation of C. albicans mitogen-activated protein kinase Cek1p, inhibition of Mkc1p activation by H2O2, and enhanced activation of Hog1p by farnesol, which were direct effects of streptococci on morphogenetic signaling. These results suggest that interactions between C. albicans and S. gordonii involve physical (adherence) and chemical (diffusible) signals that influence the development of biofilm communities. Thus, bacteria may play a significant role in modulating Candida carriage and infection processes in the oral cavity.
`It's like Maintaining a Hedge'

Since participation at the local level is frequently urged as a solution to political disengagement (Stoker, 2006), it is important to acknowledge the structural obstacles to the ready imposition of the participatory project. This article argues that this focus upon popular democratic participation in urban affairs neglects the realities of political and social life, particularly for poorer areas of cities, and the structural constraints that greatly limit the opportunities for residents to engage actively within their community. From this perspective, the miracle is how much participation occurs rather than how little.
When More Pain Is Preferred To Less: The Effect of Anger in Decision Making

It is axiomatic in social psychology that people protect the perceived worth and integrity of the self—in other words, to self-affirm. But occasionally people may express a desire for self-deprecation, such as causing the self to feel pain. Five studies explored this possibility, namely whether anger propels people toward self-inflicted pain. Compared with both sad and emotionally neutral participants, angered participants rated painful activities as more desirable (Study 1), evidenced greater mental accessibility of pain (Study 2), were more likely to choose a painful-sounding candy (jawbreaker) following a choice between two candies (Study 3), gave themselves more electrical shocks (Study 4), and scored higher on a clinical survey used to measure self-inflicted pain (Study 5). These findings suggest people have a love-hate relationship with the self: Generally, people trump up and self-affirm their intelligence, attractiveness, and benevolence, yet, when people are angry, they deprecate the self and wil.
Local Chemokine Paralysis, a Novel Pathogenic Mechanism for Porphyromonas gingivalis

ABSTRACT Periodontitis, which is widespread in the adult population, is a persistent bacterial infection associated with Porphyromonas gingivalis. Gingival epithelial cells are among the first cells encountered by both P. gingivalis and commensal oral bacteria. The chemokine interleukin 8 (IL-8), a potent chemoattractant and activator of polymorphonuclear leukocytes, was secreted by gingival epithelial cells in response to components of the normal oral flora. In contrast, P. gingivalis was found to strongly inhibit IL-8 accumulation from gingival epithelial cells. Inhibition was associated with a decrease in mRNA for IL-8. Antagonism of IL-8 accumulation did not occur in KB cells, an epithelial cell line that does not support high levels of intracellular invasion by P. gingivalis. Furthermore, a noninvasive mutant of P. gingivalis was unable to antagonize IL-8 accumulation. Invasion-dependent destruction of the gingival IL-8 chemokine gradient at sites of P. gingivaliscolonization (local chemokine paralysis) will severely impair mucosal defense and represents a novel mechanism for bacterial colonization of host tissue.
NuSTAR OBSERVATIONS OF THE COMPTON-THICK ACTIVE GALACTIC NUCLEUS AND ULTRALUMINOUS X-RAY SOURCE CANDIDATE IN NGC 5643

We present two Nuclear Spectroscopic Telescope Array (NuSTAR) observations of the local Seyfert 2 active galactic nucleus (AGN) and an ultraluminous X-ray source (ULX) candidate in NGC 5643. Together with archival data from Chandra, XMM-Newton, and Swift-BAT, we perform a high-quality broadband spectral analysis of the AGN over two decades in energy (∼0.5–100 keV). Previous X-ray observations suggested that the AGN is obscured by a Compton-thick (CT) column of obscuring gas along our line of sight. However, the lack of high-quality ≳10 keV observations, together with the presence of a nearby X-ray luminous source, NGC 5643 X–1, have left significant uncertainties in the characterization of the nuclear spectrum. NuSTAR now enables the AGN and NGC 5643 X–1 to be separately resolved above 10 keV for the first time and allows a direct measurement of the absorbing column density toward the nucleus. The new data show that the nucleus is indeed obscured by a CT column of NH ≳ 5 × 1024 cm−2. The range of 2–10 keV absorption-corrected luminosity inferred from the best-fitting models is L2–10,int = (0.8–1.7) × 1042 erg s−1, consistent with that predicted from multiwavelength intrinsic luminosity indicators. In addition, we also study the NuSTAR data for NGC 5643 X–1 and show that it exhibits evidence of a spectral cutoff at energy E ∼ 10 keV, similar to that seen in other ULXs observed by NuSTAR. Along with the evidence for significant X-ray luminosity variations in the 3–8 keV band from 2003 to 2014, our results further strengthen the ULX classification of NGC 5643 X–1.
Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension.

BACKGROUND Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce. METHODS In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. RESULTS The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONS Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).
Guiding the mind's eye: improving communication and vision by external control of the scanpath

Larry Stark has emphasised that what we visually perceive is very much determined by the scanpath, i.e. the pattern of eye movements. Inspired by his view, we have studied the implications of the scanpath for visual communication and came up with the idea to not only sense and analyse eye movements, but also guide them by using a special kind of gaze-contingent information display. Our goal is to integrate gaze into visual communication systems by measuring and guiding eye movements. For guidance, we first predict a set of about 10 salient locations. We then change the probability for one of these candidates to be attended: for one candidate the probability is increased, for the others it is decreased. To increase saliency, for example, we add red dots that are displayed very briefly such that they are hardly perceived consciously. To decrease the probability, for example, we locally reduce the temporal frequency content. Again, if performed in a gaze-contingent fashion with low latencies, these manipulations remain unnoticed. Overall, the goal is to find the real-time video transformation minimising the difference between the actual and the desired scanpath without being obtrusive. Applications are in the area of vision-based communication (better control of what information is conveyed) and augmented vision and learning (guide a person's gaze by the gaze of an expert or a computer-vision system). We believe that our research is very much in the spirit of Larry Stark's views on visual perception and the close link between vision research and engineering.
Fast and Accurate Modelling of Large TSV Arrays in 3D-ICs Using a 3D Circuit Model Validated Against Full-Wave FEM Simulations and RF Measurements

This paper presents a 3D circuit model capable of rapidly and accurately evaluating substrate noise coupling in the context of 3D integration. Since TSVs are large and noisy structures, the evaluation of electromagnetic coupling to and from TSVs has become crucial to the design of three-dimensional integrated circuits. In this work, we present a fast and accurate 3D circuit model to this end. The model is verified against full-wave simulations and wideband Sparameter measurements of three different TSV structures, including guard rings and up to four TSVs. The model maintains the accuracy of full-wave simulations while presenting a speed increase of 2 to 3 orders of magnitude. This features enables the model to investigate the coupling parameters and crosstalk voltages in very large and complex 3D volumes. Our powerful model provides new opportunities in large scale analysis, and as an example an 11x11 TSV array is simulated in both frequency-and time-domain over a wide frequency band including 121 TSVs and circuit nodes.
Patterns of Interaction in ESL Pair Work

This study investigated the nature of dyadic interaction in an adult ESL classroom. The study was longitudinal, classroom based, and examined the nature of interaction between 10 pairs of adult ESL students over a range of language tasks and over time (a semester). Four distinct patterns of dyadic interaction were found. These patterns are distinguishable in terms of equality and mutuality (Damon & Phelps, 1989). More importantly, the findings suggest that certain patterns of dyadic interaction are more conducive than others to language learning. These findings are explained by reference to Vygotsky’s theory of cognitive development.
Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites

Abstract Proteases are pivotal to parasitism, mediating biological processes crucial to worm survival including larval migration through tissue, immune evasion/modulation and nutrient acquisition by the adult parasite. In haematophagous parasites, many of these proteolytic enzymes are secreted from the intestine (nematodes) or gastrodermis (trematodes) where they act to degrade host haemoglobin and serum proteins as part of the feeding process. These proteases are exposed to components of the immune system of the host when the worms ingest blood, and therefore present targets for the development of anti-helminth vaccines. The protective effects of current vaccine antigens against nematodes that infect humans (hookworm) and livestock (barber's pole worm) are based on haemoglobin-degrading intestinal proteases and act largely as a result of the neutralisation of these proteases by antibodies that are ingested with the blood-meal. In this review, we survey the current status of helminth proteases that show promise as vaccines and describe their vital contribution to a parasitic existence.
Design of ultrawideband applicator for microwave ablation aimed at thermal therapy in liver cancer

Thermal ablation is conducted by utilizing temperature changes to destroy the abnormal tissue or restore its function. The latest technique in thermal ablation is Microwave Ablation (MW Ablation) that rely on the propagation of electromagnetic waves that is able to increase the temperature of a tissue rapidly. Changes in temperature during the ablation process will reduce the water content in the body tissue (78% of the liver tissue is composed of water) and affect the value of permittivity and conductivity of the tissue. These changes cause the impedance matching of the antenna applicator also change during the ablation process. The change on impedance will make the system does not match with the previous resonant frequency. In addition, the microwave ablation applicator, which is designed for specific frequencies (2.4 GHz and 915MHz) with narrow band characteristics will be suffered from aforementioned phenomenon. Meanwhile, according to the previous studies there are other prominent resonant frequencies that used for MW Ablation, i.e. 1.9 GHz, 6 GHz, 9.2 GHz and 10 GHz. Therefore to accommodate some of the frequencies that are widely used in microwave ablation technique and to tackle the problems arising from the reduced transmission efficiency, then an applicator that has ultrawideband (UWB) characteristics is proposed. In this paper, we design an applicator, which has the characteristics of UWB by modifying the ground plane of the applicator by a hexagonal-sectioned coil. The applicator is designed on a FR4 substrate and numerically simulated with liver phantom by using CST Microwave Studio. The proposed applicator is able to have wide bandwidth by 8.1 GHz, with lower frequency (fl) 1.84 GHz and higher frequency (fh) 10 GHz.
Combination Therapy for Managing Difficult-to-Treat Patients With Stage 2 Hypertension: Focus on Valsartan-Based Combinations

Blood pressure (BP) control rates in the United States remain low despite the availability of a wide array of treatment options. High-risk populations, including women, black individuals, and obese patients are even less likely to achieve BP targets than the general population. Uncontrolled BP can lead to serious consequences. Therefore, additional effective and well-tolerated treatment strategies are necessary, particularly for these difficult-to-treat populations. The majority of patients require 2 or more pharmacologic agents to achieve BP control. In patients with stage 2 hypertension, current guidelines recommend rational antihypertensive combinations as initial therapy. The renin–angiotensin–aldosterone system (RAAS) plays an important role in development of hypertension and progression, and the use of RAAS inhibitors has shown BP-lowering effectiveness and excellent tolerability across a continuum of patient types. Agents that block the RAAS form a reasonable foundation for combination therapy. In this article, we review data from studies of valsartan-based antihypertensive combinations in stage 2 hypertension, with a focus on women, black individuals, and obese patients.