Miracle-dz/UniFAR-FTUs huggingface dataset:
Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children

Background The antiretroviral drug nevirapine and the antimalarial artemisinin-based combination therapy artemether-lumefantrine are commonly co-administered to treat malaria in the context of HIV. Nevirapine is a known inhibitor of cytochrome P450 3A4, which metabolizes artemether and lumefantrine. To address the concern that the antiretroviral nevirapine impacts the antimalarial artemether-lumefantrine pharmacokinetics, a prospective non-randomized controlled study in children presenting with uncomplicated malaria and HIV in sub-Saharan Africa was carried out. Methods Participants received artemether-lumefantrine (20/120 mg weight-based BID) for 3 days during nevirapine-based antiretroviral therapy (ART) co-administration (158–266 mg/m2 QD). HIV positive participants who were not yet on ART drugs were also enrolled as the control group. The target enrollment was children aged 3–12 years (n = 24 in each group). Intensive pharmacokinetics after the last artemether-lumefantrine dose was assessed for artemether, its active metabolite dihydroartemisinin, and lumefantrine. Pharmacokinetic parameters (area under the plasma concentration vs. time curve (AUC), maximum concentration and day 7 lumefantrine concentrations) were estimated using non-compartmental methods and compared to controls. Results Nineteen children (16 on nevirapine and three not on ART) enrolled. Fifteen of the 16 (aged 4 to 11 years) on nevirapine-based ART were included in the pharmacokinetic analysis. Due to evolving WHO HIV treatment guidelines, insufficient children were enrolled in the control group (n = 3), so the pharmacokinetic data were compared to a historical control group of 20 HIV-uninfected children 5–12 years of age who also presented with malaria and underwent identical study procedures. Decreases of pharmacokinetic exposure [as estimated by AUC (AUC0-8hr)] were marginally significant for artemether (by -46%, p = 0.08) and dihydroartemisinin (-22%, p = 0.06) in the children on nevirapine-based ART, compared to when artemether-lumefantrine was administered alone. Similarly, peak concentration was decreased by 50% (p = 0.07) for artemether and 36% (p = 0.01) for dihydroartemisinin. In contrast, exposure to lumefantrine increased significantly in the context of nevirapine [AUC0-120hr:123% (p<0.001); Cday7:116% (p<0.001), Cmax: 95% (p<0.001)]. Conclusions Nevirapine-based ART increases the exposure to lumefantrine in pre-pubescent children with a trend toward diminished artemether and dihydroartemisinin exposure. These findings contrast with other studies indicating NVP reduces or results in no change in exposure of antimalarial drugs, and may be specific to this age group (4–12 years). Considering the excellent safety profile of artemether-lumefantrine, the increase in lumefantrine is not of concern. However, the reduction in artemisinin exposure may warrant further study, and suggests that dosage adjustment of artemether-lumefantrine with nevirapine-based ART in children is likely warranted.
HLA-B5901 serotype participates in toxic epidermal necrolysis induced by methazolamide: A case report of Chinese female

Toxic Epidermal Necrolysis (TEN) is the life and health threatening and a kind of severe adverse drug reactions characterized as the epidermal detachment illustrating with areas of denuded skin and the blisters in the whole body. We reported a case of methazolamide-induced in a TEN in a 57-year-old Chinese Han woman who was admitted in the dermatology department with a rapid progressing of erythematous, blisters, red macular and papular lesions, and maculopapular rash all over the body. As the body epidermal detachment achieves to approximately 30% of the whole body, and developed severe bullous lesions epidermal detachment achieves to 80% of the body surface, combining with the positive allele HLA-B*5901 expression, she was diagnosed as the toxic epidermal necrolysis. The disease course was keep about 15 days after stopping the drug and starting a symptomatic therapy. The positively expressed HLA-B5901 serotype, combining with the initial clinical signs of fever, dysphagia or burning eyes and influenza-like lesions (prior to mucocutaneous lesions), could act as the prognostic biomarkers for the potential occurrence of TEN in Chinese Han population. Meanwhile, the early discover and stop using the suspected drug is also an important method to improve the prognosis of TEN.
Relationship of stress, distress and inadequate coping behaviors to periodontal disease.

BACKGROUND The association of stress, distress, and coping behaviors with periodontal disease was assessed. METHODS A cross-sectional study of 1,426 subjects between the ages of 25 and 74 years in Erie County, New York, was carried out to assess these relationships. Subjects were asked to complete a set of 5 psychosocial questionnaires which measure psychological traits and attitudes including discrete life events and their impact; chronic stress or daily strains; distress; coping styles and strategies; and hassles and uplifts. Clinical assessment of supragingival plaque, gingival bleeding, subgingival calculus, probing depth, clinical attachment level (CAL) and radiographic alveolar crestal height (ACH) was performed, and 8 putative bacterial pathogens from the subgingival flora measured. RESULTS Reliability of subjects' responses and internal consistencies of all the subscales on the instruments used were high, with Cronbach's alpha ranging from 0.88 for financial strain to 0.99 for job strain, uplifts, and hassles. Logistic regression analysis indicated that, of all the daily strains investigated, only financial strain was significantly associated with greater attachment and alveolar bone loss (odds ratio, OR = 1.70, 95% CI = 1.09 to 2.65 and OR = 1.68, 95% CI = 1.20 to 2.37, respectively) after adjusting for age, gender, and cigarette smoking. When coping behaviors were evaluated, it was found that those with more financial strain who were high emotion-focused copers (a form of inadequate coping) had a higher risk of having more severe attachment loss (OR = 2.24, 95% CI = 1.15 to 4.38) and alveolar bone loss (OR = 1.91, 95% CI = 1.15 to 3.17) than those with low levels of financial strain within the same coping group, after adjustment for age, gender, and cigarette smoking. Similar results were found among the low problem-focused copers for AL (OR = 2.21, 95% CI = 1.11 to 4.38) and ACH (OR = 2.12, 95% CI = 1.28 to 3.51). However, subjects with high levels of financial strain who reported high levels of problem-based coping (considered adequate or good coping) had no more periodontal disease than those with low levels of financial strain, suggesting that the effects of stress on periodontal disease can be moderated by adequate coping behaviors. CONCLUSIONS We find that psychosocial measures of stress associated with financial strain and distress manifest as depression, are significant risk indicators for more severe periodontal disease in adults in an age-adjusted model in which gender (male), smoking, diabetes mellitus, B. forsythus, and P. gingivalis are also significant risk indicators. Of considerable interest is the fact that adequate coping behaviors as evidenced by high levels of problem-based coping, may reduce the stress-associated risk. Further studies also are needed to help establish the time course of stress, distress, and inadequate coping with respect to the onset and progression of periodontal disease, and the mechanisms that explain this association.
Comparison of Genzling method vs Hamley method allowing a postural adjustment in cycling: preliminary study

The optimization of the cyclist’s position aims to increase performance and may prevent overuse injuries. To find the optimum posture, taking into account anthropometry of the cyclist is essential. Thereby, a properly saddle height, adapted at the cyclist morphology, is primordial: it allows to increase performance (Hamley and Thomas, 1967) and to improve the pedalling biomechanics (articular kinematics and muscular activity; De Vey Mestdagh 1998). Several authors have studied this parameter to find the optimal saddle height as static method based on the inseam length (Hamley and Thomas 1967; Genzling 1980) or static method based on the knee angle during goniometric assessment with the pedal located at the bottom dead center (Holmes et al. 1994). However, it appears a substantial discrepancy between all these methods (Peveler et al., 2007). The aim of this preliminary study is to compare two statics methods based on the inseam length which are frequently used in the literature: Genzling method (1980) and Hamley method (1967).
Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation

Chemically induced skin carcinomas in mice are a paradigm for epithelial neoplasia, where oncogenic ras mutations precede p53 and INK4a/ARF mutations during the progression toward malignancy. To explore the biological basis for these genetic interactions, we studied cellular responses to oncogenic ras in primary murine keratinocytes. In wild-type keratinocytes, ras induced a cell-cycle arrest that displayed some features of terminal differentiation and was accompanied by increased expression of the p19ARF, p16INK4a, and p53 tumor suppressors. In ARF-null keratinocytes, ras was unable to promote cell-cycle arrest, induce differentiation markers, or properly activate p53. Although oncogenic ras produced a substantial increase in both nucleolar and nucleoplasmic p19ARF, Mdm2 did not relocalize to the nucleolus or to nuclear bodies but remained distributed throughout the nucleoplasm. This result suggests that p19ARF can activate p53 without overtly affecting Mdm2 subcellular localization. Nevertheless, like p53-null keratinocytes, ARF-null keratinocytes were transformed by oncogenic ras and rapidly formed carcinomas in vivo. Thus, oncogenic ras can activate the ARF-p53 program to suppress epithelial cell transformation. Disruption of this program may be important during skin carcinogenesis and the development of other carcinomas.
UNDERSTANDING THE EMERGENCE OF REQUIREMENT RISKS IN INFORMATION SYSTEMS PROJECTS

Information Systems (IS) requirement risks are one of the most important sources that contribute to project problems, such as escalation of project cost and schedule. Early identifying and managing requirement risks is therefore an important task to avoid project complexity and increase chance of project success. Earlier research has identified various requirement risks in IS project. However, there has been little research on explaining the emergence of requirement risks. This paper proposes some initial insights into the origins of requirement risks based on a case study of an IS project having requirement risks. The results of this study suggest that the emergence of requirement risks can be identified and explained from various IS development (ISD) practices and some organisational behaviours perspectives. Moreover, requirements risk can occur not only in the requirement collection and analysis phase, but also in the later phases of the ISD. Conclusion and implications for future research are also provided.
Transforming Growth Factor (TGF)-β-activated Kinase 1 (TAK1) Activation Requires Phosphorylation of Serine 412 by Protein Kinase A Catalytic Subunit α (PKACα) and X-linked Protein Kinase (PRKX)*

Background: Understanding of molecular mechanism of TAK1 activation is incomplete. Results: PKACα and PRKX phosphorylate TAK1 at serine 412 to regulate TAK1 activation in the IL-1 receptor (IL-1R) and Toll-like receptor (TLR) signaling pathways. Conclusion: TAK1 activation requires phosphorylation by PKACα and PRKX. Significance: This study advanced our understanding of the molecular mechanism of TAK1 activation. TGF-β-activated kinase 1 (TAK1) is a key kinase in mediating Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) signaling. Although TAK1 activation involves the phosphorylation of Thr-184 and Thr-187 residues at the activation loop, the molecular mechanism underlying the complete activation of TAK1 remains elusive. In this work, we show that the Thr-187 phosphorylation of TAK1 is regulated by its C-terminal coiled-coil domain-mediated dimerization in an autophosphorylation manner. Importantly, we find that TAK1 activation in mediating downstream signaling requires an additional phosphorylation at Ser-412, which is critical for TAK1 response to proinflammatory stimuli, such as TNF-α, LPS, and IL-1β. In vitro kinase and shRNA-based knockdown assays reveal that TAK1 Ser-412 phosphorylation is regulated by cAMP-dependent protein kinase catalytic subunit α (PKACα) and X-linked protein kinase (PRKX), which is essential for proper signaling and proinflammatory cytokine induction by TLR/IL-1R activation. Morpholino-based in vivo knockdown and rescue studies show that the corresponding site Ser-391 in zebrafish TAK1 plays a conserved role in NF-κB activation. Collectively, our data unravel a previously unknown mechanism involving TAK1 phosphorylation mediated by PKACα and PRKX that contributes to innate immune signaling.
Ex vivo protective effects of nicotinamide and 3‐aminobenzamide on rat synaptosomes treated with Aβ(1–42)

Alzheimer's disease (AD) is the most common form of dementia and is characterized by the presence of senile plaques and neurofibrillary tangles, along with synaptic loss. The underlying mechanisms of AD are not clarified yet, but oxidative stress and mitochondrial dysfunction are important factors. Overactivation of poly(adenosine diphosphate ribose) polymerase‐1 (PARP‐1) enzyme has been known to cause neuroinflammation and cell death in neurodegenerative processes. The aim of the present study was to investigate the protective effects of the PARP‐1 inhibitors, 3‐aminobenzamide (3‐AB) and nicotinamide (NA), against amyloid β peptide (1–42) (Aβ(1–42))‐induced oxidative damage and mitochondrial reduction capacity on isolated synaptosomes. Rats were injected intraperitoneally with 3‐AB (30–100 mg kg−1), NA (100–500 mg kg−1) or with saline for 7 days. Synaptosomes were incubated with 10–30 μM Aβ(1–42) or saline for 6 h at 37 °C. Ex vivo Aβ(1–42) treatment significantly induced oxidative stress and mitochondrial dysfunction in synaptosomes of the saline group, while synaptosomes of 3‐AB and NA groups showed significant decreases in lipid peroxidation, reactive oxygen species production and protein oxidation. Moreover, both NA and 3‐AB were able to improve the mitochondrial reduction capacity against Aβ(1–42). These data suggest that NA and 3‐AB may have protective effects in neurodegenerative processes because of the reduced levels of oxidative stress and the improvement of mitochondrial function. Copyright © 2014 John Wiley & Sons, Ltd.
The virulence-associated chrysobactin iron uptake system of Erwinia chrysanthemi 3937 involves an operon encoding transport and biosynthetic functions

The iron assimilation system of Erwinia chrysanthemi 3937 is mediated by the catechol-type siderophore chrysobactin and the outer membrane transport protein Fct. We generated a variety of subclones in high- and low-copy-number vectors from a wild-type recombinant cosmid shown previously to carry the gene cluster fct-cbsA, cbsB, cbsC, cbsE encoding chrysobactin transport and biosynthetic functions, respectively. We studied their expression in Escherichia coli enterobactin-deficient entA, entB, entC, and entE mutants. This provided evidence that the fct and cbs genes are regrouped within a single genetic unit of ca. 8 kb in the following order: fct, cbsC, cbsE, cbsB, and cbsA. The gene boundaries were determined, and the various recombinant plasmids were expressed in Escherichia coli minicells: CbsA and CbsC enzymatic activities were clearly identified as polypeptides with apparent molecular masses of 32,000 and 38,000, respectively.
Differential Induction of mRNAs for the Glycolytic and Ethanolic Fermentative Pathways by Hypoxia and Anoxia in Maize Seedlings

Fructose-1,6-bisphosphate aldolase (ALD) and enolase (ENO) from the glycolytic pathway, and pyruvate decarboxylase (PDC) and alcohol dehydrogenase 2 (ADH2) from the ethanolic fermentative pathway, are enzymes previously identified as among those synthesized selectively in O2-deficient roots of maize (Zea mays L.). The present study measured levels of transcripts representing these two pathways in 5-mm root tips, root axes (the remainder of the primary seminal root), and shoots of maize seedlings to determine how closely both pathways were co-induced and how they were modulated by changes in O2 concentration. In hypoxic seedlings with the roots in solution sparged with 4% (v/v) O2 (balance N2) and the shoots in the same gaseous atmosphere, mRNAs for Pdc1 and Adh2 in root tips both increased about 15-fold during the first 12 h, followed by a decline toward initial levels by 18 to 24 h. Message levels for Ald1 and Eno1 showed only small changes during hypoxia. When expression was examined under anoxia, the extent to which all four mRNAs increased in different tissues depended on whether the seedlings had been previously acclimated to hypoxia or were anoxically shocked. The results show that although all the genes examined increased expression during hypoxia and/or anoxia, they differed in the rapidity and magnitude of the response and in the time to reach maximal message levels: there was no common pattern of change of message levels for the glycolytic or for the fermentative enzymes.
Running head : Exocyst in Arabidopsis trichome maturation

Running head: Exocyst in Arabidopsis trichome maturation 1 2 3 Corresponding author: 4 Ivan Kulich 5 Department of Experimental Plant Biology of Faculty of Natural Sciences, Charles University 6 Vinicna 5, 12844 Prague 2, Czech Republic 7 8 e-mail: kulich@natur.cuni. cz 9 tel. : 00420221951685 10 mob.phone: 00420739053652 11 Plant Physiology Preview. Published on March 12, 2015, as DOI:10.1104/pp.15. 00112
Regulation of Mating and Filamentation Genes by Two Distinct Ste12 Complexes in Saccharomyces cerevisiae

ABSTRACT The Saccharomyces cerevisiae transcription factor Ste12 controls two distinct developmental programs of mating and filamentation. Ste12 activity is regulated by Fus3 and Kss1 mitogen-activated protein kinases through two Ste12 inhibitors, Dig1 and Dig2. Mating genes are regulated by Ste12 through Ste12 binding sites (pheromone response elements [PREs]), whereas filamentation genes are supposedly regulated by the cooperative binding of Ste12 and Tec1 on a PRE adjacent to a Tec1-binding site (TCS), termed filamentous responsive element (FRE). However, most filamentation genes do not contain an FRE; instead, they all have a TCS. By immunoprecipitation, we show that Ste12 forms two distinct complexes, Ste12/Dig1/Dig2 and Tec1/Ste12/Dig1, both in vivo and in vitro. The two complexes are formed by the competitive binding of Tec1 and Dig2 with Ste12, as Tec1 can compete off Dig2 from Ste12 in vitro and in vivo. In the Tec1/Ste12/Dig1 complex, Tec1 binds to the N terminus of Ste12 and to Dig1 indirectly through Ste12. Tec1 has low basal activity, and its transcriptional activation is provided by the associated Ste12, which is under Dig1 inhibition. Filamentation genes are bound by the Tec1/Ste12/Dig1 complex, whereas mating genes are occupied by mostly Ste12/Dig1/Dig2 with some Tec1/Ste12/Dig1. We suggest that Tec1 tethers Ste12 to TCS elements upstream of filamentation genes and defines the filamentation genes as a subset of Ste12-regulated genes.
Pupils' reasons for learning and behaving and for not learning and behaving in English and maths lessons in a secondary school.

BACKGROUND There is renewed interest in motivation and school learning, though there has been relatively little theory-linked research in English schools. AIMS In the first stage, to explore pupils' reasons for learning and behaving and for not learning and behaving in English, maths and other subjects. In the second stage, to examine differences in reasons across subjects, for learning and behaving and for not learning and behaving for boys and girls in two year groups in one secondary school. SAMPLE Stage 1, 16 pupils in years 7, 8 and 9 in two London secondary schools; Stage 2, 267 pupils in years 7 and 9 in one of these schools. METHODS Stage 1--semi-structured interviews were conducted to elicit different kinds of reasons conceptualised in terms of the Deci & Ryan's (1985) framework of self-determination. From these elicited reasons, an inventory 'Why I Learn' was designed. Stage 2--the inventory was administered to identify reasons for learning and behaving and for not learning and behaving in English and maths. RESULTS Parent introjected reasons were the highest for learning and behaving while teacher introjected and intrinsic reasons were the lowest. Intrinsic reasons were highest for not learning and behaving. Year group differences in reason levels were more significant than gender or subject differences. Reasons for learning and behaving were more differentiated from each other than reasons for not learning and behaving. DISCUSSION The results are discussed in terms of their significance for self-determination theory, research into the conditions promoting greater self-determination in school learning and further development of the inventory for programme evaluation.
Resilient virtual network embedding

Our focus, in this paper is on the embedding problem which consists on the mapping of Virtual Network (VN) resources onto physical infrastructure network. In relevant literature, number of works have been proposed to solve this challenging problem. However, few proposals have been dedicated to provide backup mapping mechanism for failing physical links. In virtualization environment a failing link will affect all VNs that span over this resource. To address these concerns, we propose in this work a resilient VN embedding (RVNE) approach that: (a) uses an adaptation of a Column Generation-based technique developed in our previous work, to calculate in a first stage a cost-efficient VN mapping while minimizing the affects of a single link failure in VN layer, and (b) proposes in a second stage a p-Cycle based VN protection approach that minimizes the backup resources while providing a full protection scheme. Experiments on large mix of VN requests show a clear advantage of resilient VN embedding model over benchmarks in terms of VN revenue, VN protection cost and resources utilization.
Regional brain glucose metabolism is altered during rapid eye movement sleep in the cat: A preliminary study

Glucose utilization was measured in 74 brain regions of the cat during states of wakefulness or rapid eye movement (REM) sleep. These data were obtained from intact, unanesthetized animals which were instrumented for objectively measuring states of consciousness. Through a chronically implanted intravenous catheter, the cats received 250 μCi of [6−14C]glucose during REM sleep (N = 3) or during wakefulness (N = 3). After spending ≈8 min in REM sleep or in quiet wakefulness, the cats were administered a lethal dose of barbiturate and the brains were removed and processed for autoradiography. The results revealed site‐specific changes in glucose metabolism during REM sleep. Significant alterations in glucose use occurred in the thalamus, the limbic system, and specific regions of the pontine reticular formation. These data demonstrate for the first time that during states comprised entirely of REM sleep there are anatomically specific changes in cerebral glucose metabolism. The majority of brain regions exhibiting REM sleep‐dependent changes in glucose metabolism either overlapped with regions known to contain cholinergic cell bodies, or with areas that receive prominent cholinergic input.