Miracle-dz/UniFAR-FTUs huggingface dataset:
Structure of a Ternary Naa50p (NAT5/SAN) N-terminal Acetyltransferase Complex Reveals the Molecular Basis for Substrate-specific Acetylation*

Background: The human Naa50p N-terminal acetyltransferase acetylates proteins on the α-amino group of methionine residues to regulate genome integrity and has elevated activity in cancer. Results: We report the structure of the Naa50p·CoA·peptide complex and related biochemistry. Conclusion: We reveal the molecular basis for substrate-specific acetylation by Naa50p. Significance: We provide a molecular scaffold for the design of Naa50p-specific inhibitors with possible therapeutic applications. The co-translational modification of N-terminal acetylation is ubiquitous among eukaryotes and has been reported to have a wide range of biological effects. The human N-terminal acetyltransferase (NAT) Naa50p (NAT5/SAN) acetylates the α-amino group of proteins containing an N-terminal methionine residue and is essential for proper sister chromatid cohesion and chromosome condensation. The elevated activity of NATs has also been correlated with cancer, making these enzymes attractive therapeutic targets. We report the x-ray crystal structure of Naa50p bound to a native substrate peptide fragment and CoA. We found that the peptide backbone of the substrate is anchored to the protein through a series of backbone hydrogen bonds with the first methionine residue specified through multiple van der Waals contacts, together creating an α-amino methionine-specific pocket. We also employed structure-based mutagenesis; the results support the importance of the α-amino methionine-specific pocket of Naa50p and are consistent with the proposal that conserved histidine and tyrosine residues play important catalytic roles. Superposition of the ternary Naa50p complex with the peptide-bound Gcn5 histone acetyltransferase revealed that the two enzymes share a Gcn5-related N-acetyltransferase fold but differ in their respective substrate-binding grooves such that Naa50p can accommodate only an α-amino substrate and not a side chain lysine substrate that is acetylated by lysine acetyltransferase enzymes such as Gcn5. The structure of the ternary Naa50p complex also provides the first molecular scaffold for the design of NAT-specific small molecule inhibitors with possible therapeutic applications.
Delay-Dependent Robust Stability and Control of Uncertain Discrete Singular Systems with State-Delay

A new delay-dependent criterion is developed for robust stability of linear discrete-time singular systems with state-delay and parametric uncertainties. The time-delay is varying between known bounds and the uncertainties are assumed to be time-invariant and norm-bounded appearing in the state and delay matrices. The new criterion is achieved by an expanded state-space system representation. A solution to delay-dependent stabilization is attained based on guaranteed cost and H� control approaches. All the developed results are conveniently cast in the format of linear matrix inequalities (LMIs) and numerical examples are presented.
Tenofovir Use is associated with a Reduction in Calculated Glomerular Filtration Rates in the Swiss HIV Cohort Study

Background A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. Methods We compared treatment-naive patients or patients with treatment interruptions ≥12 months starting either a TDF-based combination antiretroviral therapy (cART) (n=363) or a TDF-sparing regime (n=715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. Results Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58–0.72) and 0.80 (95% CI 0.76–0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR]=2.34 [95% CI 1.24–4.42]), higher baseline cGFR (HR=1.03 [95% CI 1.02–1.04] by 10 ml/min), TDF use (HR=1.84 [95% CI 1.35–2.51]) and boosted protease inhibitor use (HR=1.71 [95% CI 1.30–2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. Conclusion There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.
Variation in sweating patterns: implications for studies of hot flashes through skin conductance

Objective:The literature of sweat physiology and population variation in response to heat stress suggests that variation in sweating patterns may affect the measurement of hot flashes. This study examined variation in sweating patterns in Puebla, Mexico, and Amherst, MA, and compared the levels of concordance between subjective and objective measures of hot flashes. Design:Thirteen women in Puebla, Mexico, and 15 women in Amherst, MA, aged 45 to 61, completed surveys, body diagrams of heat flow during a hot flash, anthropometric measures, and the measurement of hot flashes through skin conductance monitoring. Hot flashes were measured through sternal (Mexico and Massachusetts) and nuchal (Mexico only) skin conductance. Results:Mexican women were significantly more likely to describe the heat of hot flashes on the back of their neck (100% vs 40%) and on their arms and/or hands (85% vs 40%) compared with women in Massachusetts. Hot flashes in the midback were associated with concordance between nuchal, but not sternal, measures of skin conductance and subjective report in Mexico. In comparing average scores for concordance between subjective and sternal measures of hot flashes, there was a higher mean score for true positives in Mexico (61% vs 29%, P = 0.06) and a significantly higher mean score for false-negative measures in Massachusetts (57% vs 21%, P = 0.04). Conclusions:Variation in rates of concordance between subjective and objective measures were not adequately explained by sweating patterns. Future studies should consider population variation in acclimatization and assess variation in the amount of sweat produced during a hot flash.
Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression.

BACKGROUND The sympathetic nervous system and proinflammatory cytokines are believed to play key roles in the pathophysiology of congestive heart failure. To evaluate a possible relationship between these neurohormonal systems, we studied the effects of chronic beta-adrenergic stimulation on the myocardial and systemic elaboration of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. METHODS AND RESULTS Male rats received either L-isoproterenol (2.4 mg. kg(-1). d(-1), n=8) or saline (n=7) via miniosmotic pumps for 7 days. Myocardial cytokine expression was analyzed by both Northern and Western blotting and localized in the tissue using immunohistochemistry. ELISA was performed to measure circulating levels of cytokines. In myocardium from control animals, neither TNF-alpha nor IL-1beta were detected, whereas IL-6 was present at very low levels. Isoproterenol led to a significant (P<0.01) increase in mRNA and protein expression of all 3 cytokines. Immunohistochemistry did not detect immunoreactivity for either cytokine in myocardium from controls; however, all 3 cytokines were readily detected (P<0.05) throughout the myocardium, localized to resident cells and vessels, in animals treated with isoproterenol. Neither treatment group had detectable levels of cytokines in the serum. CONCLUSIONS Chronic beta-adrenergic stimulation induces myocardial, but not systemic, elaboration of TNF-alpha, IL-1beta, and IL-6.
Plasma concentrations of luteinizing hormone and prolactin in the ovariectomized ewe during induced hyperthermia.

Ihe effect of induced hyperthermia on the basal as well as estradiol-induced secretion of luteiniiing hormone (LH) and on prolactin (PRL) secretion was studied in 12 ovariectomized ewes exposed every 14 days to 3 day treatment periods. Ambient conditions of dry bulb and dew point temperatures were adjusted to result in rectal temperatures that were either normal (control) or an average of 1.2#{176}Chyperthermic (experimental). Each ewe served as its own control in a switchback experimental design. On Day 2 of the 3 day treatment period, blood plasma was sampled at 10 mm intervals be- tween 0900 and 1300 h to characterize episodic patterns of LH. At 1800 h on the same day, 50 pg cstradiol-17(cid:1)3 (E2fl) was injected i.m. to provoke a preovulatory-like surge of LH on Day 3. Plasma concentrations of LII and PRL were determined in samples collected at 60 mm intervals between 0800 and 1600 h on Day 3. Induced hyperthermia caused a 4-fold increase in plasma PRL on Day 3 (P<0.01), while it caused a decrease (P<0.01) in plasma LH on Day 2. Mean concentrations of LH 14-22 h after I;. (cid:1) ‘. vere not significantly altered by hyperthermia. Maximum concentrations of estradiol-induced LII release during this time did not differ between treatment groups. Neither rhythmicity nor peri- od of the major rhythm of episodic patterns of LH on Day 2 was affected by treatment. Ihe decrease in plasma LH on Day 2 during hyperthermia was attributed to decreased LH secretion rate rather than to changes in blood volume or metabolic clearance of LI-I since neither seemed to be affected by experimental conditions. Neither LH nor PRL concentrations were significantly related to rectal temperature.
Long-term speech perception in elderly cochlear implant users.

IMPORTANCE A review of a test battery presented in both quiet and noise may clarify what the progression of speech perception abilities is in older adult cochlear implant users and whether the performance declines with advancing age. OBJECTIVE To examine whether older adults (≥65 years) with cochlear implants maintain stable speech perception performance after at least 10 years of listening experience with an external speech processor. DESIGN AND SETTING Retrospective analysis performed in an academic tertiary care center. PARTICIPANTS Fourteen older adult cochlear implant recipients with at least 10 years of listening experience. MAIN OUTCOME MEASURES Speech perception outcomes as measured with Consonant-Nucleus-Consonant words in quiet and Hearing in Noise Test sentences in quiet and steady-state noise were analyzed retrospectively at the 6-month and 1-, 5-, and 10-year postoperative follow-up intervals. RESULTS Consonant-Nucleus-Consonant word scores remained stable between 6 months and 1 year of listening experience, improved significantly (P < .001) between 1 year and 5 years, and remained stable between 5 years and 10 years. Hearing in Noise Test sentence scores in quiet and noise showed a similar pattern, with stability in performance between the 6-month to 1-year and 5-year to 10-year follow-up intervals, and significantly improved performance (P = .04) between the 1-year and 5-year follow-up intervals. CONCLUSIONS AND RELEVANCE On average, patients who undergo cochlear implantation at age 65 years or older do not experience a decline in speech perception performance with extended listening experience and may potentially continue to see improvements beyond the 1-year follow-up interval.
How Does CEO Tenure Matter? The Mediating Role of Firm-Employee and Firm-Customer Relationships

While the direct influence of CEO tenure on firm performance has been examined in the strategy literature, the underlying channels of influence have remained largely unexplored. This article draws upon the career seasons paradigm, learning perspectives, and marketing literature to examine whether firm-employee and firm-customer relationships are the pathways through which CEO tenure influences firm performance. Results from the analysis of a large data set reveal that: (1) CEO tenure has a positive and linear association with firm-employee relationship strength but an inverted U-shaped association with firm-customer relationship strength; (2) industry uncertainty intensifies these associations; and (3) firm-employee and firm-customer relationship strength mediate the effects of CEO tenure on firm performance. These findings have implications for a more balanced and nuanced view of CEO tenure. Copyright © 2013 John Wiley & Sons, Ltd.
Separation of tumor necrosis factor α isoforms by two‐dimensional polyacrylamide gel electrophoresis

The mouse macrophage cell‐line RAW264.7, stimulated with lipopolysaccharide, was used as a model for the study of the production of tumor necrosis factor (TNF) isoforms. TNF is synthesised initially as a 26 kDa transmembrane precursor, which is then processed enzymatically by a protease to release a mature molecule of 17 kDa. Dose‐dependent production of transmembrane TNF was assessed by fractionation of cell membranes and Western blot analysis followed by autoradiography and densitometry. Isoforms of both the precursor and mature molecules were separated using two‐dimensional (2‐D) electrophoresis with immobilised pH gradient 3–10 linear gels as the first dimension. After radiolabelling of cells with 35S, both cell‐associated and supernate‐associated TNF isoforms were immunoprecipitated. A large number of protein spots were visualised on the 2‐D gel map, for both the transmembrane and mature TNF species, more than have been detected previously using one‐dimensional sodium dodecyl sulphate‐polyacrylamide gel electrophoresis (SDS‐PAGE). The likelihood that these putative isoforms were the result of differential glycosylation was tested by preincubating the cells with tunicamycin. This had the effect of reducing the number of protein spots, notably the higher molecular weight species. There were a number of precursor TNF isoforms that were unchanged upon tunicamycin treatment and these presumably reflect protein modifications other than glycosylation.
Contracts for Dummies? The Performance of Investors in Contracts for Difference

Investors widely use contracts for difference (CFDs) to leverage and short sell underlying financial assets. We investigate the after cost performance of investors in Australian Securities Exchange listed share CFDs, and find that market order CFD trades earn small positive returns at the daily horizon, with negative returns reported for one month to one year horizons due to financing costs. Market orders also net sell positions, which suggests that investors use CFDs for shorting opportunities. Overall, we find that liquidity demanders in CFDs obtain favourable execution, which is inconsistent with the view that CFDs are used by naive individuals.
Effect of citric acid doping on flux pinning in bulk MgB2 prepared by chemical solution route

In this paper, we study the doping effect of citric acid (C<inf>6</inf>H<inf>8</inf>O<inf>7</inf>), from 0 to 30 wt% of the total MgB<inf>2</inf>, on the properties, such as critical temperature (T<inf>c</inf>), critical current density (J<inf>c</inf>), irreversibility field (H<inf>irr</inf>) and crystalline structure of MgB<inf>2</inf> superconductors. The XRD patterns of samples show a slightly decrease in the a-axis lattice parameter for doped MgB<inf>2</inf>, due to the partial substitution of carbon at boron site. At 10 K the citric acid doped sample exhibits the J<inf>c</inf> values greater than 3.4×10<sup>5</sup> A/cm<sup>2</sup> in self-field, which is similar to the pure one while in high field region the J<inf>c</inf> was increased by an order of magnitude in comparison to undoped one. For MgB<inf>2</inf> doped with 15 wt% citric acid, J<inf>c</inf> still remains about 10<sup>3</sup> A/cm<sup>2</sup> in 7 T at 10 K. In addition, the self-field J<inf>c</inf> of citric acid doped sample is slightly reduced at additive level higher than 10 %. The improved flux pinning behavior could easily be seen from reduced flux pinning force curves.
MAOA genotype, family relations and sexual abuse in relation to adolescent alcohol consumption

The aim of the present study was to investigate MAOA gene–environment (G*E) interactions in relation to adolescent alcohol consumption. In the county of Västmanland, Sweden, all 17–18‐year‐old students were asked to complete an anonymous questionnaire and provide a saliva sample during class hours. A total of 2263 students completed the questionnaire (77.4%) and a saliva sample was provided by 2131 participants. Failed MAOA u‐variable number of tandem repeats (VNTR) genotype analyses and internal non‐responses left 851 boys and 735 girls (total n = 1586) to be investigated. Alcohol use disorder identification test was used to measure hazardous alcohol consumption. MAOA u‐VNTR was used to measure biological risk in interaction with poor family relations and experience of sexual abuse. The model was also adjusted for non‐independent socioeconomic variables, separated parents, type of housing and parental unemployment. Results showed that the MAOA u‐VNTR, in interaction with psychosocial risk factors, such as the quality of family relations and sexual abuse, was related to high alcohol consumption among adolescents. Girls, carrying the long MAOA u‐VNTR variant showed a higher risk of being high alcohol consumers, whereas among boys, the short allele was related to higher alcohol consumption. The present study supports the hypothesis that there is a relation between MAOA u‐VNTR and alcohol consumption and that this relation is modulated by environmental factors. Furthermore, the present study also supports the hypothesis that there is a sex difference in the G*E interaction.
Update on the molecular biology of malignant mesothelioma

Malignant mesothelioma (MM) is a highly aggressive tumor with a very poor prognosis. The disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10–17 months of the first symptoms. Novel, more effective therapeutic strategies are needed for this inexorably fatal disease. Improvement in our understanding of the molecular biology of MM has identified promising new candidates for targeted treatments. In this review the key molecular signaling pathways, including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), Wnt, and the cell cycle control genes p53, pRb, and bcl‐2 that appear to play an important role in the pathogenesis of MM are explored. Cancer 2007. © 2007 American Cancer Society.
Accuracy and reliability of SPI ProX global positioning system devices for measuring movement demands of team sports.

AIM The aim of this study was to determine the accuracy and reliability of SPI ProX global positioning system (GPS) devices for measuring movement at various speeds and movement patterns as evident in team sport demands. METHODS Eleven amateur soccer players performed a 40 m straight sprint test (with 10-20-30 m split times), a zigzag test, 30 m walking, jogging and moderate intensity runs. RESULTS Results indicated that the SPI ProX GPS measurements showed acceptable accuracy for all movement patterns for distance (coefficient of variation [CV]=0.14% to 3.73%; 95% ratio limits of agreement [95% ratio LOA]=0.97 x / ÷ 1.09 to 1.00 x / ÷ 1.05) and speed (CV=4.22% to 9.52%; 95%LOA=-0.17 ± 1.70 km h-1 to 2.30 ± 1.17 km h-1) compared with the measured distance and speed determined from timing gates, respectively. Furthermore, acceptable reliability of SPI ProX GPS measures for distance (CV=0.34% to 3.81%; 95%LOA=-0.09 ± 0.23 m to -0.34 ± 2.31 m) and speed (CV=3.19% to 6.95%; 95%LOA=-0.05 ± 3.90 km h-1 to 0.42 ± 3.68 km h-1) were also evident. CONCLUSION Whilst SPI ProX GPS devices were within acceptable ranges of reliability, they remained significantly different to criterion measures of team sport movement demands.
Randomized controlled trial of acitretin versus placebo in patients at high‐risk for basal cell or squamous cell carcinoma of the skin (North Central Cancer Treatment Group Study 969251)

Chemoprevention with systemic retinoids has demonstrated promise in decreasing the incidence of new primary nonmelanoma skin cancers (NMSCs) in immunocompromised post‐transplantation recipients. There is limited evidence for the use of systemic retinoids in the nontransplantation patient. To the authors' knowledge, this is the first randomized controlled trial to assess the efficacy of acitretin as a chemopreventive agent in nontransplantation patients at high‐risk for NMSC.
Home drinking in the UK: trends and causes.

AIMS To explore the trend in the UK to consume alcohol at home rather than at licensed premises. METHODS A Medline search entering the terms 'home drinking', 'alcohol' and 'adult' covering the period 2000-2011 yielded 48 articles, of which 6 met the criteria to be included in the review. Grey literature including survey and market research data were reviewed. RESULTS In the UK, since 1970 there has been trend for beer to be consumed at home more often than in licensed premises and that the overall trend towards greater home drinking has increased since 2000. The main reasons given are convenience, cost, safety, autonomy and stress relief. There has also been an increase in the practice known as 'pre-loading' (drinking before going out). Adults who drink mainly at home report that they are aware that they run a risk of higher overall alcohol consumption but tend to play down the possibility that increased consumption may lead to longer-term harm. CONCLUSION Home drinking trends may have long-term public health consequences. Greater understanding of the drivers of this trend will help policy-makers to respond to these societal changes.
Expression and clinical significance of Ezrin and E-cadherin in esophageal squamous cell carcinoma.

BACKGROUND AND OBJECTIVE It has been proven that Ezrin protein may interact with E-cadherin protein and take part in metastasis of tumor cells. This study was to investigate the expressions of Ezrin and E-cadherin in esophageal squamous cell carcinoma (ESCC) and their relationship with the clinicopathologic factors, and analyze their diagnostic values for ESCC. METHODS The expression of Ezrin and E-cadherin in 72 specimen of ESCC and the paracancer normal squamous epithelium was detected using tissue array with SP immunohistochemistry. Their correlations to the clinicopathologic factors were analyzed statistically. RESULTS The positive rate of Ezrin was significantly higher in ESCC than in para-cancer normal squamous epithelium (90.7% vs. 46.0%, P < 0.001); the positive rate of E-cadherin was significantly lower in ESCC than in para-cancer normal squamous epithelium (27.6% vs. 97.4%, P < 0.001). Ezrin expression was related to the invasiveness and lymph node metastasis of ESCC (P < 0.05); E-cadherin expression was related to the differentiation and lymph node metastasis of ESCC (P < 0.05). The high expression of Ezrin was related to the low expression of E-cadherin (P < 0.05). CONCLUSION The activation of Ezrin and the absence of E-cadherin contribute to the tumorigenesis and metastasis of ESCC.