Miracle-dz/UniFAR-FTUs huggingface dataset:
Recruitment of Stat1 to chromatin is required for interferon-induced serine phosphorylation of Stat1 transactivation domain

The transcription factor Stat1 plays an essential role in responses to interferons (IFNs). Activation of Stat1 is achieved by phosphorylation on Y701 that is followed by nuclear accumulation. For full transcriptional activity and biological function Stat1 must also be phosphorylated on S727. The molecular mechanisms underlying the IFN-induced S727 phosphorylation are incompletely understood. Here, we show that both Stat1 Y701 phosphorylation and nuclear translocation are required for IFN-induced S727 phosphorylation. We further show that Stat1 mutants lacking the ability to stably associate with chromatin are poorly serine-phosphorylated in response to IFN-γ. The S727 phosphorylation of these mutants is restored on IFN-β treatment that induces the formation of the ISGF3 complex (Stat1/Stat2/Irf9) where Irf9 represents the main DNA binding subunit. These findings indicate that Stat1 needs to be assembled into chromatin-associated transcriptional complexes to become S727-phosphorylated and fully biologically active in response to IFNs. This control mechanism, which may be used by other Stat proteins as well, restricts the final activation step to the chromatin-tethered transcription factor.
G protein subunit Gγ13 is coexpressed with Gαo, Gβ3, and Gβ4 in retinal ON bipolar cells

We investigated the expression of Gγ13, a recently discovered G protein subunit, and a selection of Gβ subunits in retinal bipolar cells, by using a transgenic mouse strain in which green fluorescent protein is strongly expressed in a single type of cone bipolar cell. The cells have ON morphology, and patch‐clamp recordings in slices confirmed that they are of the physiological ON type. Immunohistochemistry showed that Gγ13 is expressed in rod bipolar cells and ON cone bipolar cells, where it is colocalized in the dendrites with Gαo. ON and OFF cone bipolar cells and rod bipolar cells were identified among dissociated cells by their green fluorescence and/or distinct morphology. Hybridization of single‐cell polymerase chain reaction products with cDNA probes for G protein subunits Gβ1 to 5 showed that Gβ3, Gβ4, and Gγ13 are coexpressed in ON bipolar cells but not present in OFF bipolar cells. Gβ1, 2, and 5 are expressed in partially overlapping subpopulations of cone bipolar cells. Gγ13 and Gβ3 and/or Gβ4, thus, seem selectively to participate in signal transduction by ON bipolar cells. J. Comp. Neurol. 455:1–10, 2003. © 2002 Wiley‐Liss, Inc.
Biochemical regulation of breast cancer cell expression of S1P2 (Edg‐5) and S1P3 (Edg‐3) G protein‐coupled receptors for sphingosine 1‐phosphate

G protein‐coupled receptors (GPCRs) for lysophosphatidic acid (LPA) and sphingosine 1‐phosphate (S1P) transduce signals to many functions of normal cells. Most human cancer cells upregulate S1P and LPA GPCRs, in patterns distinctive for each type of tumor. The findings that 1‐alpha, 25‐dihydroxy‐vitamin D3 (VD3) and all‐trans retinoic acid (RA) differentially alter expression of the predominant S1P3 (Edg‐3) R and S1P2 (Edg‐5) R in human breast cancer cells (BCCs) permitted analyses of their individual activities, despite a lack of selective pharmacological probes. S1P‐evoked increases in [Ca2+]i in S1P3 R‐predominant BCCs were suppressed by concentrations of VD3 and RA which decreased expression of S1P3 Rs, despite RA‐induced increases in S1P2 Rs. S1P‐elicited chemokinetic migration of S1P3 R‐predominant BCCs across a type IV collagen‐coated micropore filter also was inhibited by concentrations of VD3 and RA which decreased expression of S1P3 Rs. The RA‐induced increase in expression of S1P2 Rs did not prevent suppression by RA of S1P‐elicited chemokinesis, which appears to be mediated by S1P3 Rs, but instead exposed S1P2 R‐mediated inhibition of epidermal growth factor‐stimulated chemotaxis of BCCs. In contrast, expression of the predominant LPA2 Rs, LPA‐evoked increase in [Ca2+]i and LPA‐stimulated chemokinetic migration were suppressed concomitantly by RA but not VD3. Thus two structurally‐homologous S1P Rs of BCCs differ in coupling to [Ca2+]i signaling and have opposite effects on protein growth factor‐stimulated chemotaxis. © 2002 Wiley‐Liss, Inc.
[OP.7A.10] COMMON AND EMERGENT FACTORS ASSOCIATED WITH HYPERTENSION CONTROL IN ROMANIA

Objective: Romania is an East European country with high mortality rates for ischemic heart and cerebrovascular diseases largely attributable to an increased level of uncontrolled hypertension. We aimed to analyze the data of SEPHAR II epidemiological study (Study for the Evaluation of Prevalence of Hypertension and Cardiovascular Risk in Romania) in order to identify common and emergent factors associated with treatment control in Romanian hypertensives. Design and method: A total of 1975 subjects, selected on the base of stratified proportional sampling and consented to participate in the study, were evaluated during the two study visits. Hypertension was diagnosed according to current ESH-ESC guidelines (>/ = 140/80 mmHg). High blood pressure (BP) variability was defined as visit-to-visit standard deviation (s.d.) of systolic blood pressure (SBP) situated in the 4th percentile with values >/ = 8.49 mmHg. Pulse wave velocity in the aorta (PWVao) was recorded with an oscillometric device (Medexpert Arteriograph IrDA). Results: Uncontrolled blood pressure was positively correlated with rural area of residence, a lower level of education or income, increased PWVao, high BP variability and self-estimation of BP values as being high, whereas was inversely correlated with antihypertensive treatment based on >/ = 3 drugs, including a diuretic. According to the multivariate analysis for the validation of parameters associated with lack of BP control were found significant: a low level of education {OR = 2.86; 95% confidence interval (CI) 1.84–4.45, p < 0.0001} or income {OR = 1.04; 95% CI 1.03–1.05, p < 0.0001}, increased PWVao {OR = 1.32; 95% CI 1.23–1.43, p < 0.0001}, high BP variability {OR = 0.15; 95% CI 0.07–0.33, p < 0.0001} and treatment with less than 3 antihypertensive or with >/ = 3 drugs, not including a diuretic {OR = 1.91; 95% CI 0.95–3.84, p < 0.031}. A model based on those parameters had a 76% power of prediction for uncontrolled hypertension. Conclusions: The results of this analysis are confirming the association of uncontrolled hypertension with a low level of education or income, are highlighting the efficiency of >/ = 3 drug associations including a diuretic and are bringing up the attention on the potential impact of arterial stiffness and SBP variability on treatment control in hypertensive patients.
Plasmodium vivax gametocytes in the bone marrow of an acute malaria patient and changes in the erythroid miRNA profile

Plasmodium vivax is the most widely distributed human malaria parasite and responsible for large amounts of disease and burden [1]. The presence of P. vivax in the bone marrow was first noticed in the late 19th century [2], and examinations of sternal bone marrow aspirates were performed as an accessory to examinations of peripheral blood in malaria, including P. vivax [3]. Since then, little progress has been made in studying P. vivax infections in this tissue. One report explored accumulation of dyserythropoietic cells in anaemic infected patients [4]. In addition, two case studies reported P. vivax infections after autologous bone marrow transplantation [5][6], and a third one documented an accidental P. vivax infection due to bone marrow transplantation between a malaria-infected donor and a malaria-free receptor [7]. In Brazil, one patient with persistent thrombocytopaenia and an enlarged spleen was diagnosed with chronic P. vivax malaria after the finding of schizonts in the bone marrow aspirate [8]. In all these reports and case studies, however, parasite loads and life stages found in the bone marrow were not investigated, and no molecular tools were available to rule out mixed infections or to characterize specific parasite stages.
Reduced AZGP1 expression is an independent predictor of early PSA recurrence and associated with ERG‐fusion positive and PTEN deleted prostate cancers

Zinc‐alpha 2‐glycoprotein (AZGP1) is involved in lipid metabolism and was suggested as a candidate prognostic biomarker in prostate cancer. To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, AZGP1 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and PTEN, 3p13, 5q21 and 6q15 deletions were available from earlier studies. AZGP1 expression was strong in benign prostatic glands but absent in 38.0% of 8,510 interpretable prostate cancers. Reduced AZGP1 expression was associated with TPMRSS2:ERG fusions, both by FISH and immunohistochemical analysis (p < 0.0001 each). For example, AZGP1 was absent in 54.6% of 2,029 ERG IHC positive but in only 28.1% of 2,398 ERG negative cancers. Irrespective of the ERG status, reduced AZGP1 expression was tightly linked to high Gleason score, advanced pathological tumor stage, positive nodal status and early PSA recurrence (p < 0.0001 each). Reduced AZGP1 expression was also strongly associated with PTEN deletions. AZGP1 immunostaining was lacking in 62.7% of 842 PTEN deleted but in only 37.3% of PTEN non‐deleted cancers but retained strong prognostic influence in both subgroups (p < 0.0001 each). The prognostic role of AZGP1 expression was also independent of Gleason score, pT stage, pN stage, surgical margin status and preoperative PSA, irrespective of whether preoperative or postoperative variables were used for modeling. In conclusion, the results of our study demonstrate that reduced AZGP1 expression is strongly related to adverse prostate cancer prognosis, independently of established clinic‐pathological variables and PTEN deletions.
A Comparison of Pharmacokinetic Versus Empirical Lithium Dosing Techniques

Three methods for estimating maintenance dosage requirements of lithium carbonate were retrospectively evaluated in 20 inpatients who met criteria of the Diagnostic and Statistical Manual, Third Edition, for “bipolar disorder, manic phase. ” Dosing methods evaluated included a pharmacokinetic method, the single-point method of Perry et al.; a population-based nomogram approach, the Zetin et al. method; and a physician-based empirical dosing procedure. The ability of each dosing procedure to produce dosing recommendations that resulted in a targeted steady-state serum lithium concentration was evaluated. The empirical dosing procedure demonstrated a significant tendency (bias) to underestimate the dose necessary to produce a desired steady-state serum lithium concentration. Comparison of the predictive accuracy of the various dosing methods failed to demonstrate any statistically significant differences among the dosing procedures. There was a strong trend, however, for the Perry method to produce predictions of steady-state lithium levels that were more frequently within 0.2 mEq/L of actual levels.
Rapid up‐regulation of the neuronal serotoninergic phenotype by brain‐derived neurotrophic factor and cyclic adenosine monophosphate: Relations with raphe astrocytes

Up‐regulation of the neuronal serotoninergic phenotype in relation to astrocytic population was studied in primary cultures of rat embryonic rostral raphe. Short treatments (18 hr at day in vitro 4) with brain‐derived neurotrophic factor (BDNF) or dibutyryl‐cAMP (dBcAMP) increased the number of serotoninergic neurons by ∼80% and ∼40%, respectively, and markedly enhanced the branching (by 11‐fold and 5‐fold, respectively) and total length (by 4‐fold and 2.5‐fold, respectively) of their neurites. Concomitantly, under BDNF treatment, the astrocyte population was decreased by half and became mostly protoplasmic‐like. In contrast, dBcAMP treatment also reduced the astrocytic cell density (by one‐third) but induced a stellate morphology. Similar short treatment with the astrocyte‐derived S100β factor induced no modification of the serotonin (5‐HT) neuronal phenotype nor of astrocytes morphology. Both BDNF‐ and cAMP‐induced effects were abolished by simultaneous treatment with the specific tyrosine kinase inhibitor genistein, suggesting a role for the high‐affinity BDNF receptor tyrosine kinase (TrkB). These data suggest that BDNF and cAMP, but not S100β, rapidly induce both an up‐regulation of the 5‐HT neuronal phenotype and modifications of the neighboring astrocytes in a TrkB‐dependent manner. © 2005 Wiley‐Liss, Inc.
Pulse Wave Velocity in Kawasaki Disease

Kawasaki disease (KD) is an acute childhood febrile disease of unknown etiology. It exhibits not only coronary artery aneurysms in some cases but also systemic vasculitis. Whether KD is associated with accelerated atherosclerosis remains debatable. The measurement of pulse wave velocity (PWV) is useful as a simple, noninvasive measurement of arterial stiffness, an atherosclerotic manifestation. We herein present a systematic review of clinical studies that focused on PWV in patients with KD. A PubMed-based search identified 8 eligible studies published until June 2015. The PWV of patients with KD, regardless of antecedent coronary artery lesions, was high relative to controls, even though their blood pressure appeared to be similar. Although definitive conclusions cannot be made with the limited information, patients with KD may be at risk of systemic atherosclerosis in association with arterial stiffness. Further research, including longitudinal and outcome studies, is needed to determine the clinical significance of a potential increase in PWV in patients with KD.
Leupeptin inhibits ventilator-induced diaphragm dysfunction in rats.

RATIONALE Controlled mechanical ventilation (CMV) has been shown to result in elevated diaphragmatic proteolysis and atrophy together with diaphragmatic contractile dysfunction. OBJECTIVES To test whether administration of leupeptin, an inhibitor of lysosomal proteases and calpain, concomitantly with 24 hours of CMV, would protect the diaphragm from the deleterious effects of mechanical ventilation. METHODS Rats were assigned to either a control group or 24 hours of CMV; animals in the ventilation group received either a single intramuscular injection of saline or 15 mg/kg of the protease inhibitor, leupeptin. MEASUREMENTS AND MAIN RESULTS Compared with control animals, mechanical ventilation resulted in a significant reduction of the in vitro diaphragm-specific force production at all stimulation frequencies. Leupeptin completely prevented this reduction in force generation. Atrophy of type IIx/b fibers was present after CMV, but not after treatment with leupeptin. Cathepsin B and calpain activities were significantly higher after CMV compared with the other groups; this was abolished by treatment with leupeptin. Significant inverse correlations were found between diaphragmatic force generation and cathepsin B and calpain activity, and illustrate the deleterious role of proteolysis in diminishing diaphragmatic force production after prolonged CMV. CONCLUSIONS Administration of the protease inhibitor leupeptin concomitantly with mechanical ventilation completely prevented ventilation-induced diaphragmatic contractile dysfunction and atrophy.
Cost effectiveness and equity of a community based cardiovascular disease prevention programme in Norsjö, Sweden.

STUDY OBJECTIVE: To evaluate the cost effectiveness and equity of a community based cardiovascular disease prevention programme. DESIGN: A prospective cross sectional design. SETTING: A community based intervention to reduce cardiovascular disease in the district of Norsjö (n = 5500), Sweden. The intervention was aimed at both the general population and at individuals thought to be at special risk, the emphasis being on changing dietary habits and reducing cholesterol concentrations. PARTICIPANTS: The participants were men and women aged 30-60 years. MAIN RESULTS: The mean serum cholesterol concentration in the Norsjö population was reduced by nearly 20% during the first six years of intervention. It was estimated that the programme's overall total societal costs were 363,000 pounds and estimates of the cost per year of life saved ranged from 14,900 pounds to net savings, according to different assumptions. Taking only health care costs and savings into account, the cost per year of life saved ranged from 1100 pounds to 4050 pounds. The results varied between different sex and age groups, but not between social classes. Even if a causal relationship exists between low cholesterol concentrations and excess mortality, the estimated side effects of lowering cholesterol values in Norsjö were negligible in comparison with the expected benefits. CONCLUSIONS: The community based intervention in Norsjö seems to be cost effective even under conservative assumptions. The approach used seems to have benefited all social classes. Cost effectiveness analyses that take consequences for equity into account are valuable tools in decision making.
Massive storage of wind power to reduce CO2 emissions to produce wind-clean fuels

Wind power is being curtailed because large scale electrical energy storage systems are not available. However, a practical, large-scale, electro-thermal in situ energy storage system has been designed. Wind energy via the grid is transferred into unconventional oil deposits, such as the oil shale, tar sand or heavy oil deposits in the USA. This stored heat eventually converts the hydrocarbons into recoverable oil and gas products without generating CO2 emissions or needing much water. The energy in these wind clean fuels greatly exceeds the applied electrical energy. These wind-clean fuels can be used to offset use of foreign oil or to regenerate electrical power into back into the grid. The grid is stabilized by electronically controlling the system load. It can be used for smart grid functions. Fuel production can be sustained for over 100 years by the massive oil shale and tar sand deposits in the USA.
Child, parent, and service predictors of psychotropic polypharmacy among adolescents and young adults with an autism spectrum disorder.

OBJECTIVE This study examined the child, parent, and service factors associated with polypharmacy in adolescents and young adults with autism spectrum disorders (ASD). METHODS As part of an online survey examining health service utilization patterns among individuals with ASD, parents provided demographic and clinical information pertaining to their child. This included information on current medication use, as well as information on clinical services received, clinical history, and parent well-being. Analyses examined the bivariate association between individual child, parent, and service variables and polypharmacy. Variables significantly associated with polypharmacy were included in a multiple variable logistic regression. RESULTS Of the 363 participants sampled, ∼25% were receiving two or more psychotropic drugs concurrently. The patient's psychiatric comorbidity, history of hurting others, therapy use, and parent burden were predictors of polypharmacy. CONCLUSIONS Adolescents and young adults with ASD are a highly medicated population with multiple factors associated with psychotropic polypharmacy. Although there may be circumstances in which polypharmacy is necessary, a richer understanding of what predicts polypharmacy may lead to targeted interventions to better support these individuals and their families. Findings also highlight the need to support families of children with ASD prescribed multiple psychotropic medications.
Migraine prophylaxis by anodal transcranial direct current stimulation, a randomized, placebo-controlled trial.

BACKGROUND Migraine is a common headache syndrome in adult populations. Prophylaxis is necessary to improve the quality of life but some patients with migraine have contraindication or suffer from side effects of medication, and therefore, establishing non-medical, neuromodulatory approaches is necessary. Past evidence had shown that consecutive motor cortex (M1) stimulation with anodal transcranial direct current stimulation (tDCS) was effective to relieve central pain. OBJECTIVE To determine whether 20 consecutive days of the left M1 can be an effective prophylactic treatment for migraine. MATERIAL AND METHOD Forty-two episodic migraine patients who had never received any prophylactic treatment, failed prophylactic treatment, or discontinued treatment due to adverse events were recruited in the present study. Patients were randomized to receive either active tDCS or sham tDCS 1mA, 20 m for 20 consecutive days and followed up for 12 weeks. Differences between and within groups were determined using repeated measures ANOVA. The level of significance was set at p < 0.05. RESULTS Thirty-seven patients participated in the final analyses (active: n = 20, sham: n = 17). Between-groups comparison of attack frequency, pain intensity, and abortive medications used were performed at 4, 8, and 12 weeks after treatment. The results showed statistically significant reduction in attack frequency and abortive medications at week 4 and 8 after treatment. The pain intensity was statistically significant reduced at week 4, 8, and 12. All patients tolerated the tDCS well without any serious adverse events. CONCLUSION The present study suggests that anodal M1 tDCS may be a safe and useful clinical tool in migraine prophylaxis. The mechanism of action of anodal tDCS on neuromodulation in migraine patients needs further investigation.
The prognostic value of quality of life scores during treatment for oesophageal cancer

BACKGROUND Quality of life (QL) data are useful to evaluate the effectiveness of treatment. Accumulating evidence suggests that QL data may predict survival. AIMS In this study we investigated if baseline QL scores and changes in QL scores before and after intervention are prognostic for patients with oesophageal cancer. PATIENTS Between 1993 and 1995, 92 consecutive new patients with oesophageal cancer were studied; 89 were followed until death or the end of the study period (survival of seven patients was censored in May 1999). METHODS All patients completed the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (EORTC QLQ-C30) and the dysphagia scale of the oesophageal module (EORTC QLQ-OES24) before treatment and at regular intervals throughout the study. Cox's proportional hazards models assessed the impact of baseline QL variables and changes in QL scores on survival. RESULTS Cox's proportional hazards models, adjusting for associations between QL scores, age, and TNM stage, found that physical function at baseline was significantly associated with survival (p=0.002). An increase in physical function score of 10 points corresponded to a 12% reduction in the likelihood of death at any given time (95% confidence intervals 4–18%). Further exploratory multivariable analyses suggested that improvement in emotional function six months after treatment was significantly related to longer survival (p<0.0001). CONCLUSIONS These data provide evidence to support a relationship between patient rated scores of QL and survival. Further understanding of the associations between QL and clinical variables is needed.