Miracle-dz/UniFAR-FTUs huggingface dataset:
Interaction between the RGS domain of RGS4 with G protein α subunits mediates the voltage‐dependent relaxation of the G protein‐gated potassium channel

1 In native cardiac myocytes, there is a time dependence to the G protein‐gated inwardly rectifying K+ (KG) channel current during voltage steps that accelerates as the concentration of acetylcholine is increased. This phenomenon has been called ‘relaxation’ and is not reproduced in the reconstituted Kir3.1/Kir3.4 channel in Xenopus oocytes. We have shown that RGS4, a regulator of G protein signalling, restores relaxation to the reconstituted Kir3.1/Kir3.4 channel. In this study, we examined the mechanism of this phenomenon by expressing various combinations of membrane receptors, G proteins, Kir3.0 subunits and mutants of RGS4 in Xenopus oocytes. 2 RGS4 restored relaxation to KG channels activated by the pertussis toxin (PTX)‐sensitive G protein‐coupled m2‐muscarinic receptor but not to those activated by the Gs protein‐coupled β2‐adrenergic receptor. 3 RGS4 induced relaxation not only in heteromeric KG channels composed of Kir3.1 and Kir3.4 but also in homomeric assemblies of either an active mutant of Kir3.1 (Kir3.1/F137S) or an isoform of Kir3.2 (Kir3.2d). 4 Truncation mutants of RGS4 showed that the RGS domain itself was essential to reproduce the effect of wild‐type RGS4 on the KG channel. 5 The mutation of residues in the RGS domain which interact with the α subunit of the G protein (Gα) impaired the effect of RGS4. 6 This study therefore shows that interaction between the RGS domain and PTX‐sensitive Gα subunits mediates the effect of RGS4 on the agonist concentration‐dependent relaxation of KG channels.
Reversibility of Epithelial-Mesenchymal Transition (EMT) Induced in Breast Cancer Cells by Activation of Urokinase Receptor-dependent Cell Signaling*

Hypoxia induces expression of the urokinase receptor (uPAR) and activates uPAR-dependent cell signaling in cancer cells. This process promotes epithelial-mesenchymal transition (EMT). uPAR overexpression in cancer cells also promotes EMT. In this study, we tested whether uPAR may be targeted to reverse cancer cell EMT. When MDA-MB 468 breast cancer cells were cultured in 1% O2, uPAR expression increased, as anticipated. Cell-cell junctions were disrupted, vimentin expression increased, and E-cadherin was lost from cell surfaces, indicating EMT. Transferring these cells back to 21% O2 decreased uPAR expression and reversed the signs of EMT. In uPAR-overexpressing MDA-MB 468 cells, EMT was reversed by silencing expression of endogenously produced urokinase-type plasminogen activator (uPA), which is necessary for uPAR-dependent cell signaling, or by targeting uPAR-activated cell signaling factors, including phosphatidylinositol 3-kinase, Src family kinases, and extracellular signal-regulated kinase. MDA-MB 231 breast cancer cells express high levels of uPA and uPAR and demonstrate mesenchymal cell morphology under normoxic culture conditions (21% O2). Silencing uPA expression in MDA-MB-231 cells decreased expression of vimentin and Snail, and induced changes in morphology characteristic of epithelial cells. These results demonstrate that uPAR-initiated cell signaling may be targeted to reverse EMT in cancer.
Human dendritic cell responses to lipopolysaccharide and CD40 ligation are differentially regulated by interleukin‐10

We evaluated the effects of interleukin (IL)‐10 on the maturation of human dendritic cells (DC) induced either by lipopolysaccharide (LPS) or CD40 engagement. For this purpose, DC generated by culturing plastic‐adherent peripheral blood mononuclear cells for 7 days with granulocyte/macrophage‐colony‐stimulating factor and IL‐4 were incubated for 3 days with either LPS (10 ng/ml) or 3T6 fibroblasts transfected with the gene encoding CD40 ligand, in absence or presence of IL‐10. First we found that the membrane expression of CD83, a marker of mature DC, was inhibited by IL‐10 when induced by LPS but not by CD40 engagement. Likewise, IL‐10 inhibited LPS‐induced but not CD40‐dependent CD86 (B7.2) up‐regulation on DC. Furthermore, IL‐10 inhibited the production of IL‐8 and tumor necrosis factor‐α by DC when activated by LPS but not by CD40. In contrast, IL‐10 inhibited IL‐12 production in both activation systems. We conclude that IL‐10 differentially influences LPS‐dependent and CD40‐dependent pathways of DC maturation.
Enhancement of the antigen‐presenting function of monocytes by cholesterol: possible relevance to inflammatory mechanisms in extrinsic allergic alveolitis and atherosclerosis

Extrinsic allergic alveolitis (EAA) (synonym: hypersensitivity pneumonitis) is a hypcrscnsitivity lung disease characterized by lymphocytic infiltrates in the pulmonary interstitial tissues. We have previously reported that the numbers of lymphocytes in bronchoalveolar lavage (BAL) samples in this disease correlate with levels of cholesterol and neutral lipid‐laden “foamy” macrophages. We have also reported that the macrophages express an increased density of MHC class II antigens (in particular HLA‐DQ) which are known to be essential for antigen recognition by T lymphocytes. The aim of the present study was to explore whether cholesterol is capable of enhancing the antigen‐presenting function of mononuclear phagocytes by modulating the expression of HLA‐D region products. Incubation of purified monocytes from healthy volunteers with cholesterol in scrum‐free medium induced a significant increase in both the percentages of monocytes expressing HLA‐DQ (P<0.02) and in the intensity of expression of the three HLA‐D sub‐region products. HLA‐DQ. ‐DP and ‐DR (P<0.02, <0.01, <005. respectively). The cholesterol pre‐incubated monocytes also exhibited enhanced antigen‐presenting function (P<0.05), compared with controls pre‐incubatcd without cholesterol. These findings indicate that increases in cholesterol in the extracellular milieu may augment antigen presentation by modulating the expression of HLA‐D region products on antigen‐presenting cells. Apart from EAA. this observation may also have relevance to inflammatory mechanisms in atherosclerosis, where‘foamy’ macrophages also occur in association with hypercholestcrolaemia.
The relationship between genetic influences on alcohol dependence and on patterns of alcohol consumption.

BACKGROUND Genetic factors impact substantially both on alcohol consumption (AC) and on the risk for alcohol dependence (AD). However, we know little about the degree to which measures of AC index the genetic risk for AD. METHODS We assessed a lifetime history of AD by DSM-IV criteria and four measures of AC at the time of heaviest drinking (drink frequency, regular quantity, maximum quantity, and drunk frequency) in 5,073 adult twins from same-sex pairs from the Virginia Twin Registry. Structural models were fitted using Mx. RESULTS We found evidence for different genetic structure in the sexes. In women, genetic risk for AD and for the four measures of AC was entirely shared. In men, the AC measures captured 85% of the genetic risk for AD. In women, the genetic relationship with AD was strongest for drunk frequency and in men for both drunk frequency and regular quantity. CONCLUSIONS In a population-based sample of twins, four relatively simple measures of AC obtained for the time of lifetime heaviest drinking were able to capture all (in women) or a very large proportion (in men) of the genetic risk for the complex multi-dimensional construct of AD. If replicated, these results have practical implications for studies aiming to assess genetic risk for AD.
Factors associated with early outcome in patients with large-vessel carotid strokes

Objective To describe the severity and early neurological deterioration (END) in patients with symptomatic carotid stenosis and to analyse the influence of related factors. Methods Observational cohort study of patients with ischaemic stroke, ipsilateral carotid stenosis and without evidence of cardiac sources of embolism prospectively recorded since January 2003 to January 2012. Initial severity was categorised as mild (NIH stroke scale (NIHSS) ≤7), moderate (NIHSS 8–14) or high (NIHSS >14). Logistic ordinal and regression analyses were performed for stroke severity and END risk. Results Of 2332 ischaemic strokes attended, 338 patients were included. Stroke severity was mild in 254 (75.1%) cases, moderate in 53 (15.7%) and severe in 31 (9.2%). Adjusted ORs (95% CI) for stroke severity were: degree of carotid stenosis, 2.20 (1.55 to 3.11, p<0.001); intracranial disease, 1.93 (1.18 to 3.17, p=0.009); plasma glucose, 1.01 (1.003 to 1.02, p<0.001); and previous transient ischaemic attack (TIA), 0.37 (0.17 to 0.82, p=0.014). 78 patients (23.1%) had END. Multivariate analysis showed independent association between END and degree of carotid stenosis (OR 1.64, 1.14 to 2.34, p=0.007), previous TIA (OR 2.40, 1.25 to 4.57, p=0.008) and mean arterial pressure (OR 1.02, 1.01 to 1.04, p=0.003). Conclusions Strokes due to large vessel disease in the carotid artery are in general of mild severity and have a high rate of END. The degree of stenosis has a clear association with higher severity and END risk.
Bronchodilator Response in Patients With Normal Baseline Spirometry

BACKGROUND: Spirometry before and after bronchodilator is performed to assess air flow-limitation reversibility. In patients with normal baseline spirometry the frequency of a positive bronchodilator response, as defined by American Thoracic Society/European Respiratory Society criteria, has not been described. METHODS: We retrospectively analyzed adult patients tested in 2 academic pulmonary function testing laboratories over a 7-year period, with specific attention to patients who underwent bronchodilator testing after a normal baseline spirometry (FEV1, FVC, and FEV1/FVC within normal limits). The frequency of a positive response to bronchodilator, defined as a 12% and 200 mL increase in either FEV1 or FVC, was calculated and associated with demographic factors. RESULTS: Of the 1,394 patients with normal spirometry who were administered bronchodilator, 43 (3.1%) had a positive response. The percent of patients responding to bronchodilator were grouped according to pre-bronchodilator FEV1: > lower limit of normal to 90% of predicted = 6.9%, 90–100% of predicted = 1.9%, and > 100% of predicted = 0%. An FEV1/FVC in the lowest 2 quartiles was associated with a higher frequency of bronchodilator response. Older patients were more likely to respond to bronchodilator, but no other demographic factors were associated with a positive bronchodilator response. CONCLUSIONS: In our study population the frequency of a positive bronchodilator response in patients with normal baseline spirometry is 3.1%. None of the patients with a pre-bronchodilator FEV1 > 100% of predicted and only 1.9% of patients with an FEV1 between 90% and 100% of predicted responded. Bronchodilator testing can be omitted in patients with normal spirometry and an FEV1 above 90% of predicted, as they have a low probability of a positive response.
The kinetics of serum hCG and progesterone in response to oral and vaginal administration of misoprostol during medical termination of early pregnancy.

BACKGROUND Misoprostol is widely used in combination with mifepristone for medical termination of pregnancy. We studied the endocrine parameters of trophoblast function during medical termination of early pregnancy using mifepristone in combination with oral or vaginal misoprostol. The effect of prolonged misoprostol administration was also examined. METHODS Thirty-four women, requesting termination of pregnancy and with <or=63 days of amenorrhoea, received 200 mg of mifepristone on day 0, followed by either oral (n = 13) or vaginal (n = 21) administration of 0.8 mg of misoprostol on day 2. In 23 cases misoprostol administration was continued orally for an additional 7 days. Serum samples, collected up to 14 days following the beginning of the treatment, were analysed for hCG, progesterone and mifepristone. RESULTS hCG and progesterone concentrations continued to increase until day 2. Following misoprostol, hCG and progesterone levels declined by 70.5 +/- 8.8% and 61.3 +/- 16.3% (mean +/- SD) respectively, in 24 h. The percentage decline in hCG correlated inversely (P < 0.05) with the time taken to abort. The peak level of mifepristone measured on day 2 did not correlate with the decline in serum hCG or progesterone. The kinetics of hCG, progesterone and mifepristone were similar in the different treatment groups. CONCLUSIONS The route and duration of misoprostol administration have no effect on the kinetics of serum hCG or progesterone during medical termination of early pregnancy.
Elevated levels of plasma homocysteine in postmenopausal women in Burkina Faso

Abstract Background: Low levels of plasma homocysteine have been found in children and adult populations living in Burkina Faso in association with a low prevalence of coronary heart disease. Methods: Based on this finding, the levels of plasma homocysteine and other thiols (cysteine, cysteinylglycine, glutathione) in postmenopausal women living in Burkina Faso were evaluated with the aim of investigating whether age and life conditions influence plasma homocysteine and other thiol levels. Results: It was found that in older postmenopausal women the mean level of homocysteine was higher (16.4±6.6 μmol/L) than in fertile women (6.8±1.2μmol/L) and that thisincrease was correlated with cysteine levels (166.6±44.6μmol/L). While the glutathione level in postmenopausal women was lower (3.6±2.3μmol/L) compared with fertile women (7.0±1.7μmol/L), cysteinylglycine levels were within the normal range (29.9±9.3μmol/L). No correlation was found between homocysteine levels and serum folate, vitamin B 12, vitamin B 6, cystatin C and serum creatinine levels. The older the women were, the higher were their plasma homocysteine levels: levels up to 20.2±9. 1μmol/L were found in those >70years old. Conclusions: The elevated levels of homocysteine in the postmenopausal women of Burkina Faso must be viewed as a characteristic of older age and its metabolic consequences.
In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics

The challenge in the synthesis of protein-polymer conjugates for biological applications is to synthesize a stoichiometric (typically 1:1) conjugate of the protein with a monodisperse polymer, with good retention of protein activity, significantly improved pharmacokinetics and increased bioavailability, and hence improved in vivo efficacy. Here we demonstrate, using myoglobin as an example, a general route to grow a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) [poly(OEGMA)], with low polydispersity and high yield, solely from the N-terminus of the protein by in situ atom transfer radical polymerization (ATRP) under aqueous conditions, to yield a site-specific (N-terminal) and stoichiometric conjugate (1:1). Notably, the myoglobin-poly(OEGMA) conjugate [hydrodynamic radius (Rh): 13 nm] showed a 41-fold increase in its blood exposure compared to the protein (Rh: 1.7 nm) after IV administration to mice, thereby demonstrating that comb polymers that present short oligo(ethylene glycol) side chains are a class of PEG-like polymers that can significantly improve the pharmacological properties of proteins. We believe that this approach to the synthesis of N-terminal protein conjugates of poly(OEGMA) may be applicable to a large subset of protein and peptide drugs, and thereby provide a general methodology for improvement of their pharmacological profiles.
The double-arch modified type-1b external skeletal fixator

Summary Objectives: To describe acute correction of antebrachial angular and rotational limb deformities (ARLD) using a new external skeletal fixator (ESF). Methods: Dogs that were presented with lameness caused by ARLD were treated by radial and ulnar osteotomies and acute realignment. A modified type-1b ESF incorporating double arches (DA-ESF) and a novel connecting configuration facilitated alignment with six degrees of freedom. Bilateral deformities were corrected surgically in the same session. Aseptic preparation of both antebrachii allowed comparison of limb alignment. Radiographic evaluation was performed using centre of rotation of angulation (CORA) methodology. Results: Thirty-five antebrachii (22 dogs) underwent surgery. Postoperative limb function was graded as good (n = 31), fair (n = 2), or poor (n = 2). Persistent medial carpal instability was associated with a suboptimal outcome. Postoperative radiographic images of the frontal and sagittal plane joint angles and elbow-to-carpus translation were compared with values that were reported in previous studies, and were within published reference ranges in most cases. Complications included delayed radial osteotomy union (n = 5), delayed ulnar osteotomy union (n = 2) and implant-associated morbidity (n = 3). Clinical relevance: A practical technique for acute correction of complex antebrachial ARLD is suggested, incorporating a new configuration of ESF. Putative limitations of radio-graphic planning using CORA may be compensated by careful attention to intra-operative visual and palpatory assessment.
The Expression of 11β-Hydroxysteroid Dehydrogenase Type I by Lymphocytes Provides a Novel Means for Intracrine Regulation of Glucocorticoid Activities1

The 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes control the interconversion of active glucocorticoids (GCS) and their inactive 11-keto metabolites, a process commonly referred to as the cortisone/cortisol shuttle. Although the prereceptor metabolism of GCS by 11β-HSD is well documented in a variety of cells and tissues, it has not yet been carefully investigated in the major cell types of the immune system. In this study, we demonstrate that 11β-HSD1 transcripts, protein, and enzyme activities are actively expressed in murine CD4+, CD8+, and B220+ lymphocytes, as well as CD11c+ dendritic cells. Only reductase activity was observed in living cells, evidenced by the restricted conversion of cortisone to cortisol. Activation of CD4+ T cells increased their 11β-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4+ T cells isolated from aged donors (>16 mo) had increased 11β-HSD1 protein and an elevated capacity to convert cortisone to cortisol. The GCS generated in murine CD4+ T cells from their inactive 11-keto metabolites could activate the GCS receptor, demonstrated by an up-regulation of IL-7Rα and GCS-induced leucine zipper gene expression. The presence of a functional 11β-HSD1 provides lymphocytes with a novel intracrine regulatory mechanism that could influence such processes as lymphocyte development, effector function, and susceptibility to apoptosis. Thus, the presence of 11β-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.
Five Questions (with their Answers) on ER‐Associated Degradation

Production of a functional proteome is a major burden for our cells. Native proteins operate inside and outside the cells to eventually warrant life and adaptation to metabolic and environmental changes, there is no doubt that production and inappropriate handling of misfolded proteins may cause severe disease states. This review focuses on protein destruction, which is, paradoxically, a crucial event for cell and organism survival. It regulates the physiological turnover of proteins and the clearance of faulty biosynthetic products. It mainly relies on the intervention of two catabolic machineries, the ubiquitin proteasome system and the (auto)lysosomal system. Here, we have selected five questions dealing with how, why and when proteins produced in the mammalian endoplasmic reticulum are eventually selected for destruction.
A New Boost Switched-Capacitor Multilevel Converter With Reduced Circuit Devices

In this paper, a novel platform for the single phase switched-capacitor multilevel inverters (SCMLIs) is presented. It has several advantages over the classical topologies, such as an appropriate boosting property, higher efficiency, lower number of required dc voltage sources, and other accompanying components with less complexity and lower cost. The basic structure of the proposed converter is capable of making nine-level of the output voltage under different kinds of loading conditions. Hereby, by using the same two capacitors paralleled to a single dc source, a switched-capacitor (SC) cell is made that contributes to boosting the value of the input voltage. In this case, the balanced voltage of the capacitors can be precisely provided on the basis of the series–parallel technique and the redundant switching states. Afterward, to reach the higher number of output voltage levels, two suggested SC cells are connected to each other with a new extended configuration. Therefore, by the use of a reasonable number of required power electronic devices, and also by utilizing only two isolated dc voltage sources, which their magnitudes can be designed based on either symmetric or asymmetric types, a 17- and 49-level of the output voltage are obtained. Based on the proposed extended configuration, a new generalized version of SCMLIs is also derived. To confirm the precise performance of the proposed topologies, apart from the theoretical analysis and a complete comparison, several simulation and experimental results are also given.
Attentional systems and the allocation of cerebral resources in reading and grammatical tasks.

To evaluate the possible role of attentional centers as modulators of neural networks that mediate visual tasks involving reading and grammatical manipulations of verbs, we measured cerebral blood flow (CBF) using positron emission tomography (PET), and reaction times as subjects read verbs, "nonce verbs" such as jelt or brep, and formed past tenses of regular, irregular and nonce verbs after viewing their stems. Statistical parametric maps (SPMs) showed significant activation of the pulvinar in the read verb irregular, and generate nonce past tense tasks, compared to rest. This was confirmed by a post hoc ANOVA of CBF values from a discrete locus in the pulvinar (p = .0000417). Functional links between the pulvinar and other brain regions were shown by high correlations of CBF in the pulvinar with CBF in brain regions known to have anatomical connections to the pulvinar, particularly those mediating vision. There was also a significant relationship between task-specific reaction times and rest minus task CBF differences in a multiple regression analysis that included CBF values from the pulvinar, superior colliculus plus reticular formation, and the anterior cingulate, known attentional centers (p = .021, r2 = 0.99). Regression analyses relating reaction time to the amount of brain activated (pixels in the SPMs) and the degree of activation of the pixels (mean Z score) yielded p values of . 078 and . 074, respectively. Our data provide direct experimental evidence to support the hypothesis that attentional centers are activated in proportion to the complexity of visually mediated language tasks and that the centers that mediate attention modulate the activity of task-specific neural networks.