Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrin Activation by Dithiothreitol or Mn2+ Induces a Ligand-occupied Conformation and Exposure of a Novel NH2-terminal Regulatory Site on the β1Integrin Chain*

Integrins can be expressed in at least three functional states (i.e. latent, active, and ligand-occupied). However, the molecular bases for the transitions between these states are unknown. In the present study, changes in the accessibility of several β1 epitopes (e.g.N29, B44, and B3B11) were used to probe activation-related conformational changes. Dithiothreitol or Mn2+ activation of integrin-mediated adhesion in the human B cell line, IM9, resulted in a marked increase in the exposure of the B44 epitope, while N29 expression levels were most sensitive to dithiothreitol treatment. These results contrasted with the epitope expression patterns of spontaneously adherent K562 cells, where N29 was almost fully accessible and B44 was low. Addition of a soluble ligand resulted in a marked increase in B44 levels, suggesting that this antibody detected a ligand-induced binding site. The N29 epitope was mapped to a cysteine-rich region near the NH2 terminus of the integrin chain, thus defining a novel regulatory site. These studies indicate that the activation of integrin function by different stimuli may involve related but nonidentical conformations. Both Mn2+ and dithiothreitol appear to induce localized conformational changes that mimic a ligand-occupied receptor. This differs from the “physiologically” activated integrins on K562 cells that display a marked increase in overall epitope accessibility without exposure of the ligand-induced binding site epitopes. The increased exposure of the N29 site on K562 cells may indicate a role for this region in the regulation of integrin function.
An emerging "maternal near-miss syndrome": narratives of women who almost died during pregnancy and childbirth.

BACKGROUND An improvement in maternal health conditions can only be achieved when a reduction in the number of deaths is accompanied by a reduction in the frequency of severe complications of pregnancy. The objective of this study was to investigate women's experiences related to the burden of severe maternal morbidity. METHODS This qualitative study is based on narratives of women who survived severe complications of pregnancy and who were admitted to the intensive care unit of a public university hospital in the city of Campinas, Brazil. A sample of 30 women was recruited between April 2007 and January 2008. Before hospital discharge, eligible women who agreed to participate responded to a semidirected interview. The interviews were recorded and the transcripts received a thematic analysis. RESULTS Two major themes were identified, one more closely related to the experience of a critical illness and the other to the experience of care. A complex set of reactions was found in the women who survived, indicating the occurrence of acute stress-related disorders. CONCLUSIONS On the basis of narratives of women who almost died during pregnancy and childbirth, we reported on an acute stress disorder that may be associated with the occurrence of severe maternal complications, which we named, the "maternal near-miss syndrome. " The implementation of integrated care that encompasses the physical, psychological, social, and spiritual aspects of women's health may help to alleviate the burden that maternal complications impose on millions of women around the world.
Expression of a functional metabotropic glutamate receptor 5 on enteric glia is altered in states of inflammation

The metabotropic glutamate receptor 5 (mGluR5) is expressed by astrocytes and its expression is modulated by inflammation. Enteric glia have many similarities to astrocytes and are the most numerous cell in the enteric nervous system (ENS). We investigated whether enteric glia express a functional mGluR5 and whether expression of this receptor was altered in colitis. In both enteric plexuses of the ileum and colon of guinea pigs and mice, we observed widespread glial mGluR5 expression. Incubation of isolated segments of the guinea pig ileum with the mGluR5 specific agonist RS‐2‐chloro‐5‐hydroxyphenylglycine (CHPG) caused a dose‐dependent increase in the glial expression of c‐Fos and the phosphorylated form of the extracellular signal‐regulated kinase 1/2. Preincubation of tissues with the group I metabotropic glutamate receptor antagonist, S‐4‐carboxyphenylglycine, abolished the effects of CHPG. We examined mGluR5 expression in the guinea pig trinitrobenzene sulfonic acid and the IL‐10 gene‐deficient (IL‐10−/−) mouse models of colitis. In guinea pigs, mGluR5 immunoreactivity became diffusely localized over the colonic myenteric ganglia, suggesting a change in receptor distribution. In contrast, glial mGluR5 expression was significantly reduced in the colonic myenteric plexus of IL‐10−/− mice, as assessed with both real‐time quantitative RT‐PCR as well as immunohistochemistry and image analysis. These changes occurred without concomitant changes to enteric ganglia or glial fibrillary acidic protein expression in the IL‐10−/− mouse. Our data suggest that enteric glia are a functional target of the glutamatergic neurotransmitter system in the ENS and that changes in mGluR5 expression may be of physiological significance during colitis. © 2007 Wiley‐Liss, Inc.
Estimation of the Timing of Human Visual Perception from Magnetoencephalography

To explore the timing and the underlying neural dynamics of visual perception, we analyzed the relationship between the manual reaction time (RT) to the onset of a visual stimulus and the time course of the evoked neural response simultaneously measured by magnetoencephalography (MEG). The visual stimuli were a transition from incoherent to coherent motion of random dots and an onset of a chromatic grating from a uniform field, which evoke neural responses in different cortical sites. For both stimuli, changes in median RT with changing stimulus strength (motion coherence or chromatic contrast) were accurately predicted, with a stimulus-independent postdetection delay, from the time that the temporally integrated MEG response crossed a threshold (integrator model). In comparison, the prediction of RT was less accurate from the peak MEG latency, or from the time that the nonintegrated MEG response crossed a threshold (level detector model). The integrator model could also account for, at least partially, intertrial changes in RT or in perception (hit/miss) to identical stimuli. Although we examined MEG–RT relationships mainly for data averaged over trials, the integrator model could show some correlations even for single-trial data. The model predictions deteriorated when only early visual responses presumably originating from the striate cortex were used as the input to the integrator model. Our results suggest that the perceptions for visual stimulus appearances are established in extrastriate areas [around MT (middle temporal visual area) for motion and around V4 (fourth visual area) for color] ∼150–200 ms before subjects manually react to the stimulus.
Development and identification of Set transgenic mice

As a multifunctional protein involved in numerous biological processes, Set is expressed in several embryonic and adult organs. Furthermore, Set is overexpressed in numerous types of human cancers, including acute myeloid leukemia, breast cancer and pancreatic cancer. The expression of Set in germ cells is involved in gonad development, and the overexpression of Set has been observed in polycystic ovaries. In order to elucidate the physiological and pathological roles of Set, a Set transgenic mouse model was developed, in which the global overexpression of Set in adult tissues could be induced via the Cre/loxP system with the precise deletion of the Stop fragment in double-transgenic hybrids. This result was then confirmed by genotypical and protein analysis using polymerase chain reaction and bioluminescence imaging. In conclusion, the conditional Set transgenic mice carrying a reporter system were successfully generated. The transgenic mice open a new window for the further investigation of the function of Set using tissue-specific Cre mice and inducible Cre systems.
The Neural Selection and Integration of Actions and Objects: An fMRI Study

There is considerable evidence that there are anatomically and functionally distinct pathways for action and object recognition. However, little is known about how information about action and objects is integrated. This study provides fMRI evidence for task-based selection of brain regions associated with action and object processing, and on how the congruency between the action and the object modulates neural response. Participants viewed videos of objects used in congruent or incongruent actions and attended either to the action or the object in a one-back procedure. Attending to the action led to increased responses in a fronto-parietal action-associated network. Attending to the object activated regions within a fronto-inferior temporal network. Stronger responses for congruent action–object clips occurred in bilateral parietal, inferior temporal, and putamen. Distinct cortical and thalamic regions were modulated by congruency in the different tasks. The results suggest that (i) selective attention to action and object information is mediated through separate networks, (ii) object–action congruency evokes responses in action planning regions, and (iii) the selective activation of nuclei within the thalamus provides a mechanism to integrate task goals in relation to the congruency of the perceptual information presented to the observer.
Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant.

The antimycotic clotrimazole, a potent inhibitor of the intermediate-conductance calcium-activated K(+) channel, IKCa1, is in clinical trials for the treatment of sickle cell disease and diarrhea and is effective in ameliorating the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by clotrimazole limits its therapeutic value. We have used a rational design strategy to develop a clotrimazole analog that selectively inhibits IKCa1 without blocking cytochrome P450 enzymes. A screen of 83 triarylmethanes revealed the pharmacophore for channel block to be different from that required for cytochrome P450 inhibition. The "IKCa1-pharmacophore" consists of a (2-halogenophenyl)diphenylmethane moiety substituted by an unsubstituted polar pi-electron-rich heterocycle (pyrazole or tetrazole) or a -CN group, whereas cytochrome P450 inhibition absolutely requires the imidazole ring. A series of pyrazoles, acetonitriles, and tetrazoles were synthesized and found to selectively block IKCa1. TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole) inhibits the cloned and the native IKCa1 channel in human T lymphocytes with a K(d) of 20-25 nM and is 200- to 1,500-fold selective over other ion channels. Using TRAM-34, we show that blocking IKCa1 in human lymphocytes, in the absence of P450-inhibition, results in suppression of mitogen-stimulated [(3)H]thymidine incorporation of preactivated lymphocytes with EC(50)-values of 100 nM-1 microM depending on the donor. Combinations of TRAM-34 and cyclosporin A are more effective in suppressing lymphocyte mitogenesis than either compound alone. Our studies suggest that TRAM-34 and related compounds may hold therapeutic promise as immunosuppressants.
Evaluation of methane-utilising bacteria products as feed ingredients for monogastric animals

Bacterial proteins represent a potential future nutrient source for monogastric animal production because they can be grown rapidly on substrates with minimum dependence on soil, water, and climate conditions. This review summarises the current knowledge on methane-utilising bacteria as feed ingredients for animals. We present results from earlier work and recent findings concerning bacterial protein, including the production process, chemical composition, effects on nutrient digestibility, metabolism, and growth performance in several monogastric species, including pigs, broiler chickens, mink (Mustela vison), fox (Alopex lagopus), Atlantic salmon (Salmo salar), rainbow trout (Oncorhynchus mykiss), and Atlantic halibut (Hippoglossus hippoglossus). It is concluded that bacterial meal (BM) derived from natural gas fermentation, utilising a bacteria culture containing mainly the methanotroph Methylococcus capsulatus (Bath), is a promising source of protein based on criteria such as amino acid composition, digestibility, and animal performance and health. Future research challenges include modified downstream processing to produce value-added products, and improved understanding of factors contributing to nutrient availability and animal performance.
Identification of patients with gout: elaboration of a questionnaire for epidemiological studies

Objectives In France, the prevalence of gout is currently unknown. We aimed to design a questionnaire to detect gout that would be suitable for use in a telephone survey by non-physicians and assessed its performance. Methods We designed a 62-item questionnaire covering comorbidities, clinical features and treatment of gout. In a case–control study, we enrolled patients with a history of arthritis who had undergone arthrocentesis for synovial fluid analysis and crystal detection. Cases were patients with crystal-proven gout and controls were patients who had arthritis and effusion with no monosodium urate crystals in synovial fluid. The questionnaire was administered by phone to cases and controls by non-physicians who were unaware of the patient diagnosis. Logistic regression analysis and classification and regression trees were used to select items discriminating cases and controls. Results We interviewed 246 patients (102 cases and 142 controls). Two logistic regression models (sensitivity 88.0% and 87.5%; specificity 93.0% and 89.8%, respectively) and one classification and regression tree model (sensitivity 81.4%, specificity 93.7%) revealed 11 informative items that allowed for classifying 90.0%, 88.8% and 88.5% of patients, respectively. Conclusions We developed a questionnaire to detect gout containing 11 items that is fast and suitable for use in a telephone survey by non-physicians. The questionnaire demonstrated good properties for discriminating patients with and without gout. It will be administered in a large sample of the general population to estimate the prevalence of gout in France.
Activation of Human Orbital Fibroblasts through CD40 Engagement Results in a Dramatic Induction of Hyaluronan Synthesis and Prostaglandin Endoperoxide H Synthase-2 Expression

Human orbital fibroblasts play a putative role in the pathogenesis of thyroid-associated ophthalmopathy (TAO). We hypothesize that the hyaluronan accumulation and inflammation in TAO derive from enhanced biosynthetic activities of orbital fibroblasts. CD40, a member of the tumor necrosis factor-α receptor superfamily, is a critical signaling molecule expressed by B lymphocytes. Engagement of CD40 with CD154 or CD40 ligand results in the activation of target genes. Orbital fibroblasts also display CD40. Here we report that CD40 engagement leads to substantial increases in hyaluronan synthesis in orbital fibroblasts. The increase is approximately 5-fold above control values, is comparable to the induction elicited by IL-1β and could be attenuated with dexamethasone but not by SC 58125, a prostaglandin endoperoxide H synthase-2 (PGHS-2)-selective inhibitor. PGHS-2 is also induced by CD40 engagement in a time-dependent manner, and this is mediated through increases in levels of steady-state mRNA. The induction of PGHS-2 leads to a dramatically enhanced prostaglandin E2 production that can be blocked by SC 58125 and dexamethasone. CD40 ligand up-regulates the synthesis of IL-1α, and blocking this cytokine with exogenous IL-1 receptor antagonist (IL-1ra) or with IL-1α neutralizing antibodies partially attenuates the induction of PGHS-2. In contrast, CD40 ligand up-regulation of hyaluronan synthesis is unaffected by IL-1ra. CD40 cross-linking enhances mitogen-activated protein kinase activation, and interrupting this pathway attenuates the PGHS-2 induction. Thus the CD40/CD40 ligand bridge represents a potentially important activational pathway for orbital fibroblasts that may underlie the cross-talk between these cells and leukocytes. These findings may be relevant to the pathogenesis of TAO and provide insights into previously unrecognized, potential therapeutic targets.
Rostro-Caudal Organization of Connectivity between Cingulate Motor Areas and Lateral Frontal Regions

According to contemporary views, the lateral frontal cortex is organized along a rostro-caudal functional axis with increasingly complex cognitive/behavioral control implemented rostrally, and increasingly detailed motor control implemented caudally. Whether the medial frontal cortex follows the same organization remains to be elucidated. To address this issue, the functional connectivity of the 3 cingulate motor areas (CMAs) in the human brain with the lateral frontal cortex was investigated. First, the CMAs and their representations of hand, tongue, and eye movements were mapped via task-related functional magnetic resonance imaging (fMRI). Second, using resting-state fMRI, their functional connectivity with lateral prefrontal and lateral motor cortical regions of interest (ROIs) were examined. Importantly, the above analyses were conducted at the single-subject level to account for variability in individual cingulate morphology. The results demonstrated a rostro-caudal functional organization of the CMAs in the human brain that parallels that in the lateral frontal cortex: the rostral CMA has stronger functional connectivity with prefrontal regions and weaker connectivity with motor regions; conversely, the more caudal CMAs have weaker prefrontal and stronger motor connectivity. Connectivity patterns of the hand, tongue and eye representations within the CMAs are consistent with that of their parent CMAs. The parallel rostral-to-caudal functional organization observed in the medial and lateral frontal cortex could likely contribute to different hierarchies of cognitive-motor control.
Accumulation of Extracellular Glutamate by Inhibition of Its Uptake Is Not Sufficient for Inducing Neuronal Damage: An In Vivo Microdialysis Study

Abstract: It is well documented that neurons exposed to high concentrations of excitatory amino acids, such as glutamate and aspartate, degenerate and die. The clearance of these amino acids from the synaptic cleft depends mainly on their transport by high‐affinity sodium‐dependent carriers. Using microdialysis in vivo and HPLC analysis, we have studied the effect of the administration of inhibitors of the glutamate transporter (l‐trans‐pyrrolidine‐2,4‐dicarboxylate and dihydrokainate) on the extracellular concentration of endogenous amino acids in the rat striatum. In addition, we have analyzed whether the changes observed in the concentration of glutamate and aspartate were injurious to striatal cells. Neuronal damage was assessed by biochemical determination of choline acetyltransferase and glutamate decarboxylase activities, 7 days after the microdialysis procedure. In other experiments, pyrrolidine dicarboxylate and dihydrokainate, as well as two other inhibitors of the glutamate carrier, dl‐threo‐β‐hydroxyaspartate and l‐aspartate‐β‐hydroxamate, were microinjected into the striatum, and neuronal damage was assessed, both biochemically and histologically, 7 or 14 days after the injection. Dihydrokainate and pyrrolidine dicarboxylate produced a similar remarkable increase in the concentration of extracellular aspartate and glutamate. However, the former induced also notable elevations in the concentration of other amino acids. Clear neuronal damage was observed only after dihydrokainate administration, which was partially prevented by intraperitoneal injection of (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine maleate or by intrastriatal coinjection of 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoylbenzo(f)quinoxaline. No cell damage was observed with the other three glutamate carrier inhibitors used. It is concluded that an increased extracellular glutamate level in vivo due to dysfunction of its transporter is not sufficient for inducing neuronal damage. The neurotoxic effects of dihydrokainate could be explained by direct activation of glutamate postsynaptic receptors, an effect not shared by the other inhibitors used.
Analytical Modeling of a Square-Wave-Controlled Cascaded Multilevel STATCOM

The aim of this paper is to present an analytical, state-space model of an indirect, voltage-controlled cascaded-type multilevel static synchronous compensator (STATCOM) with ldquosquare wave control.rdquo The multilevel converter model is segmented into a dynamic and static part in order to accurately represent all internal feedback connections. Each voltage component is analyzed in detail and described mathematically by an averaged expression with an equivalent capacitance. The STATCOM model is linearized and linked with a DQ frame AC system model and the controller model, and implemented in MATLAB. The controller gains are selected by analyzing the root locus of the analytical model to give optimum responses. The validity and accuracy of the proposed model are verified against non-linear digital simulation PSCAD/EMTDC in the time and frequency domain. The model is very accurate in the subsynchronous range, and it is adequate for most control design applications and practical stability issues below 100 Hz. Furthermore, the developed model can be used for multilevel cascaded converters which exchange real power.
Bronchial thermoplasty for severe asthma

Purpose of reviewBronchial thermoplasty, which involves the delivery of radio frequency energy to the airways to reduce airway smooth muscle mass, has been recently introduced for the treatment of severe asthma. This review summarizes the preclinical development, efficacy and adverse effects of bronchial thermoplasty. In addition, the potential mechanisms of action and place in management of severe asthma are discussed. Recent findingsThe efficacy and adverse profile of bronchial thermoplasty has been assessed in three randomized controlled trials, the first two of which showed clinical benefits of bronchial thermoplasty compared with usual care in patients with moderate or severe asthma. The third trial reports the results of a comparison with sham bronchial thermoplasty in 288 adults with severe asthma. Bronchial thermoplasty improved asthma quality of life questionnaire scores compared with sham bronchial thermoplasty; in the posttreatment period, there were fewer severe exacerbations and emergency department visits. Bronchial thermoplasty causes short-term increases in asthma-related morbidity. Follow-up data to date support the long-term safety of the procedure. SummaryBronchial thermoplasty has a role in the management of patients with severe asthma who have uncontrolled symptoms despite current therapies. Future studies need to identify factors that predict a beneficial clinical response.