Miracle-dz/UniFAR-FTUs huggingface dataset:
Structures of p63 DNA binding domain in complexes with half-site and with spacer-containing full response elements

Transcription factor p63, a p53 family member, plays a role in epithelial cell development, cell cycle arrest, apoptosis, and tumorigenesis. Point mutations, primarily in the DNA binding domain (p63DBD), lead to malformation syndromes. To gain insight into differences between p63 and p53 and the impact of mutations on the structure, we have determined two crystal structures of p63DBD in complex with A/T-rich response elements. One complex contains a 10-bp DNA half-site response element (5′AAACATGTTT3′) and the other contains a 22-bp DNA full response element with a 2-bp spacer between two half-sites (5′AAACATGTTTTAAAACATGTTT3′). In both structures, each half-site binds a p63DBD dimer. The two p63DBD dimers do not interact in the presence of the DNA spacer, whereas they interact with one another in the p63DBD/10-bp complex where the DNA simulates a full response element by packing end-to-end. A unique dimer–dimer interaction involves a variable loop region, which differs in length and sequence from the counterpart loop of p53DBD. The DNA trajectories in both structures assume superhelical conformations. Surface plasmon resonance studies of p63DBD/DNA binding yielded Kd = 11.7 μM for a continuous full response element, whereas binding was undetectable with the 22-bp DNA, suggesting an important contribution of a p63DBD interdimer interface to binding and establishing that p63DBD affinity to the response element is approximately 1,000-fold lower than that of p53DBD. Analyses of the structural consequences of p63DBD mutations that cause developmental defects show that, although some mutations affect DNA binding directly, the majority affects protein stability.
Behçet's disease heterogeneity: cytokine production and oxidative burst of phagocytes are altered in patients with severe manifestations.

OBJECTIVES To test the hypothesis that classical phagocytic functions are constitutively stimulated in patients with Behçet's disease (BD). METHODS Four study groups were analysed: active BD (aBD; n=30), inactive BD (iBD; n=31); septic patients (SP; n=25); healthy controls (HC; n=30). Microbicide activity against Streptococcus pneumoniae, Streptococcus sanguinis and Candida albicans was determined by means of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and absorbance read by ELISA. Flow cytometry analysis evaluated phagocytosis (zymosan particles and microrganisms) and oxidative burst by dihidrorhodamine oxidation before and after stimulation with phorbol myristate acetate (PMA). The supernatant of PBMC cultures under TLR or microbial stimuli and of neutrophil cultures under PMA, LPS or microbial stimuli were used for determination of cytokine production by ELISA. RESULTS We found no significant differences between the BD patient groups and control groups with regard to oxidative burst, phagocytic activity, microbicide activity or cytokine production. However, the cells from patients with severe BD (based on clinical manifestation) exhibit significantly higher oxidative burst activity, both before and after PMA stimulation, compared to cells from patients with mild BD. Furthermore, we found significant correlations between the BD patients' scores on the simplified Behçet's Disease Current Activity Form adapted for Portuguese (BR-BDCAFs) and Streptococcus sanguinis-stimulated production of IL23 by PBMC and IL8 by neutrophils, and between BR-BDCAFs score and constitutive production of TNF-α, IFNγ, IL6 and IL23 by PBMC. CONCLUSIONS Patients with severe active BD do exhibit phagocytic dysfunction and some evidence of constitutive activation regarding oxidative burst and cytokine production.
Opioids in chronic musculoskeletal conditions

The use of opioids for benign disorders has been limited by concerns about these compounds’ potential adverse events and their possible misuse. However, during the last few years an increased use in nonmalignant disorders, including rheumatologic diseases, has been observed. Herein, we review the scientific evidence for opioid therapy in three common scenarios in clinical rheumatology. Low back pain is a very frequent reason for consultation. Overall, the large majority of studies show a positive, yet rather moderate, effect of opioids in pain control, as well as in other outcomes including mood, work disability and anxiety. Similarly, opioids seem to have a role in the management of hip and knee osteoarthritis; indeed, they have been included in all international guidelines for the treatment of these conditions. However, clinical studies addressing opioid use in clinical situations are plagued by methodological limitations; furthermore, the large majority of these studies only provide short-term information about opiod utilization in these patients. Finally, opioids are currently being used as complementary therapy in inflammatory joint conditions whereby they may significantly improve the quality of life of some of these patients. Regarding their safety, severe adverse events, including abnormal drug-seeking behaviour, are very rare, but mild adverse events are frequent leading to drug discontinuation in a significant number of cases.
Vibrio parahaemolyticus orchestrates a multifaceted host cell infection by induction of autophagy, cell rounding, and then cell lysis

The bacterial pathogen Vibrio parahaemolyticus utilizes a type III secretion system to cause death of host cells within hours of infection. We report that cell death is completely independent of apoptosis and occurs by a mechanism in which injection of multiple type III effectors causes induction of autophagy, cell rounding, and the subsequent release of cellular contents. Autophagy is detected by the appearance of lipidated light chain 3 (LC3) and by increases in punctae and vacuole formation. Electron microscopy reveals the production of early autophagic vesicles during infection. Consistent with phosphoinositide 3 (PI3) kinase playing a role in autophagy, treatment of infected cells with a PI3 kinase inhibitor attenuates autophagy in infected cells. Because many effectors are injected during a V. parahaemolyticus infection, it is not surprising that the presence of a sole PI3 kinase inhibitor does not prevent inevitable host-cell death. Our studies reveal an infection paradigm whereby an extracellular pathogen uses its type III secretion system to cause at least three parallel events that eventually result in the proinflammatory death of an infected host cell.
Isolation of Escherichia coli O86:K61 producing cyto‐lethal distending toxin from wild birds of the finch family

Escherichia coli was recovered from selected tissues of 43 out of a total of 46 finches found dead in the Scottish Highlands during April–May of 1994 and 1995. The isolates did not ferment sorbitol, rhamnose, sucrose or melibiose; they belonged to serogroup O86:K61, produced cytolethal distending toxin (CLDT) and possessed the eae gene sequence. The consistent recovery of organisms producing CLDT and possessing the eae gene suggests that these organisms may have played a significant role in the finch mortalities.
Regulation of expression and intracellular distribution of calreticulin, a major calcium binding protein of nonmuscle cells

In the present study we have demonstrated the presence of calreticulin, a major Ca2+‐sequestering protein of nonmuscle cells, in a variety of cell types in tissue culture. The protein localizes to the endoplasmic reticulum in most cell types and also to the nuclear envelope or nucleoli‐like structures in some cell types. Calreticulin is enriched in the rough endoplasmic reticulum, suggesting a possible involvement in protein synthesis. Calreticulin terminates with the KDEL‐COOH sequence, which is likely responsible for its endoplasmic reticulum localization. Unlike some other KDEL proteins, calreticulin expression is neither heat‐shock nor Ca2+‐shock dependent. Using a variety of metabolic inhibitors, we have shown that the pool of calreticulin in L6 cells has a relatively slow turnover and a stable intracellular distribution. In proliferating muscle cells in culture (both L6 and human skeletal muscle) calreticulin is present in the endoplasmic reticulum, and additional intranuclear staining is observed. When fusion of the L6 cells is inhibited with either a high serum concentration or TGF‐β TPA, the nucleolar staining by anticalreticulin antibodies is diminished, although the presence of calreticulin in the endoplasmic reticulum remains unchanged. In contrast, in differentiated (i.e., fused) muscle cells neither intranuclear nor intracellular staining for calreticulin is present. We conclude, therefore, that calreticulin is abundant in the endoplasmic reticulum in proliferating myoblasts, while it is present in only small amounts in sarcoplasmic reticulum membranes in terminally differentiated myotubes. We propose a model for the domain structure of calreticulin that may explain the differential subcellular distribution of this protein. Because of its widespread distribution in nonmuscle tissues, we postulate that calreticulin is a multifunctional protein that plays an important role in Ca2+ sequestering and thus that it is the nonmuscle analog of calsequestrin.
Quantum Cohomology of Minuscule Homogeneous Spaces III Semi-Simplicity and Consequences

Abstract We prove that the quantum cohomology ring of any minuscule or cominuscule homogeneous space, specialized at $q\,=\,1$ , is semisimple. This implies that complex conjugation defines an algebra automorphism of the quantum cohomology ring localized at the quantum parameter. We check that this involution coincides with the strange duality defined in our previous article. We deduce Vafa–Intriligator type formulas for the Gromov–Witten invariants.
Confirmatory factor analysis of the Parental Bonding Instrument in a Japanese population

Background. There is controversy surrounding the factor structure of the Parental Bonding Instrument (PBI), a widely used instrument for assessing perceived parental rearing behaviours. Recent studies have proposed five different factor structures, including Parker et al.'s original two-factor model. Methods. Four hundred and eighteen employed Japanese adults filled out the PBI. Maximum likelihood confirmatory factor analyses were performed to compare the five different factor structures in terms of model-fit. Results. Parker's original two-factor structure fitted the data poorly. In general, three-factor structures showed better fit. Among the three-factor structures, Murphy's model and Kendler's model were superior (the adjusted goodness-of-fit index >0·8), with the latter providing the best fit to the data (the goodness-of-fit index >0·9). When considering invariance of factor structure across gender subgroups and across age subgroups, only Kendler's model was acceptable. Conclusions. Parker's two-factor structure of the PBI may not be appropriate for assessing perceived parental rearing behaviours in a Japanese population. Three-factor structures, in particular Murphy's model and Kendler's model, are preferable. Kendler's model provided the best fit to the data and was relatively invariant across the subgroups in this study. Thus, Kendler's model might prove to be very important for obtaining a factor structure invariant across different cultures.
Di-μ-chlorido-chlorido-1κCl-(μ-1-phenyl-3-phenyliminobut-1-enolato-1:2κ3 O:O,N)bis(1-phenyl-3-phenyliminobut-1-enolato)-1κ2 N,O;2κ2 N,O-dichromium(III) toluene disolvate

In the title dichromium complex, [Cr2(C16H14NO)3Cl3]·2C7H8, each CrIII atom has a distorted octahedral coordination geometry. The complex molecule has three six-membered chelate rings formed by hydroxybutaneimine ligands and the two CrIII atoms are bridged by two Cl atoms and one O atom.
Sleep in the laboratory and sleep at home: comparisons of older insomniacs and normal sleepers.

Many laboratory polysomnographic (LPSG) studies have shown only modest sleep differences between insomniacs and matched, noncomplaining normal controls. However, the extent to which LPSG methodology affects the outcome of such comparisons has yet to be tested. In the current investigation, 32 (16 females, 16 males) older (age > or = 60 years) insomniacs and an age-matched and gender-matched sample of 32 noncomplaining normal sleepers underwent three consecutive nights of LPSG monitoring and another three consecutive nights of PSG monitoring in their homes (HPSG). By random assignment, one-half of the subjects in each group underwent LPSG first, whereas the remaining subjects underwent HPSG first. Each PSG recording was blindly scored using conventional scoring criteria, and resulting measures of total sleep period, total sleep time, sleep efficiency percent, stage 1 time, slow-wave sleep time, and rapid eye movement latency were used to compare the two subject groups within each PSG recording site (i.e. lab and home). Statistical analyses showed the normals sleepers and insomniacs evidenced similar pronounced first night effects (FNEs) when undergoing LPSG. However, neither mean values of the selected sleep parameters nor measures reflecting their night-to-night variability differentiated the insomniacs from the normal sleepers when such measures were derived from LPSG. In contrast, FNEs were generally absent for both subject groups when they underwent HPSG. Moreover, the insomniacs displayed significantly greater variability in several of their sleep measures during HPSG than did the normal sleepers. Overall, results suggest FNEs are a concern mainly when using LPSG, and HPSG may be more sensitive than LPSG for documenting sleep differences between normal sleepers and insomniacs. Additional studies are needed to determine if the findings reported herein are similar for young and middle-aged adults.
Factors associated with HD CAG repeat instability in Huntington disease

Background: The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene. Results: In this study, we used a collection of 112 sperm DNAs from male HD gene-positive members of a large Venezuelan cohort to investigate the factors associated with repeat instability. We confirm previous observations that CAG repeat length is the strongest predictor of repeat-length variability in sperm, but we did not find any correlation between CAG repeat instability and either age at the time of sperm donation or affectedness status. We also investigated transmission instability for 184 father–offspring and 311 mother–offspring pairs in this Venezuelan pedigree. Repeat-length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat-length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring. Conclusion: Significant sibling–sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.
Reliability of spatiotemporal gait outcome measures in Huntington's disease

Gait impairments are very important in Huntington's disease (HD), because loss of independence in gait is an important predictor of nursing home placement. Given this importance, it is imperative to test reliable and sensitive outcome measures that can be tested easily in various clinical environments. Here, we examined the test–retest reliability of gait outcome measures using the GAITRite instrumented carpet. We tested 12 subjects with HD and 12 age‐matched controls in two separate sessions. At each session, subjects walked across the GAITRite carpet at a comfortable speed. We used the intraclass correlation coefficient (ICC) and coefficient of variation (CoV) to measure test–retest reliability. Reliability was very high for all outcome measures (velocity, cycle time, stride length, cadence, and base of support), as seen by high ICC scores (0.86 to 0.95) and low CoV scores (0.042–0.102). In addition, the performance across the two subject groups was very different, indicating that the GAITRite is sensitive enough to distinguish between populations. Given that the GAITRite is a relatively inexpensive and portable piece of equipment, it can be used in a wide variety of clinical settings and clinical trials. Our data on high test–retest reliability and sensitivity extends the utility of the GAITRite to the HD population. © 2005 Movement Disorder Society
Influence of IL-1RN Intron 2 Variable Number of Tandem Repeats (VNTR) Polymorphism on the Age at Onset of Neuropsychiatric Symptoms in Wilson's Disease

ABSTRACT Wilson's disease (WND) is an autosomal recessive copper storage disease characterized with diverse clinical pictures with the hepatic and/or neuropsychiatric symptoms manifesting at variable age. On the basis of the existing knowledge on possible copper–proinflammatory cytokines interactions, we hypothesized that in WND hereditary, over-/underexpression of PC or anti-inflammatory cytokines may have an impact on the course of the disease. We analyzed the clinical manifestations of WND in relationship to polymorphisms within genes for interleukin-1 receptor antagonist (IL1RN intron 2 VNTR polymorphism), interleukin-1α (IL1A G4845T), IL-1β (IL1B C-511T), IL-6 (IL6 G-174C), and tumor necrosis factor (TNF G-308A) in a total sample of 332 patients. The IL1B C-511T and IL1RN VNTR polymorphisms had an impact on copper metabolism parameters. None of the studied gene polymorphisms had effect on the mode of WND manifestation (neuropsychiatric vs. hepatic). Carriership of the IL1RN *2 allele was related to earlier WND onset, especially among patients with neuropsychiatric form of the disease (median 27.5 vs. 32.0 years, p = .003). Because of the crucial modulatory role of IL1ra on IL-1α and IL-1β proinflammatory functions, IL1ra and its interactions may play a role in the pathogenesis of the neurodegenerative process in WND; our results need to be replicated, possibly in different ethnic groups.
Analysis of hemostasis alterations in sepsis

This laboratory study tested new methods to analyze hemostasis alterations in septic patients. Samples of ethylenediamine tetraacetic acid (EDTA) plasma and citrated plasma were collected from 62 patients with clinical diagnosis of sepsis. Additionally, a subset of EDTA-plasma samples from each patient was stabilized 1 + 1 with 2.5 mol/l arginine, pH 8.6, to conserve the real hemostasis activation state. EDTA–arginine plasma, EDTA plasma and citrated plasma samples were tested in duplicate. The patients at admission to the intensive care unit had 36 ± 26 (normal, 0.8 ± 0.2) ng/ml global endotoxin reactivity, 188 ± 66% (normal, 100 ± 20%) fibrinogen function, 179 ± 66% (normal, 100 ± 20%) fibrinogen antigen, 4.0 ± 3.6 (normal, 0.049 ± 0.025) μg/ml D-dimer, 313 ± 307% (normal, 100 ± 30%) plasmin–antiplasmin complex, 8.7 ± 11.4 (normal, 1.1 ± 0.7) U/ml plasminogen activator inhibitor-1, 12.1 ± 10.5 (normal, 1.3 ± 0.4) ng/ml thrombin–antithrombin III complex, 173 ± 62% (normal, 100 ± 20%) thrombin, 568 ± 225 (normal, 140 ± 42) pg/ml tissue factor, and 2.56 ± 2.48 (normal, 0.19 ± 0.04) μg/ml soluble intercellular adhesion molecule-1. Endotoxin (lipopolysaccharide and/or β-glucan) reactivity (EDTA plasma), fibrinogen function + antigen + ratio and plasminogen activator inhibitor-1 (citrated plasma), and D-dimer, soluble intercellular adhesion molecule-1, thrombin activity (EDTA–arginine-stabilized plasma) presented large aberrations in septic patients when compared with normal values and may therefore be particularly interesting as markers of hemostasis alteration. Whether the observed alterations are of clinical significance has to be determined in well defined patient groups.
Recognition using Discriminative Structured Trajectory Groups

In this paper, we develop a novel framework for action recognition in videos. The framework is based on automatically learning the discriminative trajectory groups that are relevant to an action. Different from previous approaches, our method does not require complex computation for graph matching or complex latent models to localize the parts. We model a video as a structured bag of trajectory groups with latent class variables. We model action recognition problem in a weakly supervised setting and learn discriminative trajectory groups by employing multiple instance learning (MIL) based Support Vector Machine (SVM) using pre-computed kernels. The kernels depend on the spatio-temporal relationship between the extracted trajectory groups and their associated features. We demonstrate both quantitatively and qualitatively that the classification performance of our proposed method is superior to baselines and several state-of-the-art approaches on three challenging standard benchmark datasets.
Inhibition of Renin Secretion by Angiotensin .II.∗

Summary Intravenous infusion of angiotensin II (6.3-200 ng/kg min) inhibited renin secretion in dogs under conditions of basal or elevated renin secretion. This inhibition was independent of changes in mean renal arterial blood pressure. We propose a negative feedback effect of circulating angiotensin on renin secretion.
Meta-analysis: Effects of Percutaneous Coronary Intervention Versus Medical Therapy on Angina Relief

BACKGROUND Several meta-analyses have evaluated the efficacy of percutaneous coronary intervention (PCI) compared with medical therapy, but none has focused on angina relief. PURPOSE To summarize the evidence on the degree of angina relief from PCI compared with medical therapy in patients with stable coronary artery disease. DATA SOURCES The Cochrane Library (1993 to June 2009), EMBASE (1980 to June 2009), and MEDLINE (1950 to June 2009), with no language restrictions. STUDY SELECTION Two independent reviewers screened citations to identify randomized, controlled trials of PCI versus medical therapy in patients with stable coronary artery disease. DATA EXTRACTION Two independent reviewers abstracted data on patient characteristics, study conduct, and outcomes. A random-effects model was used to combine data on freedom from angina and to perform stratified analyses based on duration of follow-up, inclusion of patients with recent myocardial infarction, coronary stent utilization, recruitment period, and utilization of evidence-based medications. DATA SYNTHESIS A total of 14 trials, enrolling 7818 patients, met the inclusion criteria. Although PCI was associated with an overall benefit on angina relief (odds ratio, 1.69 [95% CI, 1.24 to 2.30]), important heterogeneity across trials was observed. The incremental benefit of PCI observed in older trials (odds ratio, 3.38 [CI, 1.89 to 6.04]) was substantially less and possibly absent in recent trials (odds ratio, 1.13 [CI, 0.76 to 1.68]). An inverse relationship between use of evidence-based therapies and the incremental benefit of PCI was observed. LIMITATIONS Information about the long-term use of medication was incomplete in most trials. Few trials used drug-eluting stents. Meta-regression analyses used aggregated study-level data from few trials. CONCLUSION Percutaneous coronary intervention was associated with greater freedom from angina compared with medical therapy, but this benefit was largely attenuated in contemporary studies. This observation may be related to greater use of evidence-based medications in contemporary trials. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research.