julilili42/papers huggingface dataset:
Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk
2011-11-21

The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5′ of the endothelin receptor type A with P = 2.2 × 10 −8 [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 × 10 −7 , PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 × 10 −7 , PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.
Cognitive behaviour therapy and supportive therapy for bipolar disorders: relapse rates for treatment period and 2-year follow-up
2011-11-21

Background The efficacy of adjunctive psychosocial interventions such as cognitive behaviour therapy (CBT) for bipolar disorder (BD) has been demonstrated in several uncontrolled and controlled studies. However, these studies compared CBT to either a waiting list control group, brief psycho-education or treatment as usual (TAU). Our primary aim was to determine whether CBT is superior to supportive therapy (ST) of equal intensity and frequency in preventing relapse and improving outcome at post-treatment. A secondary aim was to look at predictors of survival time. Method We conducted a randomized controlled trial (RCT) at the Department of Psychology, University of Tübingen, Germany ( n =76 patients with BD). Both CBT and ST consisted of 20 sessions over 9 months. Patients were followed up for a further 24 months. Results Although changes over time were observed in some variables, they were not differentially associated with CBT or ST. CBT showed a non-significant trend for preventing any affective, specifically depressive episode during the time of therapy. Kaplan–Meier survival analyses revealed that 64.5% of patients experienced a relapse during the 33 months. The number of prior episodes, the number of therapy sessions and the type of BD predicted survival time. Conclusions No differences in relapse rates between treatment conditions were observed, suggesting that certain shared characteristics (e.g. information, systematic mood monitoring) might explain the effects of psychosocial treatment for BD. Our results also suggest that a higher number of prior episodes, a lower number of therapy sessions and a diagnosis of bipolar II disorder are associated with a shorter time before relapse.
Josephson Junction with a Magnetic-Field Tunable Ground State
2011-11-21

We consider an asymmetric 0-pi Josephson junction consisting of 0 and pi regions of different lengths L_0 and L_pi. As predicted earlier this system can be described by an effective sine-Gordon equation for the spatially averaged phase psi so that the effective current-phase relation of this system includes a \\emph{negative} second harmonic ~sin(2 psi). If its amplitude is large enough, the ground state of the junction is doubly degenerate psi=\\pmvarphi, where varphi depends on the amplitudes of the first and second harmonics. We study the behavior of such a junction in an applied magnetic field H and demonstrate that H induces an additional term ~H cos(psi) in the effective current-phase relation. This results in a non-trivial ground state \\emph{tunable} by magnetic field. The dependence of the critical current on H allows for revealing the ground state experimentally.
Import and Spread of Panton-Valentine Leukocidin–Positive Staphylococcus aureus Through Nasal Carriage and Skin Infections in Travelers Returning From the Tropics and Subtropics
2011-11-21

Geographic variation in the risk of SSTIs in travelers supports a globally heterogeneous distribution of virulent S. aureus. Complicated SSTIs in returnees from nontemperate climates are associated with PVL(+) S. aureus and promote the emergence and spread of virulent and antibiotic-resistant strains. We propose a network for the surveillance of imported S. aureus (www.staphtrav.eu).
Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimers Disease
2011-11-21

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.
Roles of the NFκB and glutathione pathways in mature human erythrocytes
2011-11-21

Abstract Anucleated erythrocytes were long considered as oxygen-transporting cells with limited regulatory functions. Components of different nuclear signaling pathways have not been investigated in those cells, yet. Surprisingly, we repeatedly found significant amounts of transcription factors in purified erythrocyte preparations, i.e. nuclear factor κB (NFκB), and major components of the canonical NFκB signaling pathway. To investigate the functional role of NFκB signaling, the effects of the preclinical compounds Bay 11-7082 and parthenolide on the survival of highly purified erythrocytes were investigated. Interestingly, both inhibitors of the NFκB pathway triggered erythrocyte programmed cell death as demonstrated by enhanced phospholipid scrambling (phosphatidylserine exposure) and cell shrinkage. Anucleated erythrocytes are an ideal cellular model allowing the study of nongenomic mechanisms contributing to suicidal cell death. As NFκB inhibitors might also interfere with the anti-oxidative defense systems of the cell, we measured the levels of reduced glutathione (GSH) after challenge with the inhibitors. Indeed, incubation of erythrocytes with Bay 11-7082 clearly decreased erythrocyte GSH levels. In conclusion, the pharmacological inhibitors of the NFκB pathway Bay 11-7082 and parthenolide interfere with the survival of erythrocytes involving mechanisms other than disruption of NFκB-dependent gene expression. Besides affecting erythrocyte survival, NFκB inhibition and induction of erythrocyte phosphatidylserine exposure may influence blood clotting. Future studies will be aimed at discriminating between NFκB-dependent and NFκB-independent GSH-mediated effects of Bay 11-7082 and parthenolide on erythrocyte death.
Effects of BCR-ABL Inhibitors on Anti-Tumor Immunity
2011-11-21

In chronic myeloid leukemia (CML), BCR-ABL-mediated oncogenic signaling can be successfully targeted with the BCRABL- inhibitors imatinib, nilotinib, and dasatinib leading to complete cytogenetic (Philadelphia chromosome not detectable upon cytogenetic testing of bone marrow) and even complete molecular (BCR-ABL not detectable by PCR in peripheral blood) responses. However, CML apparently can not be cured by BCR-ABL inhibitors alone, likely due to treatment-resistance of CML stem/progenitor cells, which provokes a relapse of disease after cessation of therapy. Evidence from patients treated with allogenic stem cell transplantation or IFN-α points to an important role of anti-tumor immunity for durable control of CML disease. Data from multiple in vitro and ex vivo studies indicate that BCR-ABL inhibitors may also influence anti-tumor immunity. Varying effects on different immune effector cell subsets and of the different compounds have been reported, the latter being due to their particular and diverse potency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibition with immunotherapeutic strategies to improve disease control in CML, immunomodulatory effects of the available BCR-ABL inhibitors may be of direct clinical relevance. Here we review the available data regarding the effects of imatinib, nilotinib, and dasatinib on dendritic cells, T cells and natural killer cells as important cellular components of anti-tumor immunity.
A 6000‐Year‐Old Hand Amputation from Bulgaria—The Oldest Case from South‐East Europe?
2011-11-21

ABSTRACT A skeleton from Tell Yunatsite in Bulgarian Thrace shows evidence of amputation of the right hand. The individual dates back to the end of the fifth millennium, connecting it to the Late Copper Age of that region. The Chalcolithic settlement on the tell ended immediately after a bellicose assault. Therefore, the question arose if the loss of the hand may be connected with this incidence. Anthropological studies in close collaboration with the archaeologists on site made clear that the abscission took place at an earlier time. This result led to a series of complex questions. These are described in this work. We will show that a congenital origin for the loss of the hand can be excluded, and that the individual survived this severe injury for a certain time span. Several possible explanations for an amputation are discussed. It turns out that a surgical intervention seems to be the most likely reason. It becomes clear that there must have been an excellent medical knowledge in the Copper Age concerning surgery and wound treatment. Furthermore, the survival of the handicapped individual documents a certain social cohesion. Copyright © 2011 John Wiley &amp; Sons, Ltd.
Global Analysis of the Staphylococcus aureus Response to Mupirocin
2011-11-22

ABSTRACT In the present study, we analyzed the response of S. aureus to mupirocin, the drug of choice for nasal decolonization. Mupirocin selectively inhibits the bacterial isoleucyl-tRNA synthetase (IleRS), leading to the accumulation of uncharged isoleucyl-tRNA and eventually the synthesis of (p)ppGpp. The alarmone (p)ppGpp induces the stringent response, an important global transcriptional and translational control mechanism that allows bacteria to adapt to nutritional deprivation. To identify proteins with an altered synthesis pattern in response to mupirocin treatment, we used the highly sensitive 2-dimensional gel electrophoresis technique in combination with mass spectrometry. The results were complemented by DNA microarray, Northern blot, and metabolome analyses. Whereas expression of genes involved in nucleotide biosynthesis, DNA metabolism, energy metabolism, and translation was significantly downregulated, expression of isoleucyl-tRNA synthetase, the branched-chain amino acid pathway, and genes with functions in oxidative-stress resistance ( ahpC and katA ) and putative roles in stress protection (the yvyD homologue SACOL0815 and SACOL1759 and SACOL2131 ) and transport processes was increased. A comparison of the regulated genes to known regulons suggests the involvement of the global regulators CodY and SigB in shaping the response of S. aureus to mupirocin. Of particular interest was the induced transcription of genes encoding virulence-associated regulators (i.e., arlRS , saeRS , sarA , sarR , sarS , and sigB ), as well as genes directly involved in the virulence of S. aureus (i.e., fnbA , epiE , epiG , and seb ).
Ficolin-2 Levels and FCN2 Haplotypes Influence Hepatitis B Infection Outcome in Vietnamese Patients
2011-11-22

Human Ficolin-2 (L-ficolins) encoded by FCN2 gene is a soluble serum protein that plays an important role in innate immunity and is mainly expressed in the liver. Ficolin-2 serum levels and FCN2 single nucleotide polymorphisms were associated to several infectious diseases. We initially screened the complete FCN2 gene in 48 healthy individuals of Vietnamese ethnicity. We genotyped a Vietnamese cohort comprising of 423 clinically classified hepatitis B virus patients and 303 controls for functional single nucleotide polymorphisms in the promoter region (-986G>A, -602G>A, -4A>G) and in exon 8 (+6424G>T) by real-time PCR and investigated the contribution of FCN2 genotypes and haplotypes to serum Ficolin-2 levels, viral load and liver enzyme levels. Haplotypes differed significantly between patients and controls (P = 0.002) and the haplotype AGGG was found frequently in controls in comparison to patients with hepatitis B virus and hepatocellular carcinoma (P = 0.0002 and P<0.0001) conferring a protective effect. Ficolin-2 levels differed significantly between patients and controls (p<0.0001). Patients with acute hepatitis B had higher serum Ficolin-2 levels compared to other patient groups and controls.The viral load was observed to be significantly distributed among the haplotypes (P = 0.04) and the AAAG haplotype contributed to higher Ficolin-2 levels and to viral load. Four novel single nucleotide polymorphisms in introns (-941G>T, -310G>A, +2363G>A, +4882G>A) and one synonymous mutation in exon 8 (+6485G>T) was observed. Strong linkage was found between the variant -986G>A and -4A>G. The very first study on Vietnamese cohort associates both Ficolin-2 serum levels and FCN2 haplotypes to hepatitis B virus infection and subsequent disease progression.
Abstract 18120: Variants of Toll Like Receptor 4 Have Prognostic Value in Patients with Dilated Cardiomyopathy
2011-11-22

Background - Dilated cardiomyopathy (DCM) may attend with innate immune activation, but its prognostic value is largely unknown. Since the innate immune Toll-like receptor 4 (TLR4) has been shown to be involved in atherosclerosis, we investigated the impact of coding polymorphisms of TLR4 on development and prognosis of DCM in patients. Methods and results - Two previously reported genetic variants of TLR4 (rs4986790, TLR4 c.1187A&gt;G, p.299D&gt;G and rs4986791,TLR4 c.1487C&gt;T, p.T399I) were investigated. Coronary artery disease and other reasons for heart failure were excluded by angiography, myocardial biopsy, two dimensional echocardiography and spirometry. There were no significant differences between genetically defined subgroups with respect to baseline risk factors, age, gender and treatment. Presence of the rs4986790 and/or the rs4986791 variant, respectively, was not associated with an increased incidence of DCM. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular (LV) ejection fraction (P=0.006) and LV dilation (P=0.015) at the follow-up evaluation when compared to carriers of the wildtype gene and isolated rs4986790 or rs4986791 variants, respectively (Figure 1). This was associated with significantly reduced levels of nt-pro brain natriuretic peptide (BNP) in patients carrying the TLR4 wildtype gene and isolated TLR4 variants at the follow-up when compared to the first admissions evaluation. Carriers of both variants did not show a significant decrease of nt-pro BNP. Conclusion - Among patients with DCM, the common presence of the TLR4 variants rs4986790 and rs4986791 predict worsened LV ejection fraction, LV dilation and nt-pro BNP levels at the course of time.
Transcription Factor NF-κB Regulates Expression of Pore-forming Ca2+ Channel Unit, Orai1, and Its Activator, STIM1, to Control Ca2+ Entry and Affect Cellular Functions
2011-11-23

The serum and glucocorticoid-inducible kinase SGK1 increases the activity of Orai1, the pore forming unit of store-operated Ca(2+) entry, and thus influences Ca(2+)-dependent cellular functions such as migration. SGK1 further regulates transcription factor nuclear factor κB (NF-κB). This study explored whether SGK1 influences transcription of Orai1 and/or STIM1, the Orai1-activating Ca(2+) sensor. Orai1 and STIM1 transcript levels were decreased in mast cells from SGK1 knock-out mice and increased in HEK293 cells transfected with active (S422D)SGK1 but not with inactive (K127N)SGK1 or in (S422D)SGK1-transfected cells treated with the NF-κB inhibitor Wogonin (100 μm). Treatment with the stem cell factor enhanced transcript levels of STIM1 and Orai1 in sgk1(+/+) but not in sgk1(-/-) mast cells and not in sgk1(+/+) cells treated with Wogonin. Orai1 and STIM1 transcript levels were further increased in sgk1(+/+) and sgk1(-/-) mast cells by transfection with active NF-κB subunit p65 as well as in HEK293 cells by transfection with NF-κB subunits p65/p50 or p65/p52. They were decreased by silencing of NF-κB subunits p65, p50, or p52 or by NF-κB inhibitor Wogonin (100 μm). Luciferase assay and chromatin immunoprecipitation defined NF-κB-binding sites in promoter regions accounting for NF-κB sensitive genomic regulation of STIM1 and Orai1. Store-operated Ca(2+) entry was similarly increased by overexpression of p65/p50 or p65/p52 and decreased by treatment with Wogonin. Transfection of HEK293 cells with p65/p50 or p65/p52 further augmented migration. The present observations reveal powerful genomic regulation of Orai1/STIM1 by SGK1-dependent NF-κB signaling.
PALS1 Is Essential for Retinal Pigment Epithelium Structure and Neural Retina Stratification
2011-11-23

The membrane-associated palmitoylated protein 5 (MPP5 or PALS1) is thought to organize intracellular PALS1-CRB-MUPP1 protein scaffolds in the retina that are involved in maintenance of photoreceptor–Müller glia cell adhesion. In humans, the Crumbs homolog 1 ( CRB1 ) gene is mutated in progressive types of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis. However, there is no clear genotype–phenotype correlation for CRB1 mutations, which suggests that other components of the CRB complex may influence the severity of retinal disease. Therefore, to understand the physiological role of the Crumbs complex proteins, especially PALS1, we generated and analyzed conditional knockdown mice for Pals1 . Small irregularly shaped spots were detected throughout the PALS1 deficient retina by confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. The electroretinography a- and b-wave was severely attenuated in the aged mutant retinas, suggesting progressive degeneration of photoreceptors. The histological analysis showed abnormal retinal pigment epithelium structure, ectopic photoreceptor nuclei in the subretinal space, an irregular outer limiting membrane, half rosettes of photoreceptors in the outer plexiform layer, and a thinner photoreceptor synaptic layer suggesting improper photoreceptor cell layering during retinal development. The PALS1 deficient retinas showed reduced levels of Crumbs complex proteins adjacent to adherens junctions, upregulation of glial fibrillary acidic protein indicative of gliosis, and persisting programmed cell death after retinal maturation. The phenotype suggests important functions of PALS1 in the retinal pigment epithelium in addition to the neural retina.
Correlation between Macular Morphology and Sensitivity in Patients with Retinitis Pigmentosa and Hyperautofluorescent Ring
2011-11-23

To assess the correlation between retinal morphology and function in patients with retinitis pigmentosa (RP) using spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging (FAF), and fundus-related perimetry and to use coregistration of data sets to achieve high-resolution structure-function correlation of human macula.Twelve patients with RP and hyperautofluorescent parafoveal ring in FAF imaging were tested. Ophthalmological examination, static and kinetic fundus-related perimetry, and SD-OCT were performed. Custom software allowed coregistration of fundus-related perimetry, SD-OCT, and FAF data sets.A high correlation between retinal sensitivity and outer retinal thickness was observed (ρ = 0.72, P < 0.0001). The median retinal sensitivity over the central circular area of normal autofluorescence was significantly higher when compared with the area over the surrounding hyperautofluorescent ring and to the area outside the ring (H = 34.2, P < 0.0001). The outer retina at the site where kinetic stimuli were perceived was better preserved and had higher retinal thickness, corresponding to higher sensitivity (H = 289, P < 0.0001). The site of the hyperautofluorescent ring correlated in SD-OCT scans with a zone of impaired integrity of the photoreceptor layer (ρ = 0.67, P = 0.0003).Retinal sensitivity to static and kinetic stimuli correlates better with outer than with overall retinal thickness. The hyperautofluorescent ring in FAF represents a transition zone from relatively well-preserved to abnormal retinal morphology and function, rendering FAF imaging a clinically significant tool for assessing the severity and progression of dysfunction in RP patients. Accurate coregistration of different modalities drastically increases the power of structure-function correlation studies and allows consistent associations to be drawn.
Prothymosin-α Interacts with Mutant Huntingtin and Suppresses Its Cytotoxicity in Cell Culture
2011-11-23

Huntington disease (HD), a fatal neurodegenerative disorder, is caused by a lengthening of the polyglutamine tract in the huntingtin (Htt) protein. Despite considerable effort, thus far there is no cure or treatment available for the disorder. Using the approach of tandem affinity purification we recently discovered that prothymosin-α (ProTα), a small highly acidic protein, interacts with mutant Htt (mHtt). This was confirmed by co-immunoprecipitation and a glutathione S-transferase (GST) pull-down assay. Overexpression of ProTα remarkably reduced mHtt-induced cytotoxicity in both non-neuronal and neuronal cell models expressing N-terminal mHtt fragments, whereas knockdown of ProTα expression in the cells enhanced mHtt-caused cell death. Deletion of the central acidic domain of ProTα abolished not only its interaction with mHtt but also its protective effect on mHtt-caused cytotoxicity. Additionally, overexpression of ProTα inhibited caspase-3 activation but enhanced aggregation of mHtt. Furthermore, when added to cultured cells expressing mHtt, the purified recombinant ProTα protein not only entered the cells but it also significantly suppressed the mHtt-caused cytotoxicity. Taken together, these data suggest that ProTα might be a novel therapeutic target for treating HD and other polyglutamine expansion disorders.