julilili42/papers huggingface dataset:
Acute regulation of metabolic genes and insulin receptor substrates in the liver of mice by one single bout of treadmill exercise
2008-11-11

Acute exercise performance represents a major metabolic challenge for the skeletal muscle, but also for the liver as the most important source of energy. However the molecular adaptation of the liver to one single bout of exercise is largely unknown. C57BL/6 mice performed a 60 min treadmill run at high aerobic intensity. Liver, soleus and white gastrocnemius muscle were removed immediately after exercise. The single bout of exercise resulted in a very rapid and pronounced induction of hepatic metabolic enzymes and regulators of metabolism or transcription: glucose‐6‐phosphatase (G6Pase; 3‐fold), pyruvate dehydrogenase kinase‐4 (PDK4; 4.8‐fold), angiopoietin‐like 4 (2.1‐fold), insulin receptor substrate (IRS)‐2 (5.1‐fold), peroxisome proliferator activated receptor‐γ coactivator 1α (PGC‐1α; 3‐fold). In soleus and white gastrocnemius muscle the up‐regulation of IRS‐2 and PDK4 was less pronounced compared with the liver and no significant induction of PGC‐1α could be detected at this early time point. Activation of AMPK was found in both liver and white gastrocnemius muscle as phosphorylation of Thr‐172. The induction of endogenous insulin secretion by a glucose load directly after the exercise bout resulted in a significantly higher PKB/Akt phosphorylation in the liver of exercised mice. The markedly enhanced IRS‐2 protein amount, and presumably reduced serine/threonine phosphorylation of the IRS proteins induced by the acute exercise could be responsible for this enhanced action of insulin. In conclusion, acute exercise induced a rapid and pronounced transcriptional adaptation in the liver, and regulated hepatic IRS proteins leading to improved cellular insulin signal transduction.
Inhibition of growth of Shiga toxin-producingEscherichia coliby nonpathogenicEscherichia coli
2008-11-11

During routine quality control testing of diagnostic methods for Shiga toxin-producing Escherichia coli (STEC) using stool samples spiked with STEC, it was observed that the Shiga toxin could not be detected in 32 out of 82 samples tested. Strains of E. coli isolated from such stool samples were shown to be responsible for this inhibition. One particular isolate, named E. coli 1307, was intensively studied because of its highly effective inhibitory effect; this strain significantly reduced growth and Shiga toxin levels in coculture of several STEC strains regardless of serovar or Shiga toxin type. The probiotic E. coli Nissle 1917 inhibited growth and reduced Shiga toxin levels in STEC cultures to an extent similar to E. coli 1307, but commensal E. coli strains and several other known probiotic bacteria (enterococci, Bacillus sp., Lactobacillus acidophilus) showed no, or only small, inhibitory effects. Escherichia coli 1307 lacks obvious fitness factors, such as aerobactin, yersiniabactin, microcins and a polysaccharide capsule, that are considered to promote the growth of pathogenic bacteria. We therefore propose strain E. coli 1307 as a candidate probiotic for use in the prevention and treatment of infections caused by STEC.
Ultrafast Whole-Body MR Angiography with Two-dimensional Parallel Imaging at 3.0 T: Feasibility Study
2008-11-11

The study was approved by the local ethics committee, and informed consent was provided by all participants prior to the examination. The aim of the study was to assess the feasibility of whole-body three-dimensional (3D) contrast material-enhanced magnetic resonance (MR) angiography with parallel imaging in the phase- and section-encoding directions (ie, integrated parallel acquisition technique [iPAT(2); Siemens, Erlangen, Germany]) for all anatomic imaging stations in combination with a single injection of contrast material. Whole-body contrast-enhanced MR angiography was performed in 23 patients at 3.0 T. Images were evaluated by two independent observers for quality on a four-point scale (where a score of 1 indicated poor image quality and a score of 4, excellent image quality); signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) were calculated for representative vessel regions in each station. Mean image quality scores were 3.13 +/- 1.15 (standard deviation) and 3.17 +/- 1.14 for observers 1 and 2, respectively (kappa = 0.81). Signal intensity measurements revealed mean SNR values between 36.2 +/- 8.0 and 56.2 +/- 17.7 and mean CNR values between 29.0 +/- 7.4 and 48.2 +/- 15.7. The data suggest that contrast-enhanced MR angiography with iPAT(2) is feasible for whole-body applications and allows acquisition of 3D data sets with adequate spatial resolution within short measurement times, facilitating a single injection of contrast material.
SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention – the TULIP Study
2008-11-12

SIRT1 plays a role for the individual lifestyle intervention response, possibly owing to decreased basal energy expenditure and a lower lipid-oxidation rate in rs12413112 X/A allele carriers. SIRT1 genetic variants may, therefore, represent a relevant determinant for the response rate of individuals undergoing caloric restriction and increased physical activity.
Spontaneous Virtual Networks: On the Road Towards the Internet´s Next GenerationSpontane Virtuelle Netze: Auf dem Weg zur nächsten Generation des Internets
2008-11-12

Abstract Novel Internet applications demand global availability of complex services that can adapt dynamically to application requirements. At the same time, pervasive Internet usage and heterogeneous access technologies impose new challenges for service deployment. We present Spontaneous Virtual Networks (SpoVNet), a methodology that enables easy development of new services with transparent support for mobility, multi-homing, and heterogeneous environments. This article presents the overlay-based architecture of SpoVNet that supports the spontaneous deployment of new services as well as a seamless transition towards future networks. SpoVNet ́s architecture offers support for the underlay aware adaptation of overlays by the use of cross-layer information. In the context of two exemplary services like a group communication service and an event service as well as two demanding applications – a realtime online game and a video streaming application – we illustrate how SpoVNet is of value in establishing services and applications for the Next Generation Internet.
4-(4-Chlorophenyl)-1-(2-hydroxy-2,2-diphenylacetyl)thiosemicarbazide
2008-11-12

The asymmetric unit of the title compound, C(21)H(18)ClN(3)O(2)S, contains two mol-ecules in which the bond lengths and angles are almost identical. Intra-molecular N-H⋯S hydrogen bonds result in the formation of two five-membered rings. In the crystal structure, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers; these dimers are linked via inter-molecular O-H⋯S hydrogen bonds, leading to infinite corrugated layers parallel to the bc plane through R(2) (2)(16) ring motifs.
Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart
2008-11-13

Our conditional serum response factor (SRF) knockout, Srf Cko , in the heart-forming region blocked the appearance of rhythmic beating myocytes, one of the earliest cardiac defects caused by the ablation of a cardiac-enriched transcription factor. The appearance of Hand1 and Smyd1, transcription and chromatin remodeling factors; Acta1, Acta2, Myl3, and Myom1, myofibril proteins; and calcium-activated potassium-channel gene activity (KCNMB1), the channel protein, were powerfully attenuated in the Srf CKO mutant hearts. A requisite role for combinatorial cofactor interactions with SRF, as a major determinant for regulating the appearance of organized sarcomeres, was shown by viral rescue of SRF-null ES cells with SRF point mutants that block cofactor interactions. In the absence of SRF genes associated with biomineralization, GATA-6, bone morphogenetic protein 4 (BMP4), and periostin were strongly up-regulated, coinciding with the down regulation of many SRF dependent microRNA, including miR1, which exerted robust silencer activity over the induction of GATA-6 leading to the down regulation of BMP4 and periostin.
Understanding the emotional expression of verbal interjections: a functional MRI study
2008-11-13

Using functional magnetic resonance imaging, the distribution of hemodynamic brain responses bound to the perceptual processing of interjections, that is 'exclamations inserted into an utterance without grammatical connection to it', was determined (vs. a silent baseline condition). These utterances convey information about a speaker's affective/emotional state by their 'tone' (emotional prosody) and/or their lexical content. Both communicative aspects of interjections elicited significant bilateral blood-oxygen-level-dependent signal changes within superior temporal cortex. In addition, affective-prosodic cues yielded hemodynamic activation of the posterior insula as well as cortical/subcortical structures engaged in the control of innate emotional behavior. These observations corroborate the suggestion that interjections might trace back to proto-speech vocalizations of an early stage of language evolution.
Light, melatonin and cancer: current results and future perspectives 1
2008-11-13

Click to increase image sizeClick to decrease image size Notes 1. This review is dedicated to Dr Vera Lapin who worked at the Vienna Cancer Research Institute in the 1970s, rediscovered the pioneering work of Bergmann, Engel and Hofstätter on the role of the pineal gland and malignancy (for review see Lapin 1976 Lapin, V. 1976. Pineal gland and malignancy. Österreich Zeitschr Onkologie., 3(3): 51–59. [PubMed] , [Google Scholar]), and herself performed outstanding experiments in this field. She encouraged us as young students (CB and HB) to take up this topic and became our “scientific mother”. She died on 25 August 2007 and we will always remember her with gratitude and admiration.
Ion Channels Modulating Mouse Dendritic Cell Functions
2008-11-15

Abstract Ca2+-mediated signal transduction pathways play a central regulatory role in dendritic cell (DC) responses to diverse Ags. However, the mechanisms leading to increased [Ca2+]i upon DC activation remained ill-defined. In the present study, LPS treatment (100 ng/ml) of mouse DCs resulted in a rapid increase in [Ca2+]i, which was due to Ca2+ release from intracellular stores and influx of extracellular Ca2+ across the cell membrane. In whole-cell voltage-clamp experiments, LPS-induced currents exhibited properties similar to the currents through the Ca2+ release-activated Ca2+ channels (CRAC). These currents were highly selective for Ca2+, exhibited a prominent inward rectification of the current-voltage relationship, and showed an anomalous mole fraction and a fast Ca2+-dependent inactivation. In addition, the LPS-induced increase of [Ca2+]i was sensitive to margatoxin and ICAGEN-4, both inhibitors of voltage-gated K+ (Kv) channels Kv1.3 and Kv1.5, respectively. MHC class II expression, CCL21-dependent migration, and TNF-α and IL-6 production decreased, whereas phagocytic capacity increased in LPS-stimulated DCs in the presence of both Kv channel inhibitors as well as the ICRAC inhibitor SKF-96365. Taken together, our results demonstrate that Ca2+ influx in LPS-stimulated DCs occurs via Ca2+ release-activated Ca2+ channels, is sensitive to Kv channel activity, and is in turn critically important for DC maturation and functions.
Dose-Intensified Combined Modality Treatment with 2 Cycles of BEACOPP Escalated Followed by 2 Cycles of ABVD and Involved Field Radiotherapy (IF-RT) Is Superior to 4 Cycles of ABVD and IFRT in Patients with Early Unfavourable Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Study Group (GHSG) HD14 Trial
2008-11-16

Abstract Purpose: Combined modality treatment consisting of 4 cycles of chemotherapy and IF-RT is the standard treatment for early unfavourable HL. Overall survival (OS) and freedom from treatment failure (FFTF) in this group of patients was 91% and 83%, respectively, at 5 years in our prior HD8 study. Thus, the rationale for HD14 was to improve on these results by increasing dose intensity using BEACOPP escalated. Methods: Between January 2003 and January 2007, 1.216 patients aged 16–60 with untreated early unfavourable stage HL (CS I, IIA with one of the following risk factors: large mediastinal mass (a), extranodal disease (b), elevated ESR (c), or ≥ 3 nodal areas (d); IIB with risk factors c and d) were randomized to either 4 cycles of ABVD (arm A) or 2x BEACOPP escalated followed by 2x ABVD (arm B). All patients received 30Gy IF-RT after chemotherapy. Primary objective was the improvement of the FFTF. Here we present the results of the predefined 3rd interim analysis within the prespecified group sequential test design. Results: Of the 1.216 patients included, 1.010 were evaluable for this analysis. Patient characteristics were well balanced between both arms. At 3 years, the FFTF for arm A is 90% (95% CI: 87%–93%), and for arm B 96% (95% CI: 94%–98%). Since the observed inverse normal test statistic exceeds the critical level, the null hypothesis of equal FFTF in each arm can already be rejected. The improved FFTF is mainly due to differences in progression and early relapses (arm A 5.9% versus arm B 1.8%). Protocol adherence for chemotherapy was high and not different in both arms (arm A 98.8%, am B 97.3%). Though the chemotherapy-intensity was higher in the experimental arm, safety was comparable to the standard treatment. Secondary neoplasias occurred in 8 patients in each arm so far. Conclusion: Based on the significantly superior FFTF of the intensified therapy (2x BEACOPP escalated + 2x ABVD + IF-RT) compared to the prior standard (4x ABVD + IF-RT), this more aggressive treatment strategy will become the new standard for early unfavourable HL patients within the GHSG. Whether the improved FFTF translates into an improved overall survival must be awaited. Future strategies should aim at identification of those patient subgroups that profit most from this approach.
NK Cell Anti-Tumor Reactivity Is Impaired by Platelet-Derived TGF-B through NKG2D Downregulation
2008-11-16

Abstract NK cells can recognize and eliminate malignant cells thereby preventing both local tumor progression and metastatic spread. Besides by the direct interaction with their target cells, NK cell activity is influenced by the interplay with other hematopoietic cells influencing the activity of both involved cell types. Recently, we and others demonstrated that thrombocytopenia inhibits metastasis in mice, which is dependent on the presence of NK cells as shown by NK cell depletion experiments (Jin et al., Nat Med2006, 12: 557; Nieswandt et al., Cancer Res1999, 59: 1295). These data suggest that thrombocytopenia indirectly inhibits tumor dissemination by allowing NK cells to exert their anti-tumor effector functions. However, yet nothing is known regarding the molecular mechanisms underlying platelet-NK cell interaction, especially in humans. Here we report that human platelets express high levels of MHC class I, and incubation of MHC class I-negative tumor cells with platelets induced formation of tumor cell-platelet aggregates resulting in tumor MHC class I “pseudoexpression” which can inhibit NK cell reactivity via KIR triggering. Furthermore, tumor cell-induced platelet aggregation, alike stimulation with classical platelet agonists such as thrombin or collagen, resulted in secretion of platelet-derived soluble factors (releasate) containing, among others, high levels of the immunoregulatory cytokine TGF-b. Presence of releasate in cocultures of NK cells and tumor target cells was found to mediate a substantial inhibition of NK cell cytotoxicity and IFN-g production. Of note, platelet releasate caused a marked downregulation of the activating immunoreceptor NKG2D expressed on NK cells, which was partially restored by a neutralizing TGF-b antibody. Confirming the functional relevance of this finding, neutralization of TGF-b in platelet releasate by the same antibody also partially restored both the impaired NK cell cytotoxicity and IFN-g production in cocultures with tumor cells. Taken together, our data demonstrate that platelets may substantially influence NK cell anti-tumor reactivity by various mechanisms including inhibition of NKG2D-mediated NK cell immunosurveillance. Further elucidation of platelet ability to confer expression of immunregulatory surface molecules to tumor cells and the various soluble factors carrying NK cell-modulatory activity may reveal novel targets to prevent tumor dissemination.
A second generation synthesis of the cruentaren A core structure based on oxetane and oxirane opening reactions
2008-11-16

A second generation synthesis of the core structure of the macrolactone cruentaren A, a potent F-ATPase inhibitor, involves the highly functionalized benzoic acid 36 and reaction of an aryl lithium intermediate with the terminal epoxide 30.A methyl benzyl ether in the aryl bromide served as a surrogate for a carboxyl function.Epoxide 30 originated from the aldol product 24.The alkyne of 30 was introduced via opening of an oxetane ring.
Functional Characterization of Signaling Events Underlying Immunostimulatory and Immunosuppressive Activity of Macrophages.
2008-11-16

Abstract Macrophages (Mo) play an important role in combating infectious pathogens and regulating adaptive immune responses. Their reactivity is, among others, guided by pattern recognition receptors including Toll like receptor 4 (TLR4), which recognizes bacterial lipopolysaccharide (LPS). After stimulation, TLR4 can associate with different adaptor proteins like e.g. MyD88 or TRIF leading to the activation of signaling molecules like MAPK or NF-κB. However, stimulation with LPS may result in equally impressive immunostimulatory and immunosuppressive Mo responses. The signaling events responsible for this diametrical behavior of different Mo subsets are yet not fully understood. To study the effects of LPS on Mo we differentiated monocytes of healthy donors with GM-CSF and M-CSF into pro-inflammatory type 1 (Mo1) or anti-inflammatory type 2 (Mo2) subsets, respectively. As expected, upon LPS stimulation the pro-inflammatory Mo1 secreted low levels of the immunosuppressive cytokine IL-10 and high levels of IL-12, while the anti-inflammatory Mo2 produced neglectable amounts of IL-12 but high levels of IL-10. To elucidate the underlying molecular mechanisms we performed gene array analyses with Mo1 compared to Mo2 from three independent donors. Interestingly, among over 50 genes involved in TLR4 signaling, only TLR4 itself and its adaptor protein MyD88 were found to be differentially regulated: Within the immunosuppressive Mo2 subset, MyD88 was significantly downregulated, while a significant upregulation of TLR4 was observed compared to the immunostimulatory Mo1 subset. The differential expression pattern were further confirmed on protein level by western blot. Since TLR4 stimulation leads to MyD88-dependent activation of the MAPK JNK, we investigated whether JNK was differentially involved in cytokine production of Mo1 and Mo2. Addition of a specific JNK inhibitor (SB600125) concentration dependently reduced TLR4-induced IL-10 but enhanced IL-12 production in Mo1, pointing to an immunoinhibitory role of JNK in Mo1. In contrast, inhibition of JNK did not alter the secreted levels of IL-12 or IL-10 in Mo2, indicating that rather MyD88-independent pathways are responsible for the anti-inflammatory behavior of Mo2. In conclusion, our data suggest that the opposite regulation of the adaptor molecule MyD88 in pro- and anti-inflammatory Mo subsets is responsible for the fact that a single, non-polymorphic receptor like TLR4 can mediate both pro- and anti-inflammatory immune responses in Mo.
Improved Outcome for Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with Poor Risk Cytogenetics – Result from An Analysis on 172 Patients Receiving FLAMSA-RIC Conditioning for Allogeneic Stem Cell Transplantatioin (SCT).
2008-11-16

Abstract To improve the results of allogeneic SCT for high-risk AML and MDS, the FLAMSA-RIC conditioning regimen for allogeneic SCT combines cytoreductive chemotherapy (fludarabine, HD AraC, amsacrine), followed three days later by reduced intensity conditioning (4Gy TBI/EDX). Since in particular patients with an unfavorable karyotype seemed to benefit from this approach (Schmid et al., JCO, 2005), we analysed the outcome of 172 patients with poor risk cytogenetics according to NCCN criteria, who had been allografted following FLAMSA-RIC conditioning in 11 European centres between 1999 and 2008. Median time from diagnosis to transplantation was 5 months. Donors were matched siblings, matched unrelated, or mismatched unrelated donors in 34%, 47%, and 19%. Patients suffered from progressive MDS (10%), de novo AML (47.5%), or secondary AML (43.5%). SCT was performed upfront, after primary induction failure, in CR1 and in relapsed disease in 17%, 33%, 22% and 28% of patients, respectively. Median patient age was 53 (18–71) years. 95 patients (56%) had a complex aberrant karyotype, 55 and 65 had abnormalities of chromosome 5 (−5/5q-) and 7 (−7/7q-), respectively. After a median follow up of 20 months, overall survival (OS) at 2 and 4 years was 46.4% and 40.5%, the respective leukemia-free survival was 37.7% and 32.0%. Causes of death were leukemia in 30%, and non-relapse mortality in 21%. Encouraging results were observed in patients with chromosome 7 aberrations or with a complex karyotype leukemia (4y OS=49.3% and 40.3%). In contrast, results were inferior in patients with chromosome 5 aberrations (4y OS=30%), mainly due to an increased rate of leukemia-associated death (p=.008). Patiens with MDS, who received allogeneic SCT as first line treatment, achieved a 4y OS of 80% despite unfavorable cytogenetics. Unlike, patients with secondary AML after MDS had an inferior outcome (4y OS=28%, p=.018). In a Cox regression model, a stage of remission at transplantation, a 8/8 or 10/10 matched family or unrelated donor, and lack of monosomy 5 or deletion 5q were associated with superior OS (p=.025, .05, and .05). In conclusion, allogeneic SCT following the FLAMSA-RIC regimen is a highly effective treatment for MDS and AML with unfavorable karyotype, comparing favourably with published data. In MDS, SCT should be performed before transformation into sAML. Long term remission is achieved in a substantial percentage of patients with complex karyotype disease and aberrations of chromosome 7. Aberrations of chromosome 5 may require alternative or additive strategies.