julilili42/papers huggingface dataset:
Metabolically healthy obesity and cardiovascular events: A systematic review and meta-analysis
2015-12-24

Abstract Aims Previous studies have provided inconsistent results about the cardiovascular risks for participants with metabolically healthy obesity (MHO). These uncertainties might partly reflect the lack of a uniform definition of MHO. We conducted a systematic review and meta-analysis to examine whether there is a suitable approach that identifies obese participants who are not at an increased risk of cardiovascular events compared with healthy normal-weight participants. Methods and results Twenty-two prospective studies were eligible for the meta-analysis. Using random-effect models, pooled relative risks (RRs) were calculated for the combined effects of obesity with the presence or absence of metabolic syndrome, insulin resistance, hypertension, diabetes, hyperlipidaemia and any of these metabolic factors. Participants with MHO defined by the absence of metabolic syndrome were at increased risk for cardiovascular events compared with healthy normal-weight participants (pooled RR 1.45, 95% confidence interval (CI) 1.20–1.70), but had lower risks than unhealthy normal-weight (RR 2.07, 95% CI 1.62–2.65) and obese (RR 2.31, 95% CI 1.99–2.69) participants. The risk associated with participants who had MHO was particularly high over the long term. Similar risk estimates were observed when MHO was defined by other approaches. Conclusions None of the approaches clearly identified an obese subgroup not at increased risk of cardiovascular events compared with normal-weight healthy participants. A benign obese phenotype might be defined by strict definitions, but insufficient studies exist to support this. More research is needed to better define MHO.
The Pig PeptideAtlas: A resource for systems biology in animal production and biomedicine
2015-12-24

Biological research of Sus scrofa , the domestic pig, is of immediate relevance for food production sciences, and for developing pig as a model organism for human biomedical research. Publicly available data repositories play a fundamental role for all biological sciences, and protein data repositories are in particular essential for the successful development of new proteomic methods. Cumulative proteome data repositories, including the PeptideAtlas, provide the means for targeted proteomics, system‐wide observations, and cross‐species observational studies, but pigs have so far been underrepresented in existing repositories. We here present a significantly improved build of the Pig PeptideAtlas, which includes pig proteome data from 25 tissues and three body fluid types mapped to 7139 canonical proteins. The content of the Pig PeptideAtlas reflects actively ongoing research within the veterinary proteomics domain, and this article demonstrates how the expression of isoform‐unique peptides can be observed across distinct tissues and body fluids. The Pig PeptideAtlas is a unique resource for use in animal proteome research, particularly biomarker discovery and for preliminary design of SRM assays, which are equally important for progress in research that supports farm animal production and veterinary health, as for developing pig models with relevance to human health research.
Hemocompatibility of styrenic block copolymers for use in prosthetic heart valves
2015-12-24

Certain styrenic thermoplastic block copolymer elastomers can be processed to exhibit anisotropic mechanical properties which may be desirable for imitating biological tissues. The ex-vivo hemocompatibility of four triblock (hard-soft-hard) copolymers with polystyrene hard blocks and polyethylene, polypropylene, polyisoprene, polybutadiene or polyisobutylene soft blocks are tested using the modified Chandler loop method using fresh human blood and direct contact cell proliferation of fibroblasts upon the materials. The hemocompatibility and durability performance of a heparin coating is also evaluated. Measures of platelet and coagulation cascade activation indicate that the test materials are superior to polyester but inferior to expanded polytetrafluoroethylene and bovine pericardium reference materials. Against inflammatory measures the test materials are superior to polyester and bovine pericardium. The addition of a heparin coating results in reduced protein adsorption and ex-vivo hemocompatibility performance superior to all reference materials, in all measures. The tested styrenic thermoplastic block copolymers demonstrate adequate performance for blood contacting applications.
Ritonavir‐Induced Suicidal Death of Human Erythrocytes
2015-12-26

Abstract The antiviral drug ritonavir has been shown to trigger suicidal death or apoptosis of tumour cells and has thus been considered for the treatment of malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca 2+ entry with increase in cytosolic Ca 2+ activity ([Ca 2+ ] i ), oxidative stress and ceramide. The present study explored whether and how ritonavir induces eryptosis. To this end, flow cytometry was employed to estimate cell volume from forward scatter, phosphatidylserine exposure at the cell surface from Annexin‐V binding, [Ca 2+ ] i from Fluo3 fluorescence, abundance of reactive oxygen species ( ROS ) from 2',7'‐dichlorodihydrofluorescein diacetate ( DCFDA ) fluorescence and ceramide abundance utilizing specific antibodies. As a result, a 48‐hr exposure of human erythrocytes to ritonavir significantly increased the percentage of Annexin‐V‐binding cells (≥5 μg/ml), significantly decreased forward scatter (≥5 μg/ml), significantly increased Fluo3 fluorescence (20 μg/ml), slightly, but significantly increased DCFDA fluorescence (20 μg/ml) and slightly, but significantly increased ceramide abundance (20 μg/ml). The effect of ritonavir on Annexin‐V binding was significantly blunted, but not fully abolished by the removal of extracellular Ca 2+ . In conclusion, ritonavir triggers erythrocyte shrinkage and phosphatidylserine translocation at the erythrocyte cell membrane, an effect in part due to the stimulation of Ca 2+ entry, oxidative stress and ceramide.
Complement Factor H and Simian Virus 40 bind the GM1 ganglioside in distinct conformations
2015-12-28

Mammalian cell surfaces are decorated with a variety of glycan chains that orchestrate development and defense and are exploited by pathogens for cellular attachment and entry. While glycosidic linkages are, in principle, flexible, the conformational space that a given glycan can sample is subject to spatial and electrostatic restrictions imposed by its overall chemical structure. Here, we show how the glycan moiety of the GM1 ganglioside, a branched, monosialylated pentasaccharide that serves as a ligand for various proteins, undergoes differential conformational selection in its interactions with different lectins. Using STD NMR and X-ray crystallography, we found that the innate immune regulator complement Factor H (FH) binds a previously not reported GM1 conformation that is not compatible with the GM1-binding sites of other structurally characterized GM1-binding lectins such as the Simian Virus 40 (SV40) capsid. Molecular dynamics simulations of the free glycan in explicit solvent on the 10 μs timescale reveal that the FH-bound conformation nevertheless corresponds to a minimum in the Gibbs free energy plot. In contrast to the GM1 conformation recognized by SV40, the FH-bound GM1 conformation is associated with poor NOE restraints, explaining how it escaped(1)H-(1)H NOE-restrained modeling in the past and highlighting the necessity for ensemble representations of glycan structures.
Investigating Deformylase and Deacylase Activity of Mammalian and Bacterial Sirtuins
2015-12-28

Abstract Lysine acylation constitutes a major group of post‐translational modifications of proteins, and is found in the proteomes of organisms from all kingdoms of life. Sirtuins are considered the main erasers of these modification marks, and thus contribute to acylation‐dependent regulation of enzyme activity, and potentially of protein quality control. We have established a substrate scaffold to enable the analysis of sirtuin activity with a broad range of acyl‐lysine modifications, including hydrophobic fatty acids. Characterization of the deacylase activity of the bacterial SrtN, which is encoded by the yhdZ gene of Bacillus subtilis , showed that this enzyme is capable of removing a broad range of acyl groups. These investigations further showed that SrtN and human SIRT1 are efficient lysine‐deformylases, thereby providing a first clue as to how this nonenzymatic modification might be removed from affected proteins.
Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype
2015-12-29

Abstract Tolerance induction toward the semiallogeneic fetus is crucial to enable a successful pregnancy; its failure is associated with abortion or preterm delivery. Skewing T cell differentiation toward a Th2-dominated phenotype seems to be pivotal in maternal immune adaption, yet underlying mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that mediate T cell suppression and are increased in cord blood of healthy newborns and in peripheral blood of pregnant women. In this study, we demonstrate that granulocytic MDSCs (GR-MDSCs) accumulate in human placenta of healthy pregnancies but are diminished in patients with spontaneous abortions. Placental GR-MDSCs effectively suppressed T cell responses by expression of arginase I and production of reactive oxygen species and were activated at the maternal–fetal interface through interaction with trophoblast cells. Furthermore, GR-MDSCs isolated from placenta polarized CD4+ T cells toward a Th2 cytokine response. These results highlight a potential role of GR-MDSCs in inducing and maintaining maternal–fetal tolerance and suggest them as a promising target for therapeutic manipulation of pregnancy complications.
Selective Visual Attention during Mirror Exposure in Anorexia and Bulimia Nervosa
2015-12-29

The results converge with theoretical models that emphasize the role of information processing in the maintenance of body dissatisfaction. Given the etiological importance of body dissatisfaction in the development of eating disorders, future studies should focus on the modification of the reported patterns.
Targeting TRPM2 Channels Impairs Radiation‐Induced Cell Cycle Arrest and Fosters Cell Death of T Cell Leukemia Cells in a Bcl‐2‐Dependent Manner
2015-12-29

Messenger RNA data of lymphohematopoietic cancer lines suggest a correlation between expression of the cation channel TRPM2 and the antiapoptotic protein Bcl‐2. The latter is overexpressed in various tumor entities and mediates therapy resistance. Here, we analyzed the crosstalk between Bcl‐2 and TRPM2 channels in T cell leukemia cells during oxidative stress as conferred by ionizing radiation (IR). To this end, the effects of TRPM2 inhibition or knock‐down on plasma membrane currents, Ca 2+ signaling, mitochondrial superoxide anion formation, and cell cycle progression were compared between irradiated (0–10 Gy) Bcl‐2‐overexpressing and empty vector‐transfected Jurkat cells. As a result, IR stimulated a TRPM2‐mediated Ca 2+ ‐entry, which was higher in Bcl‐2‐overexpressing than in control cells and which contributed to IR‐induced G 2 /M cell cycle arrest. TRPM2 inhibition induced a release from G 2 /M arrest resulting in cell death. Collectively, this data suggests a pivotal function of TRPM2 in the DNA damage response of T cell leukemia cells. Apoptosis‐resistant Bcl‐2‐overexpressing cells even can afford higher TRPM2 activity without risking a hazardous Ca 2+ ‐overload‐induced mitochondrial superoxide anion formation.
S2k guideline on diagnosis and treatment of atopic dermatitis – short version
2015-12-29

Summary Atopic dermatitis (AD) represents a pruritic, non‐contagious, chronic or chronically relapsing, inflammatory skin disease. The course of the disease may be complicated by bacterial or viral superinfections. The first manifestation of the disease and further flare‐ups are due to genetic predisposition and also to a variety of further trigger factors. The therapy regimen should be adapted to disease symptoms that are actually present and consider individual features of the disease as reported by the patients or their parents. This short version of the German guideline on AD provides an overview of evidence‐based diagnostic and treatment options. All recommendations made here are the result of a consensus of the scientific medical societies, working groups and support groups based on scientific data published to date. Abstracts and details of the studies cited are provided in the long version of this guideline (see: www.awmf.org ).
Hematopoietic Stem and Progenitor Cell Expansion in Contact with Mesenchymal Stromal Cells in a Hanging Drop Model Uncovers Disadvantages of 3D Culture
2015-12-29

Efficient ex vivo expansion of hematopoietic stem cells with a concomitant preservation of stemness and self‐renewal potential is still an unresolved ambition. Increased numbers of methods approaching this issue using three‐dimensional (3D) cultures were reported. Here, we describe a simplified 3D hanging drop model for the coculture of cord blood‐derived CD34 + hematopoietic stem and progenitor cells (HSPCs) with bone marrow‐derived mesenchymal stromal cells (MSCs). When seeded as a mixed cell suspension, MSCs segregated into tight spheroids. Despite the high expression of niche‐specific extracellular matrix components by spheroid‐forming MSCs, HSPCs did not migrate into the spheroids in the initial phase of coculture, indicating strong homotypic interactions of MSCs. After one week, however, HSPC attachment increased considerably, leading to spheroid collapse as demonstrated by electron microscopy and immunofluorescence staining. In terms of HSPC proliferation, the conventional 2D coculture system was superior to the hanging drop model. Furthermore, expansion of primitive hematopoietic progenitors was more favored in 2D than in 3D, as analyzed in colony‐forming assays. Conclusively, our data demonstrate that MSCs, when arranged with a spread (monolayer) shape, exhibit better HSPC supportive qualities than spheroid‐forming MSCs. Therefore, 3D systems are not necessarily superior to traditional 2D culture in this regard.
Auxin responsiveness of the MONOPTEROS‐BODENLOS module in primary root initiation critically depends on the nuclear import kinetics of the Aux/IAA inhibitor BODENLOS
2015-12-29

Summary Primary root formation in early embryogenesis of Arabidopsis thaliana is initiated with the specification of a single cell called hypophysis. This initial step requires the auxin‐dependent release of the transcription factor MONOPTEROS ( MP , also known as ARF 5) from its inhibition by the Aux/ IAA protein BODENLOS ( BDL , also known as IAA 12). Auxin‐insensitive bdl mutant embryos and mp loss‐of‐function embryos fail to specify the hypophysis, giving rise to rootless seedlings. A suppressor screen of rootless bdl mutant seedlings yielded a mutation in the nuclear import receptor IMPORTIN ‐ ALPHA 6 ( IMP α 6 ) that promoted primary root formation through rescue of the embryonic hypophysis defects, without causing additional phenotypic changes. Aux/ IAA proteins are continually synthesized and degraded, which is essential for rapid transcriptional responses to changing auxin concentrations. Nuclear translocation of bdl:3× GFP was slowed down in imp α 6 mutants as measured by fluorescence recovery after photobleaching ( FRAP ) analysis, which correlated with the reduced inhibition of MP by bdl in transient expression assays in imp α 6 knock‐down protoplasts. The MP – BDL module acts like an auxin‐triggered genetic switch because MP activates its own expression as well as the expression of its inhibitor BDL . Using an established simulation model, we determined that the reduced nuclear translocation rate of BDL in imp α 6 mutant embryos rendered the auxin‐triggered switch unstable, impairing the fast response to changes in auxin concentration. Our results suggest that the instability of the inhibitor BDL necessitates a fast nuclear uptake in order to reach the critical threshold level required for auxin responsiveness of the MP – BDL module in primary root initiation.
Immunotherapy of melanoma: efficacy and mode of action
2015-12-29

Summary Forty years of research have brought about the development of antibodies that induce effective antitumor immune responses through sustained activation of the immune system. These “immune checkpoint inhibitors” are directed against immune inhibitory molecules, such as cytotoxic T lymphocyte antigen 4 (CTLA‐4), programmed death 1 (PD‐1) or programmed death ligand 1 (PD‐L1). Disruption of the PD‐1/PD‐L1 interaction improves the intermediate‐term prognosis even in patients with advanced stage IV melanoma. One and a halfyears after treatment initiation, 30–60 % of these patients are still alive. While cancer immunotherapies usually do not eradicate metastases completely, they do cause a regression by 20–80 %. It is well established that the immune system is able to kill tumor cells, and this has also been demonstrated for immunotherapies. Preclinical data, however, has shown that anti‐cancer immunity is not limited to killing cancer cells. Thus, through interferon gamma and tumor necrosis factor, the immune system is able to induce stable tumor growth arrest, referred to as senescence. Ensuring patient survival by long‐term stabilization of metastatic growth will therefore become a central goal of antitumor immunotherapies. This therapeutic approach is effective in melanoma and non‐small‐cell lung cancer. Once immunotherapies also have an indication for common cancer types, drug prices will have to drop considerably in order to be able to keep them available to those dependent on such therapies.
Delayed immediate‐type hypersensitivity to red meat and innards: current insights into a novel disease entity
2015-12-29

Summary The development of component‐resolved diagnostics instead of whole extracts has brought about major advances in recent years. Particularly remarkable has been the identification of new disease entities based on the detection of IgE antibodies against specific individual components. In this context, delayed immediate‐type hypersensitivity to red meat and innards plays a key role. This disorder is more common in German‐speaking countries and likely still underdiagnosed. Affected individuals exhibit delayed type I reactions following the consumption of red meat or innards (responses to the latter are more rapid). All patients have IgE antibodies against the oligosaccharide galactose‐α‐1,3‐galactose – alpha‐gal. Those affected also have to avoid alpha‐gal‐containing drugs such as cetuximab or gelatin‐containing colloidal solutions. Also referred to as alpha‐gal syndrome, this condition is unique in that it is characterized by type I hypersensitivity to a sugar instead of a protein. Given that many patients have a history of recurrent episodes of acute urticaria or angioedema, dermatologists should be familiar with the alpha‐gal syndrome.
Potential of Diffusion Tensor Imaging and Relaxometry for the Detection of Specific Pathological Alterations in Parkinson's Disease (PD)
2015-12-29

The purpose of the present study was to evaluate the potential of multimodal MR imaging including mean diffusivity (MD), fractional anisotropy (FA), relaxation rates R2 and R2* to detect disease specific alterations in Parkinson's Disease (PD). We enrolled 82 PD patients (PD-all) with varying disease durations (≤5 years: PD≤5, n = 43; >5 years: PD>5, n = 39) and 38 matched healthy controls (HC), receiving diffusion tensor imaging as well as R2 and R2* relaxometry calculated from multi-echo T2*-weighted and dual-echo TSE imaging, respectively. ROIs were drawn to delineate caudate nucleus (CN), putamen (PU), globus pallidus (GP) and substantia nigra (SN) on the co-registered maps. The SN was divided in 3 descending levels (SL 1-3). The most significant parameters were used for a flexible discrimination analysis (FDA) in a training collective consisting of 25 randomized subjects from each group in order to predict the classification of remaining subjects. PD-all showed significant increases in MD, R2 and R2* within SN and its subregions as well as in MD and R2* within different basal ganglia regions. Compared to the HC group, the PD≤5 and the PD>5 group showed significant MD increases within the SN and its lower two subregions, while the PD≤5 group exhibited significant increases in R2 and R2* within SN and its subregions, and tended to elevation within the basal ganglia. The PD>5 group had significantly increased MD in PU and GP, whereas the PD≤5 group presented normal MD within the basal ganglia. FDA achieved right classification in 84% of study participants. Micro-structural damage affects primarily the SN of PD patients and in later disease stages the basal ganglia. Iron contents of PU, GP and SN are increased at early disease stages of PD.
Substantia Nigra Hyperechogenicity
2015-12-29

Objectives Substantia nigra hyperechogenicity is a promising biomarker for Parkinson disease (PD). Substantia nigra hyperechogenicity has previously been established as a useful diagnostic criterion in several European and Asian patient cohorts. However, diagnostic cutoff values for substantia nigra hyperechogenicity remain unknown for most patient populations. This study validated the diagnostic accuracy of substantia nigra hyperechogenicity in a large cohort of patients with PD in Estonia. Methods The study included 300 patients with PD from Estonia, representing 10% of the national PD patient population, and 200 healthy control participants. To define the optimal cutoff value in the PD cohort, data from a single assessment versus repetitive assessments by transcranial sonography were compared. With the use of 3 repetitive assessments, the diagnostic accuracy of the data was measured. In addition, calculations for percentile values were used to define substantia nigra hyperechogenicity among controls. Results Our data showed that the multiassessment approach yielded higher diagnostic accuracy than a single assessment ( P = .021). The highest diagnostic accuracy was achieved by using the measurement mean to define substantia nigra hyperechogenicity, which was 0.23 cm 2 (sensitivity, 88.7%; specificity, 92.2%), whereas single measurements detected PD with higher sensitivity (sensitivity, 93.2%; specificity, 85.1%). No significant difference was found between mean and median measurements ( P = .18). Conclusions This study indicates the diagnostic merit of transcranial sonography in PD diagnosis in an additional population and demonstrates that transcranial sonography of the substantia nigra is a relevant and useful diagnostic tool for patients with PD.