julilili42/papers huggingface dataset:
Large‐scale high‐resolution pluvial flood hazard mapping using the raster‐based hydrodynamic two‐dimensional model FloodAreaHPC
2016-12-05

Two‐dimensional ( 2D ) hydraulic models are widely used as tools for flood hazard mapping and also to support flood risk management. Yet, only few models are capable of using high‐resolution terrain data (raster‐based Digital Terrain Model with 1 m spatial resolution) on a large scale (hundreds of square kilometres and more). Central to the model approach presented in this article is the raster‐based 2D model High Performance Computing version of FloodArea ( FloodAreaHPC ), which allows for multicore processing, thus being able to model large areas without having to make compromises regarding spatial details. The model has been applied for inundation modelling of rivers, dike breaks, and heavy rainfall runoff (pluvial flooding). For the latter case, the model is coupled with a hydrologic preprocessor data base which provides spatially and temporally variable runoff coefficients based on land use, soil, and slope. The case study presented in this study has an area of 144 km 2 and is located close to Dortmund in Western Germany. The modelling results of two heavy rainfall scenarios, presented in analogue and digital flood hazard maps, were used in a Public Relations (PR) campaign to inform the public about pluvial flood risk and possible mitigation measures.
New targeted therapies for malignant lymphoma based on molecular heterogeneity
2016-12-05

Owing to tremendous advances in the understanding of mechanisms involved in the pathogenesis of malignant tumors an emerging field of novel targeted drugs has evolved within the last decade. This is of particular interest also for malignant lymphomas, constituting a heterogeneous tumor category with substantial variation in clinical outcome, ranging from indolent forms that do not require treatment over years to aggressive cases for which an immediate treatment is mandatory. The elucidation of different molecular strategies adopted by malignant cells has led to a profound profiling of tumor-specific features and consequently resulted in the development of new targeted therapies. Areas covered: A review of currently tested tailored approaches, in particular in B-cell lymphomas (B-NHL), ranging from monoclonal antibodies to inhibition of intrinsic and extrinsic effector molecules. These approaches are currently tested in several subtypes of B-NHL both in preclinical studies and in clinical trials and are summarized within this review. Expert commentary: Considering how quickly basic scientific discoveries could meanwhile be transferred to clinical trials and approvals, future perspectives for novel tailored therapeutic strategies are promising.
An analysis of the role of follicular lymphoma-associated fibroblasts to promote tumor cell viability following drug-induced apoptosis
2016-12-06

Treatment response of follicular lymphomas (FL) is highly variable. We, therefore, investigated the role of FL cancer-associated fibroblasts (CAFs) on tumor cell viability, in particular in response to treatment with cytotoxic drugs. Stromal cells outgrown from FL patients were characterized and pure CAF populations were co-cultivated with FL cells. To analyze fibroblast-mediated effects, cells in co-culture were treated with ABT-737 and Bortezomib. The adherent cell population was positive for all fibroblastic markers tested and showed increased mRNA-expression of the activation marker FAP. No effect on FL cell viability was noted when co-cultivating them with CAFs. However, stromal cells protected tumor cells from apoptosis in response to cytotoxic treatment. This might be explained by mRNA-induction of ABCC1 and ABCG2 and up-regulation of BCL2L1 in FL cells. Our finding of protective mechanisms mediated by CAFs is of pivotal impact for further studies of cytotoxic agents in FL.
Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS–EMG and TMS–EEG Phase I Study
2016-12-07

Alpha-5 gamma-aminobutyric acid type A receptors (α5-GABAARs) are located extrasynaptically, regulate neuronal excitability through tonic inhibition, and are fundamentally important for processes such as plasticity and learning. For example, pharmacological blockade of α5-GABAAR in mice with ischemic stroke improved recovery of function by normalizing exaggerated perilesional α5-GABAAR-dependent tonic inhibition. S44819 is a novel competitive selective antagonist of the α5-GABAAR at the GABA-binding site. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. Here, we used transcranial magnetic stimulation (TMS) to test the effects of a single oral dose of 50 and 100 mg of S44819 on electromyographic (EMG) and electroencephalographic (EEG) measures of cortical excitability in 18 healthy young adults in a randomized, double-blinded, placebo-controlled, crossover phase I study. A dose of 100 mg, but not 50 mg, of S44819 decreased active motor threshold, the intensity needed to produce a motor evoked potential of 0.5 mV, and the amplitude of the N45, a GABAAergic component of the TMS-evoked EEG response. The peak serum concentration of 100 mg S44819 correlated directly with the decrease in N45 amplitude. Short-interval intracortical inhibition, a TMS–EMG measure of synaptic GABAAergic inhibition, and other components of the TMS-evoked EEG response remained unaffected. These findings provide first time evidence that the specific α5-GABAAR antagonist S44819 reached human cortex to impose an increase in cortical excitability. These data warrant further development of S44819 in a human clinical trial to test its efficacy in enhancing recovery of function after ischemic stroke. SIGNIFICANCE STATEMENT The extrasynaptic α-5 gamma-aminobutyric acid type A receptor (α5-GABAAR) regulates neuronal excitability through tonic inhibition in the mammalian brain. Tonic inhibition is important for many fundamental processes such as plasticity and learning. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. This study demonstrates that S44819, a selective α5-GABAAR antagonist, increases cortical excitability in healthy human subjects, as indicated by specific markers of transcranial magnetic stimulation-induced muscle and brain responses measured by electromyography and electroencephalography. Our findings imply that tonic inhibition in human cortex can be modified effectively and that this modification can be quantified with noninvasive brain stimulation methods. The actions of S44819 may be suitable to improve plasticity and learning.
CD4:8 Ratio Above 5 Is Associated With All-Cause Mortality in CMV-Seronegative Very Old Women: Results From the BELFRAIL Study
2016-12-07

The occurrence and general applicability of the CD4:8 ratio as a surrogate predictor of mortality among the oldest old have only been tested in a few longitudinal studies. Here, the predictive value of CD4:8 ratio for mortality with respect to the role of cytomegalovirus (CMV) infection was investigated. Using polychromatic flow cytometry, the CD4:8 ratio and T-cell subsets of 235 individuals aged 81.5 years or older were analyzed, and mortality data were collected after a mean period of 3.3 years. The hazard for all-cause mortality adjusted for age, comorbidity, and CMV serostatus increased 1.53-fold (95% CI: 0.94-2.51) with every increment in the CD4:8 ratio from R < 1, to 1 < R < 5 and R > 5 among women. A negative hazard ratio of 0.50 for CMV seropositivity in women indicated an apparently protective effect of this virus. In men, no associations with survival were observed. No mediation effect could be found for the CD4:8 ratio with respect to the relationship between CMV serostatus and mortality. Very elderly CMV-negative women with a R > 5 experienced the highest mortality rates, independent of age and comorbidity. The associations of CMV serostatus and CD4:8 ratio with mortality seem to reflect distinct pathways mediating life span in very old humans.
Structural Insights into Reovirus σ1 Interactions with Two Neutralizing Antibodies
2016-12-08

ABSTRACT Reovirus attachment protein σ1 engages glycan receptors and junctional adhesion molecule-A (JAM-A) and is thought to undergo a conformational change during the proteolytic disassembly of virions to infectious subvirion particles (ISVPs) that accompanies cell entry. The σ1 protein is also the primary target of neutralizing antibodies. Here, we present a structural and functional characterization of two neutralizing antibodies that target σ1 of serotype 1 (T1) and serotype 3 (T3) reoviruses. The crystal structures revealed that each antibody engages its cognate σ1 protein within the head domain via epitopes distinct from the JAM-A-binding site. Surface plasmon resonance and cell-binding assays indicated that both antibodies likely interfere with JAM-A engagement by steric hindrance. To define the interplay between the carbohydrate receptor and antibody binding, we conducted hemagglutination inhibition assays using virions and ISVPs. The glycan-binding site of T1 σ1 is located in the head domain and is partly occluded by the bound Fab in the crystal structure. The T1-specific antibody inhibited hemagglutination by virions and ISVPs, probably via direct interference with glycan engagement. In contrast to T1 σ1, the carbohydrate-binding site of T3 σ1 is located in the tail domain, distal to the antibody epitope. The T3-specific antibody inhibited hemagglutination by T3 virions but not ISVPs, indicating that the antibody- and glycan-binding sites in σ1 are in closer spatial proximity on virions than on ISVPs. Our results provide direct evidence for a structural rearrangement of σ1 during virion-to-ISVP conversion and contribute new information about the mechanisms of antibody-mediated neutralization of reovirus. IMPORTANCE Virus attachment proteins mediate binding to host cell receptors, serve critical functions in cell and tissue tropism, and are often targeted by the neutralizing antibody response. The structural investigation of antibody-antigen complexes can provide valuable information for understanding the molecular basis of virus neutralization. Studies with enveloped viruses, such as HIV and influenza virus, have helped to define sites of vulnerability and guide vaccination strategies. By comparison, less is known about antibody binding to nonenveloped viruses. Here, we structurally investigated two neutralizing antibodies that bind the attachment protein σ1 of reovirus. Furthermore, we characterized the neutralization efficiency, the binding affinity for σ1, and the effect of the antibodies on reovirus receptor engagement. Our analysis defines reovirus interactions with two neutralizing antibodies, allows us to propose a mechanism by which they block virus infection, and provides evidence for a conformational change in the σ1 protein during viral cell entry.
Analysis of Domain Architecture and Phylogenetics of Family 2 Glycoside Hydrolases (GH2)
2016-12-08

In this work we report a detailed analysis of the topology and phylogenetics of family 2 glycoside hydrolases (GH2). We distinguish five topologies or domain architectures based on the presence and distribution of protein domains defined in Pfam and Interpro databases. All of them share a central TIM barrel (catalytic module) with two β-sandwich domains (non-catalytic) at the N-terminal end, but differ in the occurrence and nature of additional non-catalytic modules at the C-terminal region. Phylogenetic analysis was based on the sequence of the Pfam Glyco_hydro_2_C catalytic module present in most GH2 proteins. Our results led us to propose a model in which evolutionary diversity of GH2 enzymes is driven by the addition of different non-catalytic domains at the C-terminal region. This model accounts for the divergence of β-galactosidases from β-glucuronidases, the diversification of β-galactosidases with different transglycosylation specificities, and the emergence of bicistronic β-galactosidases. This study also allows the identification of groups of functionally uncharacterized protein sequences with potential biotechnological interest.
Platelets as a novel source of Gremlin-1: Implications for thromboinflammation
2016-12-08

Summary Platelets mediating haemostasis-thrombosis are central players in coronary artery disease (CAD). We characterised platelets as a novel source of Gremlin-1. Platelets express Gremlin-1 like inflammatory and endothelial cells. Gremlin-1 co-localised with P-selectin containing randomly distributed α–granules under resting state, which were peripheralised following platelet activation or adhesion over fibrinogen-coated surface. Gremlin-1 release upon activation with ADP, CRP, and TRAP was detected as enhanced surface expression; also in activated platelet supernatant as detected by Western Blot following CRP activation and by ELISA upon activation with ADP, CRP, PAR-1, and PAR4 agonist. Recombinant (rh)Gremlin-1 synergistically enhanced CRP-triggered intracellular calcium mobilisation, ADP-TRAP induced platelet activation, aggregation, and thrombin-activation triggered apoptosis; also thrombus formation ex vivo. Intracellular localisation of macrophage migration inhibitory factor (MIF) and Gremlin-1 a high-affinity binding partner and functional antagonist of MIF were found in intracoronary thrombus sections from acute coronary syndrome (ACS) patients and showed moderate overlap in α-granules of platelets. Intra-platelet Gremlin-1 levels were significantly decreased in ACS patients as compared to stable CAD (n=235). rhGremlin-1 also counteracted the anti-apoptotic and anti-thrombotic effects of rhMIF on platelets. Platelet-derived-Gremlin-1 prompted monocyte migration, facilitated adhesion under static and dynamic arterial flow conditions to collagen-adherent activated platelets; supported monocyte survival against BH-3-mimetic–induced apoptosis and macrophage differentiation in monocyte-platelet co-culture system, which were counteracted upon Gremlin-1 neutralisation. Thus platelet derived Gremlin-1 might contribute to the elevated circulating levels of Gremlin-1 in ACS and serve as a thrombo-inflammatory mediator in cardiovascular pathophysiologies.
X-ray bounds on the r-mode amplitude in millisecond pulsars
2016-12-08

r-mode astroseismology provides a unique way to study the internal composition of compact stars. Due to their precise timing, recycled millisecond radio pulsars present a particularly promising class of sources. Although their thermal properties are still poorly constrained, X-ray data is very useful for astroseismology since r-modes could strongly heat a star. Using known and new upper bounds on the temperatures and luminosities of several non-accreting millisecond radio pulsars we derive bounds on the r-mode amplitude as low as and discuss the impact on scenarios for their internal composition.
Comparison of Ventricular Inducibility with Late Gadolinium Enhancement and Myocardial Inflammation in Endomyocardial Biopsy in Patients with Dilated Cardiomyopathy
2016-12-08

Inducibilty during programmed ventricular stimulation is associated with positive late gadolinium enhancement in cardiac MRI of patients with non-ischemic dilated cardiomyopathy. The presence of myocardial fibrosis or inflammation in undirected endomyocardial biopsy does not seem to be sufficient to predict future ventricular arrhythmias.
ecancermedicalscience
2016-12-08

Evaluation of isolated tumour cells in bone marrow (BM) and peripheral blood has become a major focus of translational cancer research. The presence of disseminated tumour cells in BM is a common phenomenon observed in 30-40% of primary breast cancer patients and independently predicts reduced clinical outcome. The detection of circulating tumour cells (CTCs) in blood might become a desired alternative to the invasive and painful BM biopsy. Recent clinical trials confirmed the feasibility of CTC detection as a robust and reproducible parameter for prognostication in both adjuvant and metastatic setting. The characterisation of CTCs might become an important biomarker for therapy monitoring and help to identify specific targets for novel therapeutic strategies.
Au108S24(PPh3)16: A Highly Symmetric Nanoscale Gold Cluster Confirms the General Concept of Metalloid Clusters
2016-12-09

Abstract The reduction of (Ph 3 P)AuCl with NaBH 4 in the presence of HSC(SiMe 3 ) 3 , leads to one of the largest metalloid gold clusters: Au 108 S 24 (PPh 3 ) 16 ( 1 ). Within 1 an octahedral Au 44 core of gold atoms arranged as in Au metal is surrounded by 48 oxidized Au atoms of an Au 48 S 24 shell, a novel building block in gold chemistry. The protecting Au 48 S 24 shell is completed by additional 16 Au(PPh 3 ) units, leading to a complete protection of the gold core. Within 1 the Au–Au distances get more molecular on going from the center to the ligand shell. Cluster 1 represents novel structural motives in the field of metalloid gold clusters which also are partly typical for metal atoms in metalloid clusters: M n R m ( n &gt; m ).
CASP9 germline mutation in a family with multiple brain tumors
2016-12-09

Abstract We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which three brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li–Fraumeni‐like syndrome. Whole exome sequencing revealed a germline stop‐gain mutation (R65X) in the CASP9 gene, which encodes caspase‐9, a key molecule for the p53‐dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase‐9 immunohistochemistry showed the absence of caspase‐9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li–Fraumeni‐like family lacking a TP53 germline mutation.
Oral Motor Abilities Are Task Dependent: A Factor Analytic Approach to Performance Rate
2016-12-09

Measures of performance rates in speech-like or volitional nonspeech oral motor tasks are frequently used to draw inferences about articulation rate abnormalities in patients with neurologic movement disorders. The study objective was to investigate the structural relationship between rate measures of speech and of oral motor behaviors different from speech. A total of 130 patients with neurologic movement disorders and 130 healthy subjects participated in the study. Rate data was collected for oral reading (speech), rapid syllable repetition (speech-like), and rapid single articulator movements (nonspeech). The authors used factor analysis to determine whether the different rate variables reflect the same or distinct constructs. The behavioral data were most appropriately captured by a measurement model in which the different task types loaded onto separate latent variables. The data on oral motor performance rates show that speech tasks and oral motor tasks such as rapid syllable repetition or repetitive single articulator movements measure separate traits.
Pain reduction due to novel sensory-motor training in Complex Regional Pain Syndrome I – A pilot study
2016-12-09

Abstract Background and aims Patients suffering from Complex Regional Pain Syndrome (CRPS) of the upper limb show a changed cortical representation of the affected hand. The lip area invades the former hand area contralateral to the affected hand. This change in cortical representation is correlated to the intensity of ongoing pain in patients with CRPS. Further studies revealed that restoration of the original representation coincides with a decrease of pain. Sensory-motor training protocols can increase and/or relocate cortical somatosensory and motor representation areas of the fingers, as shown, for example, in Braille reading individuals and professional violin players. Further, there is evidence that sensory-motor discrimination training has a beneficial effect on both the intensity of pain and the mislocalization of sensory-motor cortical areas in CRPS patients. Based on these propositions, we developed a novel sensory-motor self-training paradigm for CRPS patients to use in a home-based manner. Methods Ten CRPS patients performed the sensory-motor training for 2 weeks. The training consists of a braille-like haptic task with different training modes (bi-manual, speed and memory training). During the training, as well as 1 week before and after, patients were asked to fill out pain diaries. Furthermore, measures of impairment were acquired at baseline and post training. Results Patients showed significant pain reduction after the 2 week training period. The overall disability as well as the depression scores showed a trend to improve after the 2 week training. The reduction in pain was correlated with the total amount of training performed. Conclusions This is a first proof of principle study of a novel sensory-motor self-training protocol to reduce pain in CRPS patients. The more consistent the patients trained the larger the pain reduction. Sensory-motor training, which can be performed on a regular basis at home might provide a novel interventional strategy to improve symptoms of CRPS. Implications Although a larger study needs to be conducted to confirm our findings, including long-term follow-up, the results show, that a sensory-motor home-based training is a strategy worth exploring further for the reduction of pain as well as high frequency training for patients with CRPS.
Tissue differentiation by means of high resolution optical emission spectroscopy during electrosurgical intervention
2016-12-09

Electrosurgery is the use of radio-frequency electric current for the cutting of biological tissue e.g. for resection of tumour tissue. In this work, the optical emission of plasma being generated during the electrosurgical procedure is investigated with a high resolution echelle spectrometer to find differences between tumour tissue and normal renal tissue in a pre-clinical ex vivo study. Trace elements like zinc, iron, copper and cadmium are present in the tissue spectra as well as the electrolytes magnesium, calcium, sodium and potassium and some diatomic molecules such as hydroxyl radical, cyano radical, dicarbon, nitrogen monohydride and molecular nitrogen which are mainly dissociated from polyatomic molecules. With the atomic emission line of cadmium at 228.8 nm the treated tissue can be differentiated in tumorous and healthy tissue with correct assignment of 95% for tumour tissue and 92% for normal renal tissue.