julilili42/papers huggingface dataset:
Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk
2018-08-09

Abstract We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.
Core fragmentation and Toomre stability analysis of W3(H2O)
2018-08-09

Context. The fragmentation mode of high-mass molecular clumps and the properties of the central rotating structures surrounding the most luminous objects have yet to be comprehensively characterised. Aims. We study the fragmentation and kinematics of the high-mass star-forming region W3(H 2 O), as part of the IRAM NOrthern Extended Millimeter Array (NOEMA) large programme CORE. Methods. Using the IRAM NOEMA and the IRAM 30 m telescope, the CORE survey has obtained high-resolution observations of 20 well-known highly luminous star-forming regions in the 1.37 mm wavelength regime in both line and dust continuum emission. Results. We present the spectral line setup of the CORE survey and a case study for W3(H 2 O). At ~0.′′35 (700 AU at 2.0 kpc) resolution, the W3(H 2 O) clump fragments into two cores (west and east), separated by ~2300 AU. Velocity shifts of a few km s −1 are observed in the dense-gas tracer, CH 3 CN, across both cores, consistent with rotation and perpendicular to the directions of two bipolar outflows, one emanating from each core. The kinematics of the rotating structure about W3(H 2 O) W shows signs of differential rotation of material, possibly in a disk-like object. The observed rotational signature around W3(H 2 O) E may be due to a disk-like object, an unresolved binary (or multiple) system, or a combination of both. We fit the emission of CH 3 CN (12 K −11 K ), K = 4−6 and derive a gas temperature map with a median temperature of ~165 K across W3(H 2 O). We create a Toomre Q map to study thestability of the rotating structures against gravitational instability. The rotating structures appear to be Toomre unstable close to their outer boundaries, with a possibility of further fragmentation in the differentially rotating core, W3(H 2 O) W. Rapid cooling in the Toomre unstable regions supports the fragmentation scenario. Conclusions. Combining millimetre dust continuum and spectral line data toward the famous high-mass star-forming region W3(H 2 O), we identify core fragmentation on large scales, and indications for possible disk fragmentation on smaller spatial scales.
Simultaneous Extraction of RNA and Metabolites from Single Kidney Tissue Specimens for Combined Transcriptomic and Metabolomic Profiling
2018-08-09

Tissue analysis represents a powerful tool for the investigation of disease pathophysiology. However, the heterogeneous nature of tissue samples, in particular of neoplastic, may affect the outcome of such analysis and hence obscure interpretation of results. Thus, comprehensive isolation and extraction of transcripts and metabolites from an identical tissue specimen would minimize variations and enable the economic use of biopsy material which is usually available in limited amounts. Here we demonstrate a fast and simple protocol for combined transcriptomics and metabolomics analysis in homogenates prepared from one single tissue sample. Metabolites were recovered by protein precipitation from lysates originally prepared for RNA isolation and were analyzed by LC-QTOF-MS after HILIC and RPLC separation, respectively. Strikingly, although ion suppression was observed, over 80% of the 2885 detected metabolic features could be extracted and analyzed with high reproducibility (CV ≤ 20%). Moreover fold changes of different tumor and nontumor kidney tissues were correlated to an established metabolomics protocol and revealed a strong correlation ( r<sub>p</sub> ≥ 0.75). In order to demonstrate the feasibility of the combined analysis of RNA and metabolites, the protocol was applied to kidney tissue of metformin treated mice to investigate drug induced alterations.
Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy
2018-08-09

The results lead us to suggest a regulatory role for CR1 polymorphisms on mRNA and sCR1 levels, with haplotype-specific effects increasing susceptibility to leprosy, probably by enhancing parasite phagocytosis and inflammation.
Extended periprostatic nerve distributions on the prostate surface confirmed using diffusion tensor imaging
2018-08-09

Objective To perform a descriptive microscopic study of prostatectomy specimens from 19 patients which anatomically characterizes the distributions of periprostatic nerve qualities, and to visualize these using diffusion tensor imaging ( DTI ). Materials and Methods Serial whole‐mounted sections were stained for cholinergic (neuronal nitric oxide synthase), adrenergic (tyrosine hydroxylase) and sensory (calcitonin gene‐related peptide) nerves. Extracapsular stained nerves were counted by prostate surface sector, and classified by diameter. Stain‐related relative density was calculated, and distribution patterns were evaluated. To better visualize the reported neuronal structures and independently confirm our findings, nerve concordance in five male volunteers was investigated using a 3‐Tesla magnetic resonance imaging‐ DTI system. Results At the base, cholinergic nerves were distributed from the anterolateral to posterior sectors, continuing posterolaterally (mid‐section) into the posterolateral‐posterior sector toward the apex. Adrenergic nerves were distributed across the anterolateral‐posterior sectors at the base, with the course narrowing to the posterolateral‐posterior sectors at the mid‐ and apical levels. Sensory fibres were found posterolaterally posteriorly at the base, continuing posterolaterally over the mid‐ and apical levels. Although it was not possible to determine the different nerve qualities, DTI confirmed histological findings from the base to the apex. Conclusions Different types of nerve fibres were found to vary in distribution. When linked to possible functional aspects of the different nerve types, this morphological evidence may be of importance to further protect function after radical prostatectomy (RP). To our knowledge, this is the first time that DTI has confirmed reported histological findings in nerve‐sparing RPs. DTI could be an important tool with which to correlate nerves to tumour for better preoperative planning and to incorporate imaging into treatment.
CASIN the joint: immune aging at the stem cell level
2018-08-09

In this issue of Blood, Leins et al use hematopoietic stem cell (HSC) transplantation from young or old mice into young Rag1−/− hosts to demonstrate that T- and B-cell reconstitution and acquisition of immune function is dependent on blocking the age-associated higher expression of cell division control 42 (Cdc42) in HSCs from old animals transferred to a young host. They achieved this by treating old HSCs with the specific pharmacologic Cdc42 inhibitor CASIN [2-((6-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino)ethanol], otherwise known as Pirl1-related compound 2.1
Parkinson’s disease genetics: identifying novel risk loci, providing causal insights and improving estimates of heritable risk
2018-08-09

We performed the largest genetic study of Parkinson9s disease to date, involving analysis of 11.4M SNPs in 37.7K cases, 18.6K 9proxy-cases9 and 1.4M controls, discovering 39 novel risk loci. In total, we identified 92 putative independent genome-wide significant signals including 53 at previously published loci. Next, we dissected risk within these loci, identifying 22 candidate independent risk variants in close proximity to one another representing multiple risk signals in one locus (20 variants proximal to known risk loci). We then employed tests of causality within a Mendelian randomization framework to infer functional genomic consequences for genes within loci of interest in concert with protein-centric network analyses to nominate likely candidates for follow-up investigation. This report also shows expression network signatures of PD loci to be heavily brain enriched and different in comparison to Alzheimer9s disease. We also used risk scoring methods to improve genetic predictions of disease risk, and show that GWAS signals explain 11-15% of the heritable risk of PD at thresholds below genome-wide significance. Additionally, these data also suggest genetic correlations relating to risk overlapping with brain morphology, smoking status and educational attainment. Further analyses of smoking initiation and cognitive performance relating to PD risk in more comprehensive datasets show complex etiological links between PD risk and these traits. These data in sum provide the most comprehensive understanding of the genetic architecture of PD to date, revealing a large number of additional loci, and demonstrating that there remains a considerable genetic component of this disease that has not yet been discovered.
Validation of a Lower Back “Wearable”-Based Sit-to-Stand and Stand-to-Sit Algorithm for Patients With Parkinson's Disease and Older Adults in a Home-Like Environment
2018-08-10

<b>Introduction:</b> Impaired sit-to-stand and stand-to-sit movements (postural transitions, PTs) in patients with Parkinson's disease (PD) and older adults (OA) are associated with risk of falling and reduced quality of life. Inertial measurement units (IMUs, also called "wearables") are powerful tools to monitor PT kinematics. The purpose of this study was to develop and validate an algorithm, based on a single IMU positioned at the lower back, for PT detection and description in the above-mentioned groups in a home-like environment. <b>Methods:</b> Four PD patients (two with dyskinesia) and one OA served as algorithm training group, and 21 PD patients (16 without and 5 with dyskinesia) and 11 OA served as test group. All wore an IMU on the lower back and were videotaped while performing everyday activities for 90-180 min in a non-standardized home-like environment. Accelerometer and gyroscope signals were analyzed using discrete wavelet transformation (DWT), a six degrees-of-freedom (DOF) fusion algorithm and vertical displacement estimation. <b>Results:</b> From the test group, 1,001 PTs, defined by video reference, were analyzed. The accuracy of the algorithm for the detection of PTs against video observation was 82% for PD patients without dyskinesia, 47% for PD patients with dyskinesia and 85% for OA. The overall accuracy of the PT direction detection was comparable across groups and yielded 98%. Mean PT duration values were 1.96 s for PD patients and 1.74 s for OA based on the algorithm (<i>p</i> < 0.001) and 1.77 s for PD patients and 1.51 s for OA based on clinical observation (<i>p</i> < 0.001). <b>Conclusion:</b> Validation of the PT detection algorithm in a home-like environment shows acceptable accuracy against the video reference in PD patients without dyskinesia and controls. Current limitations are the PT detection in PD patients with dyskinesia and the use of video observation as the video reference. Potential reasons are discussed.
Paul, the Law and Judaism: Stoification of the Jewish Approach to the Law in Paul’s Letter to the Romans
2018-08-10

Abstract One of the major issues in Pauline studies of the last decades has been the picture of Judaism painted by Paul especially in his Letter to the Romans. To that end, scholarship first and foremost adduced contemporary Jewish sources without, however, reaching satisfactory results. The present paper, therefore, takes a different approach in that it works out the Stoic influence on Paul’s argumentation. To begin with, the Stoic character of the dilemma of the “I” in Rom 7:14–25, that wills the good, but fails to do so, is demonstrated. Thereupon, it is shown that Paul transfers insights of Stoic psychology not only to the Jewish-Adamitic “I” but also to Israel’s approach to the law that is reached by neither one. Paul in Romans, therefore, can be said to stoify the Jewish approach to the law which especially reflects in the formula “righteousness by works of the law”.
Are you Concerned? Patient Testimonials in Medical Communication Affect Healthy Recipients' Emotions and Memory
2018-08-10

Medical communication and health care intervention programs often include testimonials (i.e., an account of individuals' experiences) when addressing health-related topics. Numerous findings provide evidence of the effectiveness of such testimonials on intentions for health behavior change. However, little is known about whether and how testimonials affect healthy lay people's reception of health information (e.g., in journalistic reports about medical innovations). The present studies tested whether using patients vs. doctors as testimonial protagonists in communication affects unconcerned recipients' affective experiences and their memory performance regarding text content. Two experiments (Prestudy: N = 43; Main Experiment: N = 97, university student samples) demonstrated that using patients as protagonists elicited stronger negative and weaker positive emotions in recipients than using doctors as protagonists. Results of one of the experiments further suggested that the affective experience influenced recipients' memory performance so that less positive and more negative DBS-related information was remembered when patients were protagonists, due to elicited negative emotions. The findings are discussed with regard to their implications for medical communication.
Functionally disconnected: A look at how study design influences neurofeedback data and mechanisms in attention-deficit/hyperactivity disorder
2018-08-10

Neurofeedback (NF) is a form of behavioral therapy used to treat e.g. attention-deficit/hyperactivity disorder (ADHD). Briefly, subjects are fed-back a putatively dysfunctional parameter of their brain activity in real time and must learn to control it in a suggested direction. NF protocols for ADHD have been used in practice for decades, though no clear standards on NF design have been implemented. Furthermore, studies often present only data from the general outcome of the NF treatment and do not look at how exactly the NF paradigm affects brain functionality, or what exactly the NF is training. The current study is two-fold: firstly, we look at how the functional connectivity (FC) patterns within key networks associated with ADHD differ between rests, feedback trials, success and failure in a complete functional near-infrared spectroscopy-based NF experiment on adults with ADHD. Secondly, due to methodological concerns discovered during the analysis of our data, we address important considerations in the design of NF that are often ignored in protocols being used widely in therapy and research today. In particular, we examine the common average reference and its impact on network activity as well as the importance of balancing the randomization in a design. Finally, we discuss how these methodological considerations may have influenced our FC results.
Unity and diversity in working memory load: Evidence for the separability of the executive functions updating and inhibition using machine learning
2018-08-10

Abstract Objective According to current theoretical models of working memory (WM), executive functions (EFs) like updating, inhibition and shifting play an important role in WM functioning. The models state that EFs highly correlate with each other but also have some individual variance which makes them separable processes. Since this theory has mostly been substantiated with behavioral data like reaction time and the ability to execute a task correctly, the aim of this paper is to find evidence for diversity (unique properties) of the EFs updating and inhibition in neural correlates of EEG data by means of using brain-computer interface (BCI) methods as a research tool. To highlight the benefit of this approach we compare this new methodology to classical analysis approaches. Methods An existing study has been reinvestigated by applying neurophysiological analysis in combination with support vector machine (SVM) classification on recorded electroenzephalography (EEG) data to determine the separability and variety of the two EFs updating and inhibition on a single trial basis. Results The SVM weights reveal a set of distinct features as well as a set of shared features for the two EFs updating and inhibition in the theta and the alpha band power. Significance In this paper we find evidence that correlates for unity and diversity of EFs can be found in neurophysiological data. Machine learning approaches reveal shared but also distinct properties for the EFs. This study shows that using methods from brain-computer interface (BCI) research, like machine learning, as a tool for the validation of psychological models and theoretical constructs is a new approach that is highly versatile and could lead to many new insights.
Common holdings and strategic manager compensation: The case of an asymmetric triopoly
2018-08-10

Abstract We study an asymmetric triopoly in a heterogeneous product market where quantity decisions are delegated to managers. The two biggest firms are commonly owned by shareholders such as index funds, whereas the smallest firm is owned by independent shareholders. Under such a common holding owner structure, the owners have an incentive to coordinate when designing their manager compensation schemes. This coordination leads to a reallocation of production and induces a redistribution of profits. The trade volume in the market is reduced so that shareholder coordination is detrimental to consumer surplus as well as welfare.
Diagnosis of invasive fungal diseases in haematology and oncology: 2018 update of the recommendations of the infectious diseases working party of the German society for hematology and medical oncology (AGIHO)
2018-08-11

Summary Invasive fungal diseases ( IFD ) are a primary cause of morbidity and mortality in patients with haematological malignancies. These infections are mostly life‐threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other Non‐ Aspergillus moulds are increasingly identified in case of documented IFD . For definite diagnosis of IFD , a combination of diagnostic tools have to be applied, including conventional mycological culture and non‐conventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. Although varying widely in cancer patients, the risk of invasive fungal infection is highest in those with allogeneic stem cell transplantation and those with acute leukaemia and markedly lower in patients with solid cancer. Since the last edition of Diagnosis of Invasive Fungal Diseases recommendations of the German Society for Hematology and Oncology in 2012, integrated care pathways have been proposed for the management and therapy of IFD s with either a diagnostic driven strategy as opposed to a clinical or empirical driven strategy. This update discusses the impact of this additional evidence and effective revisions.
The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma
2018-08-11

Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR. The CAR expression on NKT cells and their in vitro functionality were analyzed. A transfection efficiency of more than 80% was achieved. Upon stimulation with melanoma cells, CAR-NKT cells produced cytokines antigen-specifically. Compared with conventional CAR-T cells, cytokine secretion of CAR-NKT cells was generally lower. Specific cytotoxicity, however, was similar with CAR-NKT cells showing a trend towards improved cytotoxicity. Additionally, CAR-NKT cells could kill target cells through their endogenous TCRs. In summary, it is feasible to generate CAR-NKT cells by using mRNA electroporation. Their CAR-mediated cytotoxicity is at least equal to that of conventional CAR-T cells, while their intrinsic cytotoxic activity is maintained. Thus, CAR-NKT cells may represent a valuable alternative to conventional CAR-T cells for cancer immunotherapy.
Towards the development of general rules describing landscape heterogeneity–multifunctionality relationships
2018-08-11

Abstract Rapid growth of the world's human population has increased pressure on landscapes to deliver high levels of multiple ecosystem services, including food and fibre production, carbon storage, biodiversity conservation, and recreation. However, we currently lack general principles describing how to achieve this landscape multifunctionality. We combine theoretical simulations and empirical data on 14 ecosystem services measured across 150 grasslands in three German regions. In doing so, we investigate the circumstances under which spatial heterogeneity in a driver of ecosystem functioning (an “ecosystem‐driver,” e.g., the presence of keystone species, land‐use intensification, or habitat types) increases landscape‐level ecosystem multifunctionality. Simulations based on theoretical data demonstrated that relationships between heterogeneity and landscape multifunctionality are highly variable and can range from nonsignificant to strongly positive. Despite this variability, we could identify criteria under which heterogeneity‐landscape multifunctionality relationships were most strongly positive: this happened when multiple ecosystem services responded contrastingly (both positively and negatively) to an ecosystem‐driver. These findings were confirmed using empirical data, which showed that heterogeneity in land‐use intensity (LUI) promoted landscape multifunctionality in cases where functions with both positive (e.g., plant biomass) and negative (e.g., flower cover) responses to land use intensification were included. For example, the simultaneous provisioning of ecosystem functions related to forage production (generally profiting from land‐use intensification), biodiversity conservation and recreation (generally decreasing with land‐use intensification) was highest in landscapes consisting of sites varying in LUI. Synthesis and applications . Our findings show that there are general principles governing landscape multifunctionality. A knowledge of these principles may support land management decisions. For example, knowledge of relationships between ecosystem services and their drivers, such as land use type, can help estimate the consequences of increasing or decreasing heterogeneity for landscape‐level ecosystem service supply, although interactions between landscape units (e.g., the movement of pollinators) must also be considered.