julilili42/papers huggingface dataset:
μ-opioid system in alcohol dependence: Carfentanil-PET, risk of relapse and synopsis with post mortem data.
2015-05-01

524 Objectives [11C]Carfentanil (CFN) binds selectively to the μ opiate receptor (MOR) and revealed elevated MOR in the ventral striatum (VS) of abstinent alcoholics. Interpretation of these findings (increased MOR expression vs reduced competition by endogenous ligand) and clinical relevance is still unclear. Methods 38 alcoholics underwent CFN-PET two weeks after detoxification ( Results 1) PET: Higher VS BPnd was associated with lower relapse rate: BPnd-main effect p=.002 (unweighted mean in AA und AG); interaction p=.01 (stronger BPnd effect in AG). BPnd effect confirmed by median split log rank p=.015. 2) Post-mortem: VS-MOR reduced by 50% in Pts. with increased blood alcohol at the time of death (n=16) and by 23% in the other pts. (p Conclusions Reduced MOR in the VS of alcoholics (post mortem) can at least in part be explained by compensatory downregulation. PET findings of increased MOR availability during early abstinence therefore might reflect reduced competition by the endogenous ligand. The correlation between PET findings and relapse behavior demonstrates the clinical relevance of the opiate system.
Somatic MyD88 mutations and a germline IRAK2 variant contribute to lymphoma by differential effects on NF-κB (INM7P.354)
2015-05-01

Abstract Within innate immune signaling pathways, Myeloid differentiation (MyD) 88 and Interleukin-1 receptor associated kinases (IRAKs) fulfill pivotal roles downstream of multiple Toll-like receptors (TLR). Somatic MyD88 mutations in B cells were reported to affect lymphomagenesis by constitutive hyperactivation of NF-κB. We here show that oncogenic mutants augment spontaneous TIR domain oligomerization into so-called Myddosome signaling complexes driving NF-κB activation. Blocking of MyD88 oligomerization consequently induced the death of MyD88-mutated but not unmutated lymphoma cells. In line with the involvement of the MyD88 axis in lymphomagenesis we detected a genetic association of a coding germline variant of IRAK2, a MyD88 interactor, with increased risk (OR = 1.43, 95% confidence interval 1.06-1.93, p=0.018) to develop lymphoma in a German cohort (n=387). This variant is frequently found in 15-44% of individuals of different ethnic groups. Unexpectedly, this variant was associated with reduced NF-κB activation and cytokine responses to TLR agonists in healthy donors. Mechanistically, the IRAK2 variant retained intact binding to but impaired ubiquitination of TRAF6, a vital step in signal transduction. Thus our findings confirm the involvement of MyD88/IRAK in lymphoma but suggest that MyD88 and IRAK2 may contribute differently to oncogenic signaling. Additionally we highlight IRAK2 genetic variants as a critical factor and potentially novel biomarker for human lymphomagenesis.
Influence of human TLR and NLR genetic variants on colorectal cancer - involvement of commensal bacterial detection, gut immunity or microbiome diversity? (HUM1P.311)
2015-05-01

Abstract Studies on TLR and NLR knock out mice have suggested these pattern recognition receptors (PRRs) drastically affect gut mucosal immunity and composition of the gut microbiome, which may give rise to diseases such as colorectal cancer. We have identified several coding SNPs in TLR5 and different NLR (including the so far enigmatic group of development-associated NLRs) to be associated with different parameters of colorectal cancer, and for TLR5 have observed a functional effect in human blood immune cells. With a view to further elucidating the underlying mechanisms of these SNPs in colorectal cancer, we have begun to investigate the role of these PRR variants on gut immune activation levels and microbiome diversity in humans. Our hypothesis is that functional TLR and NLR variants are associated with different immune potential in the gut, shaping or being shaped by the host microbiome. We have built-up, genotyped and started to assay a cohort of 125 healthy volunteers and established stool assays for sIgA and cytokine levels by ELISA, cellular contents by flow cytometry analysis and PRR stimulating potential. Additionally, a functional characterization of coding NLR SNPs in cellular model systems is being carried out. Our studies dissect the functional impact and relationship of host genetic factors and the microbiome in humans, which may reveal novel targets in the diagnosis or treatment of colorectal cancer or other gut-related diseases.
Quantitative and functional pulsed arterial spin labeling in the human brain at 9.4 t
2015-05-02

Purpose The feasibility of multislice pulsed arterial spin labeling (PASL) of the human brain at 9.4 T was investigated. To demonstrate the potential of arterial spin labeling (ASL) at this field strength, quantitative, functional, and high‐resolution (1.05 × 1.05 × 2 mm 3 ) ASL experiments were performed. Methods PASL was implemented using a numerically optimized adiabatic inversion pulse and presaturation scheme. Quantitative measurements were performed at 3 T and 9.4 T and evaluated on a voxel‐by‐voxel basis. In a functional experiment, activation maps obtained with a conventional blood‐oxygen‐level‐dependent (BOLD)‐weighted sequence were compared with a functional ASL (fASL) measurement. Results Quantitative measurements revealed a 23% lower perfusion in gray matter and 17% lower perfusion in white matter at 9.4 T compared with 3 T. Furthermore almost identical transit delays and bolus durations were found at both field strengths whereas the calculated voxel volume corrected signal‐to‐noise ratio was 1.9 times higher at 9.4 T. This result was confirmed by the high‐resolution experiment. The functional experiment yielded comparable activation maps for the fASL and BOLD measurements. Conclusion Although PASL at ultrahigh field strengths is limited by high specific absorption rate, functional and quantitative perfusion‐weighted images showing a high degree of detail can be obtained. Magn Reson Med 75:1054–1063, 2016. © 2015 Wiley Periodicals, Inc.
Work ethics from an Islamic Perspective
2015-05-03

From the beginning of Islam, the question of one’s private or public behavior has been closely related to one’s faith or spiritual state. Based on certain Qur’anic references to human responsibility such as divine vicegerency on earth and the Prophetic noble example of human excellence Muslim scholars have developed a special domain of study devoted to what is known as mu’amalat or transactions. The notion of work ethics within this field of study occupies one of the major themes as it is well illustrated in the present article by (Prof.) Khalfaoui. The author has presented an Islamic perspective on business and its development within Islamic culture from the early period of Islam to later times. The first part of the article deals with the Qur’anic and Sunnatic conceptions of business and its institution within an Islamic context. The second part delves further into legal treatment of work developed by Muslim Jurists and other scholars. Finally in a brief conclusion of the study the author fairly related the religious implication of work ethics to the subject of business within the traditional Islamic perspective.
An Overview of Dual-Phase Steels: Advances in Microstructure-Oriented Processing and Micromechanically Guided Design
2015-05-04

Dual-phase (DP) steel is the flagship of advanced high-strength steels, which were the first among various candidate alloy systems to find application in weight-reduced automotive components. On the one hand, this is a metallurgical success story: Lean alloying and simple thermomechanical treatment enable use of less material to accomplish more performance while complying with demanding environmental and economic constraints. On the other hand, the enormous literature on DP steels demonstrates the immense complexity of microstructure physics in multiphase alloys: Roughly 50 years after the first reports on ferrite-martensite steels, there are still various open scientific questions. Fortunately, the last decades witnessed enormous advances in the development of enabling experimental and simulation techniques, significantly improving the understanding of DP steels. This review provides a detailed account of these improvements, focusing specifically on (a) microstructure evolution during processing, (b) experimental characterization of micromechanical behavior, and (c) the simulation of mechanical behavior, to highlight the critical unresolved issues and to guide future research efforts.
Social and intertemporal differences of basic numeracy in Pannonia (first century BCE to third century CE)
2015-05-04

In this study, we assess the human capital of Roman legionaries, officers and the civilian population born between the first century BCE and the third century CE in Pannonia (today's West Hungary). Age-heaping techniques allow the measurement of human capital for this early period, although we need to discuss intensively potential selectivity. We find that the Roman military benefited strongly from occupational choice selectivity: those social groups who decided for a military career had better numeracy values than the remainder of the population. This applied especially to the first centuries BCE and CE. Over time, however, the civilian population converged to the military occupational groups. This 'military bias' analysis also contributes to the debate about long-term growth determinants: in some societies, the most educated parts of the elites selected a military career, rather than opting for entreprenuerial activities which might have impacted more positively on macroeconomic growth.
Fighting Sleep at Night: Brain Correlates and Vulnerability to Sleep Loss
2015-05-04

Objective Even though wakefulness at night leads to profound performance deterioration and is regularly experienced by shift workers, its cerebral correlates remain virtually unexplored. Methods We assessed brain activity in young healthy adults during a vigilant attention task under high and low sleep pressure during night‐time, coinciding with strongest circadian sleep drive. We examined sleep‐loss–related attentional vulnerability by considering a PERIOD3 polymorphism presumably impacting on sleep homeostasis. Results Our results link higher sleep‐loss–related attentional vulnerability to cortical and subcortical deactivation patterns during slow reaction times (i.e., suboptimal vigilant attention). Concomitantly, thalamic regions were progressively less recruited with time‐on‐task and functionally less connected to task‐related and arousal‐promoting brain regions in those volunteers showing higher attentional instability in their behavior. The data further suggest that the latter is linked to shifts into a task‐inactive default‐mode network in between task‐relevant stimulus occurrence. Interpretation We provide a multifaceted view on cerebral correlates of sleep loss at night and propose that genetic predisposition entails differential cerebral coping mechanisms, potentially compromising adequate performance during night work. Ann Neurol 2015;78:235–247
Rapid generation of NY-ESO-1-specific CD4+THELPER1 cells for adoptive T-cell therapy
2015-05-04

Tumor-associated antigens such as NY-ESO-1 are expressed in a variety of solid tumors but absent in mature healthy tissues with the exception of germline cells. The immune system anti-cancer attack is mediated by cell lysis or induction of growth arrest through paralysis of tumor cells, the latter of which can be achieved by tumor-specific CD4<sup>+</sup>, IFNγ-producing T<sub>Helper</sub> type 1 (T<sub>H</sub>1) cells. Translation of these immune-mediated mechanisms into clinical application has been limited by availability of immune effectors, as well as the need for complex <i>in vitro</i> protocols and regulatory hurdles. Here, we report a procedure to generate cancer-testis antigen NY-ESO-1-targeting CD4<sup>+</sup> T<sub>H</sub>1 cells <i>in vitro</i> for cancer immunotherapy in the clinic. After in vitro sensitization by stimulating T cells with protein-spanning, overlapping peptide pools of NY-ESO-1 in combination with IL-7 and low dose IL-2, antigen-specific T cells were isolated using IFNγ capture technique and subsequently expanded with IL-2, IL-7 and IL-15. Large numbers of NY-ESO-1-specific CD4<sup>+</sup> T cells with a T<sub>H</sub>1 cytokine profile and lower numbers of cytokine-secreting CD8<sup>+</sup> T cells could be generated from healthy donors with a high specificity and expansion potential. Manufactured CD4<sup>+</sup> T cells showed strong specific T<sub>H</sub>1-responses with IFNγ<sup>+</sup>, TNFα<sup>+</sup>, IL-2<sup>+</sup> and induced cell cycle arrest and apoptosis in tumor cells. The protocol is GMP-grade and approved by the regulatory authorities. The tumor-antigen specific CD4<sup>+</sup> T<sub>H</sub>1 lymphocytes can be adoptively transferred as a T-cell therapy to boost anticancer immunity and this novel cancer treatment approach is applicable to both T cells from healthy allogeneic donors as well as to autologous T cells derived from cancer patients.
Superluminescence from an optically pumped molecular tunneling junction by injection of plasmon induced hot electrons
2015-05-04

Here, we demonstrate a bias-driven superluminescent point light-source based on an optically pumped molecular junction (gold substrate/self-assembled molecular monolayer/gold tip) of a scanning tunneling microscope, operating at ambient conditions and providing almost three orders of magnitude higher electron-to-photon conversion efficiency than electroluminescence induced by inelastic tunneling without optical pumping. A positive, steadily increasing bias voltage induces a step-like rise of the Stokes shifted optical signal emitted from the junction. This emission is strongly attenuated by reversing the applied bias voltage. At high bias voltage, the emission intensity depends non-linearly on the optical pump power. The enhanced emission can be modelled by rate equations taking into account hole injection from the tip (anode) into the highest occupied orbital of the closest substrate-bound molecule (lower level) and radiative recombination with an electron from above the Fermi level (upper level), hence feeding photons back by stimulated emission resonant with the gap mode. The system reflects many essential features of a superluminescent light emitting diode.
First-person privilege, judgment, and avowal
2015-05-04

It is a common intuition that I am in a better position to know my own mental states than someone else's. One view that takes this intuition very seriously is Neo-Expressivism, providing a “non-epistemic” account of first-person privilege. But some have denied that we enjoy any principled first-person privilege, as do those who have the Third-Person View, according to which there is no deep difference in our epistemic position with regard to our own and others' mental states. Despite their apparently deep differences, I argue that Neo-Expressivism and the Third-Person View differ in their location of first-person privilege. This difference in the source of first-person privilege allows the key elements of each of these views to be compatible, and can even be combined into a single view about the nature of introspection and self-knowledge. The compatibility of these two views that otherwise appear to be in direct opposition is methodologically significant, highlighting several dialectical lessons that clarify the existing debate about first-person privilege. The main lesson to take away is that there are likely other underexplored possibilities for careful synthesis of already existing views, which could shed new light on the nature of first-person privilege, introspection, and self-knowledge.
Higgs boson production in association with top quarks in the POWHEG BOX
2015-05-05

We present results from the analytic calculation of top+antitop+Higgs\\nhadronic production at Next-to-Leading Order in QCD interfaced with\\nparton-shower Monte Carlo event generators in the POWHEG BOX framework. We\\nconsider kinematic distributions of the top quark and Higgs boson at the 8 TeV\\nLarge Hadron Collider and study the theoretical uncertainties due to specific\\nchoices of renormalization/factorization scales and parton-showering\\nalgorithms, namely PYTHIA and HERWIG. The importance of spin-correlations in\\nthe production and decay stages of a top/antitop quark is discussed on the\\nexample of kinematic distributions of leptons originating from the top/antitop\\ndecays. The corresponding code is now part of the public release of the POWHEG\\nBOX.\\n
The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease
2015-05-05

Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116.
Influence of thrust belt geometry and shortening rate on thermochronometer cooling ages: Insights from thermokinematic and erosion modeling of the Bhutan Himalaya
2015-05-05

Advancements in thermochronology and numerical modeling offer the potential to associate the age of thermochronometric samples to both exhumational and deformational processes. However, understanding how these components are related in compressional systems requires linking the geometry and magnitude of fault slip to the distribution and amount of erosion. To address this, we apply a 2-D thermokinematic model to a forward modeled balanced cross section to quantify the cooling history in fold-thrust belt settings. The restored cross section provides a kinematic path of rocks and structures necessary to reproduce the surface geology. By assigning ages to displacement amounts, we produced a range of potential velocity vectors used to calculate heat transport, erosion, and rock cooling. We test the predicted ages against a suite of previously published thermochronometric data from the Bhutan Himalaya to explore the utility of the data to constrain the timing, rate, and geometry of fault motion as well as variations in the exhumation rate. We evaluate the cooling history associated with a constant rate of shortening of 18 mm/yr, rates that are 2.0, 1.5, 0.75, and 0.5 times the constant rate, and rates that vary with time to determine which kinematic history best matches the measured cooling ages. The combination of relatively old apatite fission track and zircon (U-Th)/He measured ages and younger (15–9 Ma) 40Ar/39Ar ages from white mica is best matched with faster rates (relative to constant rates) between 11.5 and 8 Ma and slower than constant rates from 17 to 11.5 Ma and 8 Ma to present.
An Overdose of the Arabidopsis Coreceptor BRASSINOSTEROID INSENSITIVE1-ASSOCIATED RECEPTOR KINASE1 or Its Ectodomain Causes Autoimmunity in a SUPPRESSOR OF BIR1-1-Dependent Manner
2015-05-05

Abstract The membrane-bound BRASSINOSTEROID INSENSITIVE1-ASSOCIATED RECEPTOR KINASE1 (BAK1) is a common coreceptor in plants and regulates distinct cellular programs ranging from growth and development to defense against pathogens. BAK1 functions through binding to ligand-stimulated transmembrane receptors and activating their kinase domains via transphosphorylation. In the absence of microbes, BAK1 activity may be suppressed by different mechanisms, like interaction with the regulatory BIR (for BAK1-INTERACTING RECEPTOR-LIKE KINASE) proteins. Here, we demonstrated that BAK1 overexpression in Arabidopsis (Arabidopsis thaliana) could cause detrimental effects on plant development, including growth arrest, leaf necrosis, and reduced seed production. Further analysis using an inducible expression system showed that BAK1 accumulation quickly stimulated immune responses, even under axenic conditions, and led to increased resistance to pathogenic Pseudomonas syringae pv tomato DC3000. Intriguingly, our study also revealed that the plasma membrane-associated BAK1 ectodomain was sufficient to induce autoimmunity, indicating a novel mode of action for BAK1 in immunity control. We postulate that an excess of BAK1 or its ectodomain could trigger immune receptor activation in the absence of microbes through unbalancing regulatory interactions, including those with BIRs. Consistently, mutation of SUPPRESSOR OF BIR1-1, which encodes an emerging positive regulator of transmembrane receptors in plants, suppressed the effects of BAK1 overexpression. In conclusion, our findings unravel a new role for the BAK1 ectodomain in the tight regulation of Arabidopsis immune receptors necessary to avoid inappropriate activation of immunity.
Platelet G i protein Gα i2 is an essential mediator of thrombo-inflammatory organ damage in mice
2015-05-05

Significance Platelet activation is crucial for hemostasis and thrombosis but also contributes to inflammation and progression of tissue damage following ischemia/reperfusion injury. Here we demonstrate that platelet activation through the G i protein Gα i2 not only controls hemostatic responses but also thrombo-inflammatory tissue damage following cerebral and cardiac ischemia. Our report on a dual role of G i proteins in platelet function opens new options for pharmaco-therapeutic strategies fighting ischemic diseases such as heart attack and stroke.
Identifying and Rationalizing the Conditions for the Isomerization of 1,5-Cyclooctadiene in Iridium Complexes by Experimental and Theoretical Mechanistic Studies
2015-05-05

The independent synthesis of the biscarbene complexes [Ir(cod)(vegiR)]PF6 (2) (cod =1,5-cyclooctadiene, vegiR = bidentate N-heterocyclic carbene) as well as their isomerized complexes [Ir(1-κ-4,5,6-η-C8H12)(NCCH3)(vegiR)]PF6 (3) is described. We elucidated acetic acid as the catalyst and coordinated acetonitrile as the thermodynamic driving force for this cod-isomerization. By using the stronger trifluoroacetic acid, we isolated complex [Ir(cod)(F3CCO2)(H)(veginPr)]PF6 (7a) as an intermediate of the isomerization. From H/D exchange experiments as well as DFT calculations, we conclude that after formation of the Ir–H complex, an olefin insertion, followed by a concerted metalation-deprotonation step and a coordination of acetonitrile, is the mechanistic pathway. On the basis of our findings, we were able to carry out the cod-isomerization for the first time also for the less-electron-rich complex [Ir(2,2′-bipy)(cod)]PF6 (8) (2,2-bipy = 2,2′-bipyridine).
Ellipsis and Information Structure
2015-05-05

Abstract This chapter surveys elliptical phenomena and their interrelatedness to central information-structural notions. The term ellipsis most generally refers to the omission of linguistic material, structure, and/or sound. The ellipsis site is crucially connected to the notion of givenness of the unpronounced or deleted string. The remnants of the ellipsis site, which occur to the left or right of the omitted material, are frequently connected to the notion of contrastive topic and focus. The core question of modern linguistic theory is how syntactic and information-structural theories interact in accounting for the licensing of the different types of elliptical phenomena. The discussion shows that information structure and discourse factors influence the form and the interpretation of ellipsis.