julilili42/papers huggingface dataset:
A Clinical Drug‐Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin
2019-06-27

A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10 mg adefovir‐dipivoxil (OAT1; renal clearance (CL R )), 100 mg sitagliptin (OAT3; CL R ), 500 mg metformin (several renal transporters; CL R ), 2 mg pitavastatin (OATP1B1; clearance/ F ), and 0.5 mg digoxin (intestinal P‐gp, renal P‐gp, and OATP4C1; peak plasma concentration (C max ) and CL R ). Using a randomized six‐period, open change‐over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80–1.25). Primary metrics supported the absence of relevant interactions, whereas secondary metrics suggested that mainly adefovir was a victim of minor drug‐drug interactions (DDIs). All drugs were well tolerated. This cocktail may be another useful tool to assess transporter‐based DDIs in vivo .
Deciphering hydroa vacciniforme
2019-06-27

In this issue of Blood , Cohen et al describe a series of hydroa vacciniforme (HV)–like lymphoproliferative disorder (HV-LPD) cases in whites; they confirm that HV-LPD is an Epstein-Barr virus (EBV)–related lymphoproliferation with earlier disease onset and lower EBV DNA levels in blood with a lower risk of developing a systemic disease when compared with nonwhites. 1
Neolithic settlement dynamics derived from archaeological data and colluvial deposits between the Baar region and the adjacent low mountain ranges, southwest Germany
2019-06-27

Abstract. The present study combines archaeological data with archaeopedological data from colluvial deposits to infer Neolithic settlement dynamics between the Baar region, the Black Forest and the Swabian Jura. A review of the state of archaeological research and an analysis of the processes leading to the discovery of the Neolithic sites and thereby the formation of the current archaeological site distribution in these landscapes is presented. The intensity of land use in the study area is compared with other landscapes in southern Germany using site frequencies. Phases of colluvial deposition are dated using AMS 14C ages of charcoals and luminescence ages of sediments and interpreted as local proxies for a human presence. Archaeological source criticism indicates that the distribution of the Neolithic sites is probably distorted by factors such as superimposition due to erosion and weathering effects limiting the preservation conditions for Neolithic pottery. A reconstruction of Neolithic settlement dynamics is achieved by complementing the archaeological data with phases of colluviation. Evidence for a continuous land use in the Baar region throughout the Neolithic is provided and sporadic phases of land use on the Swabian Jura and in the Black Forest are identified. In the late and final Neolithic, an intensification of colluvial formation can be noticed in the low mountain ranges.
Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models
2019-06-27

Ketogenic diet (KD) is getting in the focus as auxiliary cancer therapy, since it provides sufficient energy supply for healthy cells, while impairing energy production in tumor cells underlying the Warburg effect. Thereby, it can assist in inhibiting tumor growth and simultaneously counteract cachexia, which is frequently observed in cancer patients under chemotherapy. In order to provide molecular evidence for the proposed synergistic inhibition of tumor growth, we applied untargeted quantitative metabolome analysis on a breast cancer xenograft mouse model. Healthy mice and such bearing breast cancer xenografts and receiving chemotherapy were compared after treatment with control diet and KD. Metabolomic profiling was performed on plasma samples, applying high-performance liquid chromatography coupled to tandem mass spectrometry. Statistical analysis revealed metabolic fingerprints comprising numerous significantly regulated features in the group of mice bearing breast cancer. This fingerprint disappeared after treatment with KD, resulting in recovery to the metabolic status observed in healthy mice receiving control diet. Moreover, amino acid metabolism as well as fatty acid transport were found to be affected by both, the tumor and the applied KD. Our results provide clear evidence of a significant molecular effect of KD in the context of tumor growth inhibition.
Thermochronology and Exhumation History of the Northeastern Fennoscandian Shield Since 1.9 Ga: Evidence From 40Ar/39Ar and Apatite Fission Track Data From the Kola Peninsula
2019-06-27

Abstract Results from thermochronological studies have multiple applications to various problems in tectonics and landform evolution. However, up to now a lack of thermochronological data from the northeastern Fennoscandian Shield has complicated the interpretation of tectonothermal evolution of the region. Here, we use both new and previously published multimineral 40 Ar/ 39 Ar data (amphibole, mica, and feldspar) on the various Precambrian magmatic and metamorphic complexes to reconstruct the thermal history of NE Fennoscandia within the Kola Peninsula area in the interval 1900–360 Ma. Using the apatite fission track method as well as a numerical model of the heating‐cooling process of northeastern Fennoscandia's upper crust, we have reconstructed its thermal evolution for the interval 360–0 Ma. According to our model, since Lapland‐Kola orogenesis (1930–1905 Ma) northeastern Fennoscandia experienced a quasi‐monotonous cooling with the average rate of ~0.15 °C/Myr, which is equal to an exhumation rate of ~1–2 m/Myr. New apatite fission track data and time‐temperature modeling reveal a “hidden” endogenous thermal event in the NE Fennoscandia that took place between 360 and 300 Ma. This we attribute to an elevated geothermal gradient due to Baltica's drift over the African large low shear‐wave velocity province in the lowest mantle and/or thermal blanketing by insulating Devonian‐Carboniferous sedimentary/volcanic cover. Our model is further supported by evidence of Late Devonian‐Carboniferous rifting in the East and South‐Western Barents Basin, as well as various 360–300 Ma magmatic events within SW Fennoscandia and the Baltic countries.
Intrinsic roles in the crosshair – strategic analysis of multi-site role implementation with an adapted matrix map approach
2019-06-27

The Matrix Map enables to catch intuitively the status of intrinsic roles' profiles regarding role pattern, implicit-explicit relation and programs agreement. Thus, interpretation and informed discussions are fostered. Further target-oriented analyses and strategic developments can be conducted to enhance transparency and resource-efficiency.
Effects of Compton scattering on the neutron star radius constraints in rotation-powered millisecond pulsars
2019-06-27

\\nThe aim of this work is to study the possible effects and biases on the radius constraints for rotation-powered millisecond pulsars when using Thomson approximation to describe electron scattering in the atmosphere models, instead of using exact formulation for Compton scattering. We compare the differences between the two models in the energy spectrum and angular distribution of the emitted radiation. We also analyse a self-generated, synthetic, phase-resolved energy spectrum, based on Compton atmosphere and the most X-ray luminous, rotation-powered millisecond pulsars observed by the Neutron star Interior Composition ExploreR (NICER). We derive constraints for the neutron star parameters using both the Compton and Thomson models. The results show that the method works by reproducing the correct parameters with the Compton model. However, biases are found in both the size and the temperature of the emitting hotspot, when using the Thomson model. The constraints on the radius are still not significantly changed, and therefore the Thomson model seems to be adequate if we are interested only in the radius measurements using NICER.\\n
Elevated Mitral Valve Pressure Gradient Is Predictive of Long‐Term Outcome After Percutaneous Edge‐to‐Edge Mitral Valve Repair in Patients With Degenerative Mitral Regurgitation (MR), But Not in Functional MR
2019-06-28

Background This study analyzed the effects on long‐term outcome of residual mitral regurgitation ( MR ) and mean mitral valve pressure gradient ( MVPG ) after percutaneous edge‐to‐edge mitral valve repair using the MitraClip system. Methods and Results Two hundred fifty‐five patients who underwent percutaneous edge‐to‐edge mitral valve repair were analyzed. Kaplan–Meier and Cox regression analyses were performed to evaluate the impact of residual MR and MVPG on clinical outcome. A combined clinical end point (all‐cause mortality, MV surgery, redo procedure, implantation of a left ventricular assist device) was used. After percutaneous edge‐to‐edge mitral valve repair, mean MVPG increased from 1.6±1.0 to 3.1±1.5 mm Hg ( P &lt;0.001). Reduction of MR severity to ≤2+ postintervention was achieved in 98.4% of all patients. In the overall patient cohort, residual MR was predictive of the combined end point while elevated MVPG &gt;4.4 mm Hg was not according to Kaplan–Meier and Cox regression analyses. We then analyzed the cohort with degenerative and that with functional MR separately to account for these different entities. In the cohort with degenerative MR , elevated MVPG was associated with increased occurrence of the primary end point, whereas this was not observed in the cohort with functional MR . Conclusions MVPG &gt;4.4 mm Hg after MitraClip implantation was predictive of clinical outcome in the patient cohort with degenerative MR . In the patient cohort with functional MR , MVPG &gt;4.4 mm Hg was not associated with increased clinical events.
Boswellic extracts and 11-keto-ß-boswellic acids prevent type 1 and type 2 diabetes mellitus by suppressing the expression of proinflammatory cytokines
2019-06-28

Preclinical and clinical data suggest that BE and/or 11-keto-ß-boswellic acids by inhibiting the expression of proinflammatory cytokines from immune-competent cells, may prevent insulitis and insulin resistance in type 1 and type 2 diabetes, respectively, and therefore may be an option in the treatment/prevention of type 1 and type 2 diabetes. It is hypothesized that molecularly, BE and 11-keto-ß-boswellic acids act via interference with the IκB kinase/Nuclear Transcription Factor-κB (IKK/NF-κB) signaling pathway through inhibition of the phosphorylation activity of IKK. However, further investigations and well-designed clinical studies are required.
Emotional, cognitive and social factors of antimicrobial prescribing: can antimicrobial stewardship intervention be effective without addressing psycho-social factors?
2019-06-28

Abstract There is increasing evidence that psycho-social factors can influence antimicrobial prescribing practice in hospitals and the community, and represent potential barriers to antimicrobial stewardship interventions. Clinicians are conditioned both by emotional and cognitive factors based on fear, uncertainty, a set of beliefs, risk perception and cognitive bias, and by interpersonal factors established through social norms and peer and doctor–patient communication. However, a gap is emerging between research and practice, and no stewardship recommendation addresses the most appropriate human resource allocation or modalities to account for psycho-social determinants of prescribing. There is a need for translation of the evidence available from human behaviour studies to the design and implementation of stewardship interventions and policies at hospital and community levels. The integration of behaviour experts into multidisciplinary stewardship teams seems essential to positively impact on prescribers’ communication and decision-making competencies, and reduce inappropriate antibiotic prescribing.
Critical Neuronal Models with Relaxed Timescale Separation
2019-06-28

Power laws in nature are considered to be signatures of complexity. The theory of self-organized criticality (SOC) was proposed to explain their origins. A long-standing principle of SOC is the separation of timescales axiom. It dictates that external input is delivered to the system at a much slower rate compared to the timescale of internal dynamics. The statistics of neural avalanches in the brain was demonstrated to follow a power law, indicating closeness to a critical state. Moreover, criticality was shown to be a beneficial state for various computations leading to the hypothesis that the brain is a SOC system. However, for neuronal systems that are constantly bombarded by incoming signals, the separation of timescales assumption is unnatural. Recently, it was experimentally demonstrated that a proper correction of the avalanche detection algorithm to account for the increased drive during task performance leads to a change of the power-law exponent from 1.5 to approximately 1.3, but there is so far no theoretical explanation for this change. Here, we investigate the importance of timescale separation, by partly abandoning it in various models. We achieve it by allowing for an external input during the avalanche, without compromising the separation of avalanches. We develop an analytic treatment and provide numerical simulations of a simple neuronal model. If the input strength scales as one over the network size, we call it a moderate input regime. In this regime, a scale-free behavior is observed; i.e., the avalanche size follows a 1.25 power law, independent of the exact size of the input. For a perfectly timescale separated system, an exponent of 1.5 is observed. Thus, the universality class of the system is changed by the external input, and the change of the exponent is in good agreement with experimental observations from nonhuman primates. We confirm our analytical findings by simulations of the more realistic branching network model.
Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer
2019-06-28

Adoptive transfer of T cells transgenic for tumor-reactive T-cell receptors (TCR) is an attractive immunotherapeutic approach. However, clinical translation is so far limited due to challenges in the identification of suitable target antigens as well as TCRs that are concurrent safe and efficient. Definition of key characteristics relevant for effective and specific tumor rejection is essential to improve current TCR-based adoptive T-cell immunotherapies. We here characterized in-depth two TCRs derived from the human leukocyte antigen (HLA)-mismatched allogeneic repertoire targeting two different myeloperoxidase (MPO)-derived peptides presented by the same HLA-restriction element side by side comprising state of the art biochemical and cellular <i>in vitro, in vivo</i>, and <i>in silico</i> experiments. <i>In vitro</i> experiments reveal comparable functional avidities, off-rates, and cytotoxic activities for both TCRs. However, we observed differences especially with respect to cytokine secretion and cross-reactivity as well as <i>in vivo</i> activity. Biochemical and <i>in silico</i> analyses demonstrate different binding qualities of MPO-peptides to the HLA-complex determining TCR qualities. We conclude from our biochemical and <i>in silico</i> analyses of peptide-HLA-binding that rigid and high-affinity binding of peptides is one of the most important factors for isolation of TCRs with high specificity and tumor rejection capacity from the MHC-mismatched repertoire. Based on our results, we developed a workflow for selection of such TCRs with high potency and safety profile suitable for clinical translation.
Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
2019-06-28

Abstract Cyclic AMP (cAMP) is involved in multiple biological processes. However, little is known about its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent) regulates conventional type-2 Dendritic Cells (cDC2s), but not cDC1s and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors (TFs) for Th2 induction. Genetic loss of IRF4 phenocopies the effects of cAMP signaling on Th17-induction, indicating that the cAMP effect is secondary to repression of IRF4. Moreover, signaling in cDC2s by a PRR-dependent microbial product, curdlan, represses IRF4 and KLF4, resulting in a pro-Th17 phenotype. These results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the novel cDC2 and cDC17 classification. In addition, the data reveal that cAMP signaling can alter DCs function and fate by repressing IRF4 and KLF4, a pathway that can be harnessed for immuno-regulation.
Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson’s disease
2019-06-28

Abstract Objective To assess genetic modifiers of Parkinson’s disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk alleles Methods We analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226). Results There was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = −1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = −2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037). Interpretation Analysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4 .
Two Sides of One Coin: A Comparison of Clinical and Neurobiological Characteristics of Convicted and Non-Convicted Pedophilic Child Sexual Offenders
2019-06-29

High prevalence of child sexual offending stand in contradiction to low conviction rates (one-tenth at most) of child sexual offenders (CSOs). Little is known about possible differences between convicted and non-convicted pedophilic CSOs and why only some become known to the judicial system. This investigation takes a closer look at the two sides of “child sexual offending” by focusing on clinical and neurobiological characteristics of convicted and non-convicted pedophilic CSOs as presented in the Neural Mechanisms Underlying Pedophilia and sexual offending against children (NeMUP)*-study. Seventy-nine male pedophilic CSOs were examined, 48 of them convicted. All participants received a thorough clinical examination including the structured clinical interview (SCID), intelligence, empathy, impulsivity, and criminal history. Sixty-one participants (38 convicted) underwent an inhibition performance task (Go/No-go paradigm) combined with functional magnetic resonance imaging (fMRI). Convicted and non-convicted pedophilic CSOs revealed similar clinical characteristics, inhibition performances, and neuronal activation. However, convicted subjects’ age preference was lower (i.e., higher interest in prepubescent children) and they had committed a significantly higher number of sexual offenses against children compared to non-convicted subjects. In conclusion, sexual age preference may represent one of the major driving forces for elevated rates of sexual offenses against children in this sample, and careful clinical assessment thereof should be incorporated in every preventive approach.
An exploratory study of patients’ sudden losses during outpatient CBT and therapists’ experience of difficulties
2019-06-29

Abstract Objective Patients’ sudden deterioration in symptomatology, also called sudden losses, is a rarely explored phenomenon. Method Psychological distress of 1,763 patients treated by 140 therapists was monitored after every therapy session. Patient‐reported outcome measures and patients’ therapy satisfaction was assessed. Therapists rated their experience of difficulties for every patient repeatedly over the course of therapy. Results More than one‐quarter of patients (26.5%) experienced at least one sudden loss during therapy. Patients with sudden losses did not differ significantly in psychotherapy outcome and therapy satisfaction from patients without sudden shifts. Therapists did not experience professional self‐doubt more often when working with sudden loss patients. Conclusion Sudden losses were not necessarily harmful for the outcome of psychotherapy and patients’ global therapy satisfaction. The results suggest that sudden losses can be compensated over the course of treatment.
Effects of Leachates from UV-Weathered Microplastic in Cell-Based Bioassays
2019-06-30

Standard ecotoxicological testing of microplastic does not provide insight into the influence that environmental weathering by, e.g., UV light has on related effects. In this study, we leached chemicals from plastic into artificial seawater during simulated UV-induced weathering. We tested largely additive-free preproduction polyethylene, polyethylene terephthalate, polypropylene, and polystyrene and two types of plastic obtained from electronic equipment as positive controls. Leachates were concentrated by solid-phase extraction and dosed into cell-based bioassays that cover (i) cytotoxicity; (ii) activation of metabolic enzymes via binding to the arylhydrocarbon receptor (AhR) and the peroxisome proliferator-activated receptor (PPARγ); (iii) specific, receptor-mediated effects (estrogenicity, ERα); and (iv) adaptive response to oxidative stress (AREc32). LC-HRMS analysis was used to identify possible chain-scission products of polymer degradation, which were then tested in AREc32 and PPARγ. Explicit activation of all assays by the positive controls provided proof-of-concept of the experimental setup to demonstrate effects of chemicals liberated during weathering. All plastic leachates activated the oxidative stress response, in most cases with increased induction by UV-treated samples compared to dark controls. For PPARγ, polyethylene-specific effects were partially explained by the detected dicarboxylic acids. Since the preproduction plastic showed low effects often in the range of the blanks future studies should investigate implications of weathering on end consumer products containing additives.
RTransferEntropy — Quantifying information flow between different time series using effective transfer entropy
2019-07-01

This paper shows how to quantify and test for the information flow between two time series with Shannon transfer entropy and Rényi transfer entropy using the R package RTransferEntropy. We discuss the methodology, the bias correction applied to calculate effective transfer entropy and outline how to conduct statistical inference. Furthermore, we describe the package in detail and demonstrate its functionality by means of several simulated processes and present an application to financial time series. Keywords: Shannon transfer entropy, Rényi transfer entropy, Effective transfer entropy, Bootstrap inference, R