julilili42/papers huggingface dataset:
Impact of organ-on-a-chip technology on pharmaceutical R&D costs
2019-06-08

Healthcare systems are faced with the challenge of providing innovative treatments, while shouldering high drug costs that pharmaceutical companies justify by the high costs of R&D. An emergent technology that could transform R&D efficiency is organ-on-a-chip. The technology bridges the gap between preclinical testing and human trials through better predictive models, significantly impacting R&D costs. Here, we present an expert survey on the future role of organ-on-a-chip in drug discovery and its potential quantitative impact. We find that the technology has the potential to reduce R&D costs significantly, driven by changes in direct costs, success rates and the length of the R&D process. Finally, we discuss regulatory challenges to efficiency improvements.
Oncogenic BRAF Alterations and Their Role in Brain Tumors
2019-06-08

Alterations of the v-raf murine sarcoma viral oncogene homolog B (BRAF) have been extensively studied in several tumor entities and are known to drive cell growth in several tumor entities. Effective targeted therapies with mutation-specific small molecule inhibitors have been developed and established for metastasized malignant melanoma. The BRAF V600E mutation and KIAA1549-BRAF fusion are alterations found in several brain tumors and show a distinct prognostic impact in some entities. Besides the diagnostic significance for the classification of central nervous system tumors, these alterations present possible therapy targets that may be exploitable for oncological treatments, as it has been established for malignant melanomas. In this review the different central nervous system tumors harboring BRAF alterations are presented and the diagnostic significance, prognostic role, and therapeutic potential are discussed.
The gender pay gap in European executive boards: the role of executives’ pathway into the board
2019-06-08

We provide cross-country evidence on the gender pay gap on executive boards in large European companies and show that the pathway into the board – internal promotion versus external recruitment – matters for the size of the gap. We find evidence that among executives, women are paid less than men – especially when they were recruited from outside. Since for external candidates, gender stereotyping, and discrimination might be more pronounced than for internal candidates, our results support a power-and-discrimination-based view rather than a market-based view. Our empirical analysis is based on individual pay data for 359 executive board members in 75 firms in six countries (UK, France, Germany, Italy, Spain, and Switzerland) from 2011 to 2014. We find an unadjusted pay penalty for women of around 17% and an estimated adjusted gender pay gap of around 11%. The size of the adjusted gender pay gap crucially depends on the executives' pathway into the board: Among the executives who were recruited from outside the firm, women receive an estimated 19% less than men. Our article suggests that the pathway into the board matters for women's bargaining position and should be explored in future studies.
Development of a Novel Polymer-Based mRNA Coating for Surgical Suture to Enhance Wound Healing
2019-06-08

A therapeutic strategy to improve wound healing has become an increasingly important medical task due to the rising incidence of adiposity and type II diabetes as well as the proceeding population aging. In order to cope with the resulting burdens, new strategies to achieve rapid and complete wound healing must now be developed. Accordingly, the development of a bioactive wound dressing in the form of a messengerRNA (mRNA)-bearing poly(lactide-co-glycolide acid) (PLGA) coating on surgical suture is being pushed further with this study. Furthermore, the evaluation of the polymer-based transfection reagent Viromer RED has shown that it can be used for the transfection of eukaryotic cells: The mRNA gets properly complexed and translated into a functional protein. In addition, the mRNA-PLGA coating triggered the expression of the keratinocyte growth factor (KGF) in HaCat cells although KGF is not expressed under physiological conditions. Moreover, transfection via surgical sutures coated with mRNA does not affect the cell viability and a proinflammatory reaction in the transfected cells is not induced. These properties make the mRNA-PLGA coating very attractive for the in vivo application. For the future, this could mean that through the use of mRNA-coated sutures in surgical wound closure, cells in the wound area can be transfected directly, thus accelerating and improving wound healing.
Effects of Compton scattering on the neutron star radius constraints in rotation-powered millisecond pulsars
2019-06-08

The 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.
Combined Ion-Trapping and Mass Balance Models To Describe the pH-Dependent Uptake and Toxicity of Acidic and Basic Pharmaceuticals in Zebrafish Embryos (Danio rerio)
2019-06-09

The aim of the current study was to understand and develop models to predict the pH-dependent toxicity of ionizable pharmaceuticals in embryos of the zebrafish Danio rerio. We found a higher uptake and toxicity with increasing neutral fraction of acids (diclofenac, genistein, naproxen, torasemide, and warfarin) and bases (metoprolol and propranolol). Simple mass balance models accounting for the partitioning to lipids and proteins in the zebrafish embryo were found to be suitable to predict the bioconcentration after 96 h of exposure if pH values did not differ much from the internal pH of 7.55. For other pH values, a kinetic ion-trap model for the zebrafish embryo explained the pH dependence of biouptake and toxicity. The total internal lethal concentrations killing 50% of the zebrafish embryos (ILC<sub>50</sub>) were calculated from the measured BCF and LC<sub>50</sub>. The resulting ILC<sub>50</sub> were independent of external pH. Critical membrane concentrations were deduced by an internal mass balance model, and apart from diclofenac, whose specific toxicity in fish had already been established, all pharmaceuticals were confirmed to act as baseline toxicants in zebrafish.
Who lived on the Swiss Plateau around 3300 BCE? Analyses of commingled human skeletal remains from the dolmen of Oberbipp
2019-06-09

Abstract Nowadays, the discovery and excavation of an almost intact Late Neolithic dolmen is rare, as those monuments were often visible in the landscape and have been investigated or destroyed in earlier times; therefore, information about the buried individuals has often been lost. The excavation of the dolmen, a stone grave chamber, from Oberbipp, Switzerland, in 2012 provided a unique opportunity to study human skeletal remains from a Late Neolithic collective burial (3350–2650 BCE). Over 2,000 fragmented and commingled skeletal elements were recovered and form the basis of this morphological study. Established morphological methods were employed to evaluate the minimum number of individuals, age at death, sex, stature, and the presence of pathological alterations and trauma. Sex was determined additionally by aDNA analysis. Elements of the entire human skeleton were recovered indicating a primary burial site. At least 42 individuals ( femora ) from all age classes (57%:43% adults to subadults) were buried in the dolmen. Based on aDNA analysis ( n = 23, partes petrosae ) slightly more males than females (44%:35% males to females, 22% indeterminate) were recovered. Stature was estimated from complete femora ( n = 3) indicating an average body height between 154–157 cm. Pathological alterations and trauma could be observed on several bones, however, without indications for major interpersonal violence. The caries intensity of Swiss samples seems to be higher compared with other Neolithic European sites. A possible separation of burial areas for males and females based on the recovery of skeletal elements within the dolmen along with aDNA results is postulated. In addition, this article contributes to a better understanding of Late Neolithic populations in Central Europe.
Education modulates brain maintenance in presymptomatic frontotemporal dementia
2019-06-10

Objective Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time. Methods Two-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling. Results Highly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers. Conclusions This longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.
The inner rod of virulence‐associated type III secretion systems constitutes a needle adapter of one helical turn that is deeply integrated into the system's export apparatus
2019-06-10

Summary Type III secretion injectisomes are essential virulence factors for many pathogenic bacteria by mediating the transport of effector proteins into eukaryotic host cells. The secretion conduit of injectisomes is formed by a helical assembly of three hydrophobic proteins (SctR, SctS and SctT), an inner rod (SctI) and a needle filament (SctF). SctI is thought to play a role in switching between the secretion of different substrate classes and assembly of the inner rod has been implicated in regulating the length of the needle filament. While high‐resolution structures of the hydrophobic components and of the needle filament have been solved, little is known about the structure and the assembly of the inner rod, which impedes the deeper assessment of its function. Here we show by exhaustive in vivo photocrosslinking that SctI engages in extensive interactions with SctR and SctT throughout its entire length. Our data imply that the inner rod serves as an adapter between the export apparatus and the needle filament by forming one helical turn. We show that assembly of the inner rod does not play a role in needle length control nor in substrate specificity switching. Instead, our findings imply that inner rod assembly must precede assembly of the needle filament.
de.NBI Cloud federation through ELIXIR AAI
2019-06-10

<ns4:p>The academic de.NBI Cloud offers compute resources for life science research in Germany. </ns4:p><ns4:p> At the beginning of 2017, de.NBI Cloud started to implement a federated cloud consisting of five compute centers, with the aim of acting as one resource to their users. A federated cloud introduces multiple challenges, such as a central access and project management point, a unified account across all cloud sites and an interchangeable project setup across the federation. In order to implement the federation concept, de.NBI Cloud integrated with the ELIXIR authentication and authorization infrastructure system (ELIXIR AAI) and in particular Perun, the identity and access management system of ELIXIR. The integration solves the mentioned challenges and represents a backbone, connecting five compute centers which are based on OpenStack and a web portal for accessing the federation.This article explains the steps taken and software components implemented for setting up a federated cloud based on the collaboration between de.NBI Cloud and ELIXIR AAI. Furthermore, the setup and components that are described are generic and can therefore be used for other upcoming or existing federated OpenStack clouds in Europe.</ns4:p>
Changes in drug load during lacosamide combination therapy: A noninterventional, observational study in German and Austrian clinical practice
2019-06-10

Abstract Introduction Effects of antiepileptic drug (AED) load changes in patients with focal seizures have not been well evaluated. Methods SP1065 (NCT01673282) was a noninterventional, prospective, observational study conducted in a clinical practice setting. Patients (aged ≥18 years) with focal seizures were enrolled within 7 days of being prescribed adjunctive lacosamide. Observation period was ~6 months. Drug load was assessed using percentage change in ratio of actual prescribed dose and World Health Organization defined daily dose (DDD) for concomitant AEDs and all AEDs (including lacosamide). Subgroups were defined for patients with at least one concomitant sodium channel–blocking AED (SCB [+]) and those without (SCB [−]). Results A total of 311 patients were assessed for safety, 302 for measurement of drug load, and 240 for effectiveness. Ratio of AED dose to DDD decreased for concomitant AEDs (−9.6%) and increased for all AEDs (including lacosamide; 15.5%). Median reduction in focal seizure frequency per 28 days was 100% (range: −100, 2275.8). 70.4% and 61.7% of patients had a ≥50% or ≥75% reduction in seizure frequency, respectively; 50.8% became seizure‐free. In the SCB (+) subgroup (n = 149), ratio of AED dose to DDD decreased for concomitant AEDs (−15.0%) and increased for all AEDs (10.7%). In the SCB (−) subgroup (n = 153), ratio of AED dose to DDD decreased for concomitant AEDs (−4.4%) and increased for all AEDs (20.2%). Fifty‐seven patients (18.3%) reported ADRs, most commonly dose &gt;400 mg/d (7.1%). Seventeen patients (5.5%) had ADRs leading to discontinuation. Significance Addition of lacosamide resulted in reduction of concomitant AED drug load regardless of whether concomitant AEDs were SCB (+) or SCB (−). These results indicate that addition of lacosamide in patients with focal seizures could allow clinicians to withdraw or reduce the dose of less well‐tolerated or less effective AEDs.
Treating Vestibular Schwannomas with Gamma-Knife Radiosurgery Versus Microsurgery: Long-Term Follow-up of 702 Cases
2019-06-10

Background: The three treatment options currently considered for vestibular schwannoma are expectant treatment, microsurgery and radiosurgey, and to date no class I evidence favors one treatment over the others. Aim of Study:The objective of this study was to compare long-term functional outcome after gamma knife radiosurgery versus surgical treatment.Methods: A group of 275 patients submitted to microsurgery and 427 patients treated with radiosurgery in two different centers were followed-up for 15.2± 13.6 months and 45.6 ± 26.8 months, respectively.We assessed tumor volumetry based on serial MR images, facial nerve function, hearing function, tinnitus, trigeminal symptoms and vertigo, and compared them between treatment groups.Results: Based on normalized volumetry over time, surgery was more efficient for tumor control than radiosurgery (p<0.001).After radiosurgery, hearing and facial nerve functions remained stable regardless of tumor size.On the other hand, after surgery, there was clinical deterioration for both small and large tumors, yet the deterioration for small tumors was very discrete, rendering quite similar functional results across groups in this category.Furthermore, surgery alleviated symptoms like facial hypoesthesia, dizziness, and tinnitus more effectively than radiosurgery. Conclusion:These results represent an important contribution to the field and offer evidence-based criteria to support the indication of a particular treatment modality according to the patient's expectations and professional activity.
Neurotechnology-aided interventions for upper limb motor rehabilitation in severe chronic stroke
2019-06-11

Abstract Upper limb motor deficits in severe stroke survivors often remain unresolved over extended time periods. Novel neurotechnologies have the potential to significantly support upper limb motor restoration in severely impaired stroke individuals. Here, we review recent controlled clinical studies and reviews focusing on the mechanisms of action and effectiveness of single and combined technology-aided interventions for upper limb motor rehabilitation after stroke, including robotics, muscular electrical stimulation, brain stimulation and brain computer/machine interfaces. We aim at identifying possible guidance for the optimal use of these new technologies to enhance upper limb motor recovery especially in severe chronic stroke patients. We found that the current literature does not provide enough evidence to support strict guidelines, because of the variability of the procedures for each intervention and of the heterogeneity of the stroke population. The present results confirm that neurotechnology-aided upper limb rehabilitation is promising for severe chronic stroke patients, but the combination of interventions often lacks understanding of single intervention mechanisms of action, which may not reflect the summation of single intervention’s effectiveness. Stroke rehabilitation is a long and complex process, and one single intervention administrated in a short time interval cannot have a large impact for motor recovery, especially in severely impaired patients. To design personalized interventions combining or proposing different interventions in sequence, it is necessary to have an excellent understanding of the mechanisms determining the effectiveness of a single treatment in this heterogeneous population of stroke patients. We encourage the identification of objective biomarkers for stroke recovery for patients’ stratification and to tailor treatments. Furthermore, the advantage of longitudinal personalized trial designs compared to classical double-blind placebo-controlled clinical trials as the basis for precise personalized stroke rehabilitation medicine is discussed. Finally, we also promote the necessary conceptual change from ‘one-suits-all’ treatments within in-patient clinical rehabilitation set-ups towards personalized home-based treatment strategies, by adopting novel technologies merging rehabilitation and motor assistance, including implantable ones.
Time‐Dependent Myocardial Necrosis in Patients With ST‐Segment–Elevation Myocardial Infarction Without Angiographic Collateral Flow Visualized by Cardiac Magnetic Resonance Imaging: Results From the Multicenter STEMI‐SCAR Project
2019-06-11

Background Acute complete occlusion of a coronary artery results in progressive ischemia, moving from the endocardium to the epicardium (ie, wavefront). Dependent on time to reperfusion and collateral flow, myocardial infarction ( MI ) will manifest, with transmural MI portending poor prognosis. Late gadolinium enhancement cardiac magnetic resonance imaging can detect MI with high diagnostic accuracy. Primary percutaneous coronary intervention is the preferred reperfusion strategy in patients with ST ‐segment–elevation MI with &lt;12 hours of symptom onset. We sought to visualize time‐dependent necrosis in a population with ST ‐segment–elevation MI by using late gadolinium enhancement cardiac magnetic resonance imaging (STEMI‐SCAR project). Methods and Results ST ‐segment–elevation MI patients with single‐vessel disease, complete occlusion with TIMI (Thrombolysis in Myocardial Infarction) score 0, absence of collateral flow (Rentrop score 0), and symptom onset &lt;12 hours were consecutively enrolled. Using late gadolinium enhancement cardiac magnetic resonance imaging, the area at risk and infarct size, myocardial salvage index, transmurality index, and transmurality grade (0–50%, 51–75%, 76–100%) were determined. In total, 164 patients (aged 54±11 years, 80% male) were included. A receiver operating characteristic curve (area under the curve: 0.81) indicating transmural necrosis revealed the best diagnostic cutoff for a symptom‐to‐balloon time of 121 minutes: patients with &gt;121 minutes demonstrated increased infarct size, transmurality index, and transmurality grade (all P &lt;0.01) and decreased myocardial salvage index ( P &lt;0.001) versus patients with symptom‐to‐balloon times ≤121 minutes. Conclusions In MI with no residual antegrade and no collateral flow, immediate reperfusion is vital. A symptom‐to‐balloon time of &gt;121 minutes causes a high grade of transmural necrosis. In this pure ST ‐segment–elevation MI population, time to reperfusion to salvage myocardium was less than suggested by current guidelines.
H.E.S.S. andSuzakuobservations of the Vela X pulsar wind nebula
2019-06-11

Context. Pulsar wind nebulae (PWNe) represent the most prominent population of Galactic very-high-energy gamma-ray sources and are thought to be an efficient source of leptonic cosmic rays. Vela X is a nearby middle-aged PWN, which shows bright X-ray and TeV gamma-ray emission towards an elongated structure called the cocoon. Aims. Since TeV emission is likely inverse-Compton emission of electrons, predominantly from interactions with the cosmic microwave background, while X-ray emission is synchrotron radiation of the same electrons, we aim to derive the properties of the relativistic particles and of magnetic fields with minimal modelling. Methods. We used data from the Suzaku XIS to derive the spectra from three compact regions in Vela X covering distances from 0.3 to 4 pc from the pulsar along the cocoon. We obtained gamma-ray spectra of the same regions from H.E.S.S. observations and fitted a radiative model to the multi-wavelength spectra. Results. The TeV electron spectra and magnetic field strengths are consistent within the uncertainties for the three regions, with energy densities of the order 10 −12 erg cm −3 . The data indicate the presence of a cutoff in the electron spectrum at energies of ~ 100 TeV and a magnetic field strength of ~6 μ G. Constraints on the presence of turbulent magnetic fields are weak. Conclusions. The pressure of TeV electrons and magnetic fields in the cocoon is dynamically negligible, requiring the presence of another dominant pressure component to balance the pulsar wind at the termination shock. Sub-TeV electrons cannot completely account for the missing pressure, which may be provided either by relativistic ions or from mixing of the ejecta with the pulsar wind. The electron spectra are consistent with expectations from transport scenarios dominated either by advection via the reverse shock or by diffusion, but for the latter the role of radiative losses near the termination shock needs to be further investigated in the light of the measured cutoff energies. Constraints on turbulent magnetic fields and the shape of the electron cutoff can be improved by spectral measurements in the energy range ≳ 10 keV.