julilili42/papers huggingface dataset:
Defining the phenotypical spectrum associated with variants in TUBB2A
2020-06-22

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. Methods In order to further refine the phenotypical spectrum associated with TUBB2A , clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. Results We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. Conclusion The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype–phenotype correlations could be established, suggesting the role of additional modifiers.
The capability approach as a bridging framework across health promotion settings: theoretical and empirical considerations
2020-06-22

Summary Health promotion research has increasingly called for transdisciplinary approaches. Such calls ask for bridging frameworks that define comprehensive sets of health determinants and appropriately conceptualize the roles of population groups as well as other relevant actor groups in the co-production of health. This article aims to present the seminal capability approach by Sen and Nussbaum as a potentially suitable framework for such bridging endeavors to guide health promotion research. It highlights domains of the capability approach that appear to be particularly relevant to bridging diverse disciplines and settings. Such domains particularly refer to the agency of decisive actor groups (population groups, professionals, policymakers and researchers) as well as to the differentiation of personal, social and environmental conversion factors that disciplines define within their specific epistemologies and ontologies. The article uses empirical examples from a German research consortium that aimed to promote physical activity in five different settings while fostering cooperation and conceptual alignment between several academic disciplines and sub-disciplines to highlight benefits and challenges of using the capability approach as a bridging framework for transdisciplinary health promotion. We conclude that the capability approach might serve as bridging framework to guide future transdisciplinary research if partners involved continuously exchange to develop a shared understanding of the issues to be researched.
Energy Level Engineering in Organic Thin Films by Tailored Halogenation
2020-06-22

Abstract In modern electronics, it is essential to adapt band structures by adjusting energy levels and band gaps. At first sight, this “band structure engineering” seems impossible in organic semiconductors, which usually exhibit localized electronic states instead of Bloch bands. However, the strong Coulomb interaction in organic semiconductors allows for a continuous shift of the ionization energy (IE) over a wide range by mixing molecules with halogenated derivatives that exhibit different quadrupole moments. Here, this effect of energy level engineering on blends of pentacene and two fluorinated derivatives, in which the position but not the number of fluorine atoms differ, is studied. Structural investigations confirm that pentacene forms intermixed phases in blends with the fluorinated species. The investigation of electronic properties and simulations reveals a much larger shift of the ionization energy (1.5 eV) than in previous studies, allowing to test this model in a range not investigated so far, and emphasizing the role of the position of the halogen atoms. The tuning effect is preserved in electronic devices such as field‐effect transistors and significantly influences device characteristics.
Development of a capillary electrophoresis–mass spectrometry method for the analysis of metformin and its transformation product guanylurea in biota
2020-06-22

Abstract A method with capillary electrophoresis coupled to mass spectrometry was optimized to determine the uptake of metformin and its metabolite guanylurea by zebrafish ( Danio rerio ) embryos and brown trout ( Salmo trutta f. fario ) exposed under laboratory conditions. Metformin was extracted from fish tissues by sonication in methanol, resulting in an absolute recovery of almost 90%. For the extraction of guanylurea from brown trout, solid-phase extraction was implemented with a recovery of 84%. The use of a mixture of methanol and glacial acetic acid as a non-aqueous background electrolyte was vital to achieve robust analysis using a bare fused-silica capillary with an applied voltage of +30 kV. Problems with adsorption associated with an aqueous background electrolyte were eliminated using a non-aqueous background electrolyte made of methanol/acetic acid (97:3) with 25 mM ammonium acetate (for zebrafish embryos) or 100 mM ammonium acetate (for brown trouts), depending on the sample complexity and matrix influences. High resolution and high separation selectivity from matrix components were achieved by optimization of the ammonium acetate concentration in the background electrolyte. An extensive evaluation of matrix effects was conducted with regard to the complex matrices present in the fish samples. They required adapting the background electrolyte to higher concentrations. Applying this method to extracts of zebrafish embryos and brown trout tissue samples, limits of detection for both metformin and guanylurea in zebrafish embryos (12.2 μg/l and 15 μg/l) and brown trout tissues (15 ng/g and 34 ng/g) were in the low μg/l or ng/g range. Finally, metformin and guanylurea could be both quantified for the first time in biota samples from exposure experiments.
In vivo test of a radiography‐based navigation system for control of derotational osteotomies
2020-06-22

Abstract Malalignment of the femur is a frequently encountered problem in orthopaedics entailing manifold consequences for the affected patients. Corrective osteotomies, necessary to restore the physiological and anatomical relationships, face great challenges due to no existing reliable gold standard for intraoperative control of torsional malalignment. The aim of this study was to test a novel radiography‐based navigation tool for control of derotational osteotomies in a clinical environment. In a first—and preliminary—case‐controlled study on 12 patients (level 3 of evidence), the achieved torsional correction measured with implementation of the navigation tool was compared with measurements from pre‐ and postoperative computed tomography (CT) scans. The navigation tool was able to acquire and process all relevant data and capture possible malrotation during surgery with only little deviations of 1.61° ± 0.86° (mean ± standard deviation) from the measurements based on CT scans. Next, the system will be used to assist surgeons for more precise treatment avoiding maltorsion after derotational osteotomies.
P4 In-Network Source Protection for Sensor Failover
2020-06-22

Automated systems like industrial applications or autonomous cars heavily rely on sensor information. To increase reliability, several sensors may be used to provide identical data, e.g., temperatures or velocity. Applications exploiting this data may either use both data streams or rely on a single primary data stream until the primary stream fails. This increases the complexity of the application and is prone to errors. In this paper we present a prototype and mechanisms for in-network sensor failover. Our novel prototype detects the failure of a primary sensor and delivers in turn the data of a redundant sensor to the application.
Measuring the Impact of MiFID II on Information Asymmetries Using Microstructure Models
2020-06-22

This paper evaluates the impact of the Markets in Financial Instruments Directive II (MiFID II) regulation on information asymmetries. The microstructure models of Madhavan et al. (1997) and Glosten and Harris (1988) are adapted to estimate potential changes in the adverse selection component of the spread. I use trade and quote data of 50 German stocks traded at the Cboe Europe Equities exchange. To classify trades in presence of uncertainly about the sequence of trades and quotes within a second, a robust classification method is developed. I find a short-term increase in adverse selection and transaction cost after the MiFID II implementation. A long-term reduction of information asymmetries due to the regulation is indicated and discussed. Keywords: Market Microstructure; MiFID II / Markets in Financial Instruments Directive II; Information Asymmetry in Limit Order Books; Trade Classification; Financial Market Regulation.
The many Spanishes of an Andean-Amazonian crossroads
2020-06-23

Abstract In the Southern Peruvian Amazon, agricultural migrants from the Andes have brought Quechua and Andean Spanish into the traditional Amazonian territory of Matsigenka speakers. This chapter offers an ethnographic and socio-historical view of Andean Spanish on one corner of this Amazonian frontier. The social life of Spanish in this region is illustrated through the lives of three community-mates, whose speech exhibits diverse contact effects reflecting the diversity of their frontier experiences. This case shows how, unlike Spanish in the Andes, which developed in the highlands without a major migratory influx from other regions, Amazonian varieties of Spanish emerged as more or less heterogeneous populations from other places migrated and came together with the speakers of dozens of local indigenous languages.
Physiologically-Based Pharmacokinetic (PBPK) Modeling of Buprenorphine in Adults, Children and Preterm Neonates
2020-06-23

Buprenorphine plays a crucial role in the therapeutic management of pain in adults, adolescents and pediatric subpopulations. However, only few pharmacokinetic studies of buprenorphine in children, particularly neonates, are available as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling allows the prediction of drug exposure in pediatrics based on age-related physiological differences. The aim of this study was to predict the pharmacokinetics of buprenorphine in pediatrics with PBPK modeling. Moreover, the drug-drug interaction (DDI) potential of buprenorphine with CYP3A4 and P-glycoprotein perpetrator drugs should be elucidated. A PBPK model of buprenorphine and norbuprenorphine in adults has been developed and scaled to children and preterm neonates, accounting for age-related changes. One-hundred-percent of the predicted AUClast values in adults (geometric mean fold error (GMFE): 1.22), 90% of individual AUClast predictions in children (GMFE: 1.54) and 75% in preterm neonates (GMFE: 1.57) met the 2-fold acceptance criterion. Moreover, the adult model was used to simulate DDI scenarios with clarithromycin, itraconazole and rifampicin. We demonstrate the applicability of scaling adult PBPK models to pediatrics for the prediction of individual plasma profiles. The novel PBPK models could be helpful to further investigate buprenorphine pharmacokinetics in various populations, particularly pediatric subgroups.
Analyzing Particle-Associated Pollutant Transport to Identify In-Stream Sediment Processes during a High Flow Event
2020-06-23

Urban areas are a leading source of polycyclic aromatic hydrocarbons (PAHs) that result from combustion processes and are emitted into rivers, especially during rain events and with particle wash-off from urban surfaces. In-stream transport of suspended particles and attached PAHs is linked strongly to sediment turnover processes. This study aimed to identify particle exchange processes that contribute to the transport of suspended particles during flood events. An urban high-flow signal was tracked in high temporal resolution at two sampling sites in the Ammer River (South-western Germany). Samples were analyzed for turbidity, total suspended solids concentrations (TSS), particle-size distribution, organic carbon, and PAH. Maximum discharge and the highest TSS occurred nearly simultaneously at the upstream sampling site, whereas a temporally shifted course was observed for downstream. The total load of particles was similar, yet a decrease of PAH mass (~28%) and an increase of the particulate organic carbon (POC) content (~3.5%-points) occurred. Coarser particles (≥26 μm) dominated at the beginning of the event at both sampling sites. The signal of remobilized riverbed sediment increases downstream and leads to well-established, robust linear correlations between TSS and PAHs. This study highlights that riverbed sediment acts as intermediate storage for contaminated particles from upstream sources that shape, together with the fresh urban input, the “particle signature” of suspensions moving through catchments during high discharge conditions.
The effect of age and gender on anti‐saccade performance: Results from a large cohort of healthy aging individuals
2020-06-23

Abstract By 2050, the global population of people aged 65 years or older will triple. While this is accompanied with an increasing burden of age‐associated diseases, it also emphasizes the need to understand the effects of healthy aging on cognitive processes. One such effect is a general slowing of processing speed, which is well documented in many domains. The execution of anti‐saccades depends on a well‐established brain‐wide network ranging from various cortical areas and basal ganglia through the superior colliculus down to the brainstem saccade generators. To clarify the consequences of healthy aging as well as gender on the execution of reflexive and voluntary saccades, we measured a large sample of healthy, non‐demented individuals ( n = 731, aged 51–84 years) in the anti‐saccade task. Age affected various aspects of saccade performance: The number of valid trials decreased with age. Error rate, saccadic reaction times (SRTs), and variability in saccade accuracy increased with age, whereas anti‐saccade costs, accuracy, and peak velocity of anti‐saccades and direction errors were not affected by age. Gender affected SRTs independent of age and saccade type with male participants having overall shorter SRTs. Our rigid and solid statistical testing using linear mixed‐effect models provide evidence for a uniform slowing of processing speed independent of the actually performed eye movement. Our data do not support the assumption of a specific deterioration of frontal lobe functions with aging.
Elevated Plasmodium sporozoite infection and multiple insecticide resistance in the principal malaria vectors Anopheles funestus and Anopheles gambiae in a forested locality close to the Yaoundé airport, Cameroon
2020-06-23

<ns4:p><ns4:bold>Background:</ns4:bold>Reducing the burden of malaria requires better understanding of vector populations, particularly in forested regions where the incidence remains elevated. Here, we characterized malaria vectors in a locality near the Yaoundé international airport, Cameroon, including species composition, abundance,<ns4:italic>Plasmodium</ns4:italic>infection rate, insecticide resistance profiles and underlying resistance mechanisms.</ns4:p><ns4:p><ns4:bold>Methods:</ns4:bold>Blood-fed adult mosquitoes resting indoors were aspirated from houses in April 2019 at Elende, a village located 2 km from the Yaoundé-Nsimalen airport. Female mosquitoes were forced to lay eggs to generate F<ns4:sub>1</ns4:sub>adult progeny. Bioassays were performed to assess resistance profile to insecticides. The threshold of insecticide susceptibility was defined above 98% mortality rate and mortality rates below 90% were indicative of confirmed insecticide resistance. Furthermore, the molecular basis of resistance and<ns4:italic>Plasmodium</ns4:italic>infection rates were investigated.</ns4:p><ns4:p><ns4:bold>Results:</ns4:bold><ns4:italic>Anopheles funestus</ns4:italic>s.s. was most abundant species in Elende (85%) followed by<ns4:italic>Anopheles gambiae</ns4:italic>s.s. (15%) with both having a similar sporozoite rate. Both species exhibited high levels of resistance to pyrethroids (&lt;40% mortality).<ns4:italic>An. gambiae</ns4:italic>s.s. was also resistant to DDT (9.9% mortality) and bendiocarb (54% mortality) while susceptible to organophosphate.<ns4:italic>An. funestus</ns4:italic>s.s. was resistant to dieldrin (1% mortality), DDT (86% mortality) but susceptible to carbamates and organophosphates. The L119F-GSTe2 resistance allele (8%) and G119S<ns4:italic>ace</ns4:italic>-1 resistance allele (15%) were detected in<ns4:italic>An. funestus</ns4:italic>s.s. and<ns4:italic>An. gambiae</ns4:italic>s.s., respectively<ns4:italic>.</ns4:italic>Furthermore, the high pyrethroid/DDT resistances in<ns4:italic>An. gambiae</ns4:italic>s.s. corresponded with an increase frequency of 1014F<ns4:italic>kdr</ns4:italic>allele (95%). Transcriptional profiling of candidate cytochrome P450 genes reveals the over-expression of<ns4:italic>CYP6P5</ns4:italic>,<ns4:italic>CYP6P9a</ns4:italic>and<ns4:italic>CYP6P9b.</ns4:italic></ns4:p><ns4:p><ns4:bold>Conclusion:</ns4:bold>The resistance to multiple insecticide classes observed in these vector populations alongside the high<ns4:italic>Plasmodium</ns4:italic>sporozoite rate highlights the challenges that vector control programs encounter in sustaining the regular benefits of contemporary insecticide-based control interventions in forested areas.</ns4:p>
The micromorphology of loess‐paleosol sequences in central Alaska: A new perspective on soil formation and landscape evolution since the Late Glacial period (c. 16,000 cal yr BP to present)
2020-06-23

Abstract The middle Tanana Valley of central Alaska contains a well‐preserved record of human occupation and paleoenvironmental change since the Late Glacial period (c. 16,000 cal yr BP) and is a critical region for understanding human dispersal into the Americas. Micromorphology analysis of soils and sediments from six archaeological sites yields valuable information about soil formation processes and landscape evolution during the Late Glacial and into the Holocene. At the macroscale, site stratigraphies are very similar, and thin organic‐rich layers (locally known as “stringers”) are commonly interpreted as buried soils. However, at the microscale, these layers exhibit significant differences in the degree of bioturbation, organic matter humification, and boundary abruptness, indicating that pedogenesis was not the sole process at every site. In this way, our microscale analysis addresses issues of equifinality related to site formation interpretations, a persistent problem with subarctic and high‐latitude stratigraphy. Additionally, this study reveals a certain level of landform and landscape instability within a broader trend of regional increases in pedogenesis and vegetation coverage, adding to the existing model of heterogeneity across this subarctic landscape. Here we demonstrate the utility of micromorphology to test field interpretations and improve models of Late Glacial landscape evolution in high‐latitude contexts.
Quality assurance in melanoma care: guideline‐based quality indicators for melanoma – implementation, evaluation and update process
2020-06-23

Summary Background In 2018, an update of the German evidence‐based (S3) guidelines “Diagnosis, Therapy and Follow‐up of Melanoma” first issued in 2013 was published under the auspices of the German Guideline Program in Oncology. The update also included a revision of existing guideline‐based quality indicators (QIs). Patients and methods Using a standardized multi‐step process, the guideline‐derived QIs were revised by a multidisciplinary, interprofessional working group based on the strong (level A) recommendations contained in the guideline update as well as on a systematic literature search for international indicators and on the outcomes of existing QIs as reported by certified German skin cancer centers. Results Based on the original set of twelve guideline‐based QIs agreed upon in 2013, the working group developed an updated set containing nine indicators. Four QIs were kept unchanged; two were modified; two were removed; and three new QIs were added. Unlike 2013, the working group was now able to incorporate the outcomes of QIs previously implemented at the various skin cancer centers. Conclusions Close cooperation between guideline group and certification commission allows for the implementation of guideline‐based QIs in cancer care. Measured outcomes form the basis for updating both the guidelines and the QI development process. They provide information about the care of cancer patients in a real‐world setting as well as on guideline adherence and the feasibility of QIs themselves. This is a dynamic process that can be described in a transparent manner and that requires regular updating.
Phosphoproteomics of short-term hedgehog signaling in human medulloblastoma cells
2020-06-23

Abstract Background Aberrant hedgehog (HH) signaling is implicated in the development of various cancer entities such as medulloblastoma. Activation of GLI transcription factors was revealed as the driving force upon pathway activation. Increased phosphorylation of essential effectors such as Smoothened (SMO) and GLI proteins by kinases including Protein Kinase A, Casein Kinase 1, and Glycogen Synthase Kinase 3 β controls effector activity, stability and processing. However, a deeper and more comprehensive understanding of phosphorylation in the signal transduction remains unclear, particularly during early response processes involved in SMO activation and preceding GLI target gene regulation. Methods We applied temporal quantitative phosphoproteomics to reveal phosphorylation dynamics underlying the short-term chemical activation and inhibition of early hedgehog signaling in HH responsive human medulloblastoma cells. Medulloblastoma cells were treated for 5.0 and 15 min with Smoothened Agonist (SAG) to induce and with vismodegib to inhibit the HH pathway. Results Our phosphoproteomic profiling resulted in the quantification of 7700 and 10,000 phosphosites after 5.0 and 15 min treatment, respectively. The data suggest a central role of phosphorylation in the regulation of ciliary assembly, trafficking, and signal transduction already after 5.0 min treatment. ERK/MAPK signaling, besides Protein Kinase A signaling and mTOR signaling, were differentially regulated after short-term treatment. Activation of Polo-like Kinase 1 and inhibition of Casein Kinase 2A1 were characteristic for vismodegib treatment, while SAG treatment induced Aurora Kinase A activity. Distinctive phosphorylation of central players of HH signaling such as SMO, SUFU, GLI2 and GLI3 was observed only after 15 min treatment. Conclusions This study provides evidence that phosphorylation triggered in response to SMO modulation dictates the localization of hedgehog pathway components within the primary cilium and affects the regulation of the SMO-SUFU-GLI axis. The data are relevant for the development of targeted therapies of HH-associated cancers including sonic HH-type medulloblastoma. A deeper understanding of the mechanisms of action of SMO inhibitors such as vismodegib may lead to the development of compounds causing fewer adverse effects and lower frequencies of drug resistance.