bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical utility of circulating tumor DNA as a response and follow-up marker in cancer therapy
Authors: Boonstra Pieter A. , Wind Thijs T. , van Kruchten Michel , Schuuring Ed , Hospers Geke A. P. , van der Wekken Anthonie J. , de Groot Derk-Jan , Schröder Carolien P. , Fehrmann Rudolf S. N. , Reyners Anna K. L.
Published: May 2020

Response evaluation for cancer treatment consists primarily of clinical and radiological assessments. In addition, a limited number of serum biomarkers that assess treatment response are available for a small subset of malignancies. Through recent technological innovations, new methods for measuring tumor burden and treatment response are becoming available. By utilization of highly sensitive techniques, tumor-specific mutations in circulating DNA can be detected and circulating tumor DNA (ctDNA) can be quantified. These so-called liquid biopsies provide both molecular information about the genomic composition of the tumor and opportunities to evaluate tumor response during therapy. Quantification of tumor-specific mutations in plasma correlates well with tumor burden. Moreover, with liquid biopsies, it is also possible to detect mutations causing secondary resistance during treatment. This review focuses on the clinical utility of ctDNA as a response and follow-up marker in patients with non-small cell lung cancer, melanoma, colorectal cancer, and breast cancer. Relevant studies were retrieved from a literature search using PubMed database. An overview of the available literature is provided and the relevance of ctDNA as a response marker in anti-cancer therapy for clinical practice is discussed. We conclude that the use of plasma-derived ctDNA is a promising tool for treatment decision-making based on predictive testing, detection of resistance mechanisms, and monitoring tumor response. Necessary steps for translation to daily practice and future perspectives are discussed.
Regional Variations in Alirocumab Dosing Patterns in Patients with Heterozygous Familial Hypercholesterolemia During an Open-Label Extension Study
Authors: Langslet Gisle , Hovingh G. Kees , Guyton John R. , Baccara-Dinet Marie T. , Letierce Alexia , Manvelian Garen , Farnier Michel
Published: May 2020

Purpose

During the alirocumab open-label extension study ODYSSEY OLE (open-label extension; NCT01954394), physicians could adjust alirocumab dosing for enrolled patients, who were diagnosed with heterozygous familial hypercholesterolemia (HeFH) and who had completed previous phase III clinical trials with alirocumab. This post hoc analysis evaluated the differences in physician–patient dosing decisions between the regions of Western Europe, Eastern Europe, North America, and the rest of the world (ROW).

Methods

Patients (n = 909) who received starting dose alirocumab 75 mg every 2 weeks (Q2W) during ODYSSEY OLE (patients from FH I, FH II, and LONG TERM parent studies) were included. Low-density lipoprotein cholesterol (LDL-C) levels were blinded until week 8; subsequently, LDL-C values were communicated to physicians. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible.

Results

Mean LDL-C values used for the decision to increase dose from 75 to 150 mg Q2W were higher in Eastern Europe (3.7 mmol/L; 144.0 mg/dL) and ROW (3.8 mmol/L; 145.2 mg/dL) compared with Western Europe (3.1 mmol/L; 118.6 mg/dL) and North America (3.3 mmol/L; 126.6 mg/dL). Irrespective of region, the mean LDL-C at the time of decision to maintain at 75 mg Q2W was approximately 1.8 mmol/L (70 mg/dL). During ODYSSEY OLE (median treatment duration of 131.7 weeks), alirocumab was shown to have no unexpected long-term safety concerns.

Conclusions

In this OLE study, the observed variations in clinical treatment decisions suggest that physicians may perceive the severity of HeFH and/or the treatment of HeFH differently depending on their region.
From Path Integrals to Dynamical Algebras: A Macroscopic View of Quantum Physics
Authors: Buchholz Detlev , Fredenhagen Klaus
Published: May 2020

The essence of the path integral method in quantum physics can be expressed in terms of two relations between unitary propagators, describing perturbations of the underlying system. They inherit the causal structure of the theory and its invariance properties under variations of the action. These relations determine a dynamical algebra of bounded operators which encodes all properties of the corresponding quantum theory. This novel approach is applied to non-relativistic particles, where quantum mechanics emerges from it. The method works also in interacting quantum field theories and sheds new light on the foundations of quantum physics.
Language and imagined Gesellschaft: Émile Durkheim’s civil-linguistic nationalism and the consequences of universal human ideals
Authors: Tada Mitsuhiro
Published: May 2020

When Thomas Luckmann, a pioneer of the “linguistic turn” in sociology, regarded Émile Durkheim as a source for the sociology of language, he had lifeworldly community–building in mind. However, the French sociologist himself understood language in the context ofcivil society–building. To Durkheim, language was a “social thing in the highest degree” that enabled general ideas and intermediated them to people. Abstract human ideals like the civil religion since the French Revolution could be shared through (a common) language. Thus, Durkheim took the exclusive use of French in the Third Republic’s laic public education for granted, ignoring the patois in the country: This “child of the Enlightenment” considered French to be a universal language ofGesellschaftand, beyond ethno-communal elements, to work as a basis for the organic solidarity of French national civil society where the social division of labor was progressing. Durkheim’s theory was predicated on civil-linguistic, not ethnolinguistic, nationalism.
Why do startups pursue initial coin offerings (ICOs)? The role of economic drivers and social identity on funding choice
Authors: Schückes Magnus , Gutmann Tobias
Published: May 2020

Initial coin offerings (ICOs) are a novel form of funding that has driven billions of dollars into the blockchain ecosystem, potentially challenging traditional funding vehicles such as business angel or venture capital investments. However, little is known of entrepreneurs’ rationales for leveraging this emerging form of financing. This article investigates the economic and behavioral factors that motivate entrepreneurs to fund their startup operations with ICOs. By conducting in-depth interviews with C-level managers or founders of ICO-funded startups, our analysis reveals four dimensions that have an impact on the decision: (1) funding, (2) community building, (3) tokenomics, and (4) personal and ideological drivers. Our findings suggest that the entrepreneur’s social identity in conjunction with the enabling mechanisms of the blockchain technology shape entrepreneurial pursuits and funding choice. We contribute to the literature on entrepreneurial finance by increasing understanding of ICOs and to the literature on entrepreneurial decision making by providing qualitative insights into the influence of founder identity on key decisions in startups such as financing.
Zurück zur Norm? Kompromissbildung zwischen geschlechtstypischen und -untypischen Berufsaspirationen, Bewerbungs- und Ausbildungsberufen
Authors: Kleinert Corinna , Schels Brigitte
Published: May 2020

Die Studie untersucht, inwieweit Schülerinnen und Schüler in Haupt- und Realschulzweigen zum Ende der Schulzeit geschlechts(un)typische Aspirationen haben, sich in ihren Bewerbungen und mit dem ersten Ausbildungsberuf jedoch für davon abweichende Berufe entscheiden. Die Untersuchung zieht dafür Daten aus einer lokalen Längsschnittbefragung Jugendlicher im Schulentlassjahr aus dem Jahr 2011/2012 heran, die sich für betriebliche und schulische Ausbildungsplätze beworben haben. Mit Mehrebenenmodellen werden Differenzen in der Geschlechtstypik zwischen realistischen Berufsaspirationen, Zielberufen im Bewerbungsverlauf sowie dem ersten Ausbildungsberuf geschätzt. In den Ergebnissen stellt sich die Bewerbungsphase als Prozess der Kompromissbildung hin zur geschlechterkonformen Norm dar. Dabei weichen die Bewerbungsberufe und Ausbildungsberufe der jungen Frauen unabhängig vom Schultyp und Schulleistungen stärker von ihren Aspirationen ab als bei den jungen Männern. Insbesondere junge Frauen aus den höheren Statusgruppen geben untypischere Aspirationen im Bewerbungsprozess auf. Bei den jungen Männern sind vor allem die Bewerbungs- und Ausbildungsberufe von Hauptschülern sowie Schülern mit geschlechtsuntypischen Notenrelationen geschlechterkonformer als ihre Aspirationen. In Summe tragen diese Anpassungsprozesse im Bewerbungsverhalten und der Platzierung im Ausbildungssystem – zusätzlich zu geschlechtstypischen Aspirationen – zur Persistenz beruflicher Segregation in Deutschland bei.
Calibration of High-Frequency Mechanical Impact Simulation Based on Drop Tests
Authors: Gkatzogiannis Stefanos , Knoedel Peter , Ummenhofer Thomas
Published: May 2020

A series of drop tests was implemented in the present study in order to allow the reproduction of a single impact identical to the high frequency mechanical impact (HFMI) under monitored conditions in the laboratory. Therewith, characterization of the investigated material’s mechanical behavior by explicitly considering possible irregularities concerning the present deformation modes would be enabled. Main goal was the determination of the investigated material’s dynamic yield stress for various strain rates inside the spectrum of interest, so that the Cowper–Symonds viscous material model would be calibrated for the subsequent HFMI simulation. The values of the dynamic yield stress extracted by the present drop tests show good agreement with other experimental methods regarding the investigated material S355. The introduction of the calibrated material behavior on the present drop tests in the finite element (FE) analysis of HFMI led to reduced preciseness though, in comparison with the FE analysis, which considered high strain rate tensile tests found in literature. A series of conclusions was drawn from both the experimental and numerical investigations, confirming most of the initial expectations. Further work is proposed, in order to clarify an incompatibility met during the numerical investigations.
Ensemble forecasting system for the management of the Senegal River discharge: application upstream the Manantali dam
Authors: Ndione Didier Maria , Sambou Soussou , Kane Seïdou , Diatta Samo , Sane Moussé Landing , Leye Issa
Published: May 2020

Providing useful inflow forecasts of the Manantali dam is critical for zonal consumption and agricultural water supply, power production, flood and drought control and management (Shin et al., Meteorol Appl 27:e1827, 2019). Probabilistic approaches through ensemble forecasting systems are often used to provide more rational and useful hydrological information. This paper aims at implementing an ensemble forecasting system at the Senegal River upper the Manantali dam. Rainfall ensemble is obtained through harmonic analysis and an ARIMA stochastic process. Cyclical errors that are within rainfall cyclical behavior from the stochastic modeling are settled and processed using multivariate statistic tools to dress a rainfall ensemble forecast. The rainfall ensemble is used as input to run the HBV-light to product streamflow ensemble forecasts. A number of 61 forecasted rainfall time series are then used to run already calibrated hydrological model to produce hydrological ensemble forecasts called raw ensemble. In addition, the affine kernel dressing method is applied to the raw ensemble to obtain another ensemble. Both ensembles are evaluated using on the one hand deterministic verifications such the linear correlation, the mean error, the mean absolute error and the root-mean-squared error, and on the other hand, probabilistic scores (Brier score, rank probability score and continuous rank probability score) and diagrams (attribute diagram and relative operating characteristics curve). Results are satisfactory as at deterministic than probabilistic scale, particularly considering reliability, resolution and skill of the systems. For both ensembles, correlation between the averages of the members and corresponding observations is about 0.871. In addition, the dressing method globally improved the performances of ensemble forecasting system. Thus, both schemes system can help decision maker of the Manantali dam in water resources management.
Barriers to Insurance as a Flood Risk Management Tool: Evidence from a Survey of Property Owners
Authors: Thistlethwaite Jason , Henstra Daniel , Brown Craig , Scott Daniel
Published: May 2020

By using risk-adjusted price signals to transfer responsibility for property-level flood protection and recovery from governments to property owners, flood insurance represents a key tenet of the flood risk management (FRM) paradigm. The Government of Canada has worked with insurers to introduce flood insurance for the first time as a part of a broader shift towards FRM to limit the growing costs of flooding. The viability of flood insurance in Canada, however, has been questioned by research that disputes the utility of purchasing coverage by property owners. This study tested this assumption by drawing on public opinion survey data to assess factors that influence decisions about the utility of insurance. The findings reveal that Canadians have limited knowledge of flood insurance coverage, exhibit a low willingness-to-pay for both insurance and property-level flood protection measures, and expect governments to shoulder much of the financial burden of flood recovery through disaster assistance.
Development of ground vibration test based flutter emulation technique
Authors: Yun J.-M. , Han J.-H.
Published: May 2020

In demand of simpler and alternative ground flutter test, a new technique that emulates flutter on the ground has recently emerged. In this paper, an improvement of the test technique is made and verified through the experimental work. The technique utilizes general ground vibration test (GVT) devices. The key idea is to emulate the distributed unsteady aerodynamic force by using a few concentrated actuator forces; referred to as emulated flutter test (EFT) technique. The EFT module contains two main logics; namely, real-time aerodynamic equivalent force calculator and multi-input-multi-output (MIMO) force controller. The module is developed to emulate the subsonic, linear flutter on a specified target structure, which is a thin aluminum clamped-plate with aspect ratio (AR) of 2.25. In this study, doublet hybrid method (DHM) was applied to model the subsonic aerodynamic force, which restricts the application to a 2-dimensional structure. Given that, correlation of several experimental works, such as wind-tunnel flutter test, EFT using laser displacement sensor (LDS), and EFT using accelerometer, on the target structure are investigated to verify the technique. In addition to the flutter boundary, flutter mode shape and trend of aerodynamic damping effect are also presented in this work. Together with these various kinds of test results, application of more compact actuator and an accelerometer as a sensor, makes the current technique the most advanced ground flutter emulation test method.
Benefit–Cost Analysis of Community-Led Total Sanitation: Incorporating Results from Recent Evaluations
Authors: Radin Mark , Jeuland Marc , Wang Hua , Whittington Dale
Published: May 2020

We analyze the economic costs and benefits of “community-led total sanitation” (CLTS), a sanitation intervention that relies on community-level behavioral change, in a hypothetical rural region in sub-Saharan Africa with 200 villages and 100,000 people. The analysis incorporates data on the effectiveness of CLTS from recent randomized controlled trials and other evaluations. The net benefits of this intervention are estimated both with and without the inclusion of a positive health externality, that is, the additional reduction in diarrhea for an individual when a sufficient proportion of other individuals in the community construct and use latrines and thereby decrease the overall load of waterborne pathogens and fecal bacteria in the environment. We find that CLTS interventions would pass a benefit–cost test in many situations, but that outcomes are not as favorable as some previous studies suggest. The model results are sensitive to baseline conditions, including the value of time, income level used to calculate the value of a statistical life, discount rate, case fatality rate, diarrhea incidence, and time spent traveling to defecation sites. We conclude that many communities likely have economic investment opportunities that are more attractive than CLTS, and recommend careful economic analysis of CLTS in specific locations.
Integral functionals under the excursion measure
Authors: Wiśniewolski Maciej
Published: May 2020

A new approach to the problem of finding the distribution of integral functionals under the excursion measure is presented. It is based on the technique of excursion straddling a time, stochastic analysis, and calculus on local time, and it is done for Brownian motion with drift reflecting at 0, and under some additional assumptions for some class of Itó diffusions. The new method is an alternative to the classical potential-theoretic approach and gives new specific formulas for distributions under the excursion measure.
Influence of dietary zinc on growth, zinc bioaccumulation and expression of genes involved in antioxidant and innate immune in juvenile mud crabs (Scylla paramamosain)
Authors: Luo Jiaxiang , Zhu Tingting , Jin Min , Cheng Xin , Yuan Ye , Wang Xuexi , Lu Jingjing , Jiao Lefei , Tocher Douglas R. , Zhou Qicun
Published: May 2020

The aim of the present study was to investigate the effects of dietary Zn level on growth performance, Zn bioaccumulation, antioxidant capacity and innate immunity in juvenile mud crabs (Scylla paramamosain). Six semi-purified diets were formulated to contain dietary Zn levels of 44·5, 56·9, 68·5, 97·3, 155·6 or 254·7 mg/kg. Dietary Zn level significantly influenced percentage weight gain (PWG), with the highest observed in crabs fed the diet containing 97·3 mg/kg Zn. Tissue Zn concentrations significantly increased as dietary Zn levels increased from 44·5 to 254·7 mg/kg. Retention of Zn in hepatopancreas increased with dietary Zn levels up to 68·5 mg/kg and then significantly decreased. Moreover, inadequate dietary Zn (44·5 and 56·9 mg/kg) reduced antioxidation markers including total superoxide dismutase (SOD) and Cu/Zn SOD activities and total antioxidant level. Crabs fed the diet with 44·5 mg/kg Zn also showed significantly lower expression of genes involved in antioxidant status, such as Cu/Zn SOD, glutathione peroxidase, catalase and thioredoxin than those fed diets containing 68·5 and 97·3 mg/kg Zn. The highest activities of phenoloxidase and alkaline phosphatase were recorded in crabs fed the diets containing 68·5 and 97·3 mg/kg Zn. Expression levels of prophenoloxidase and toll-like receptor 2 were higher in crabs fed the 97·3 mg/kg Zn diet compared with crabs fed the other diets. Based on PWG alone, the optimal dietary Zn level was estimated to be 82·9 mg/kg, with 68·5 to 97·3 mg/kg recommended for maintaining optimal Zn bioaccumulation, oxidation resistance and innate immune response of juvenile mud crabs.
Wi-Fi Fine Time Measurement: Data Analysis and Processing for Indoor Localisation
Authors: Yu Yue , Chen Ruizhi , Liu Zuoya , Guo Guangyi , Ye Feng , Chen Liang
Published: May 2020

Indoor positioning systems have received increasing attention for supporting location-based services in indoor environments. Wi-Fi based indoor localisation has become attractive due to its extensive distribution and low cost properties. IEEE 802.11-2016 now includes a Wi-Fi Fine Time Measurement (FTM) protocol which can be used for Wi-Fi ranging between intelligent terminal and Wi-Fi access point. This paper introduces a framework of Wi-Fi FTM data acquisition and processing that can be used for indoor localisation. We analyse the main factors that affect the accuracy of Wi-Fi ranging and propose a calibration, filtering and modelling algorithm that can effectively reduce the ranging error caused by clock deviation, non-line-of-sight (NLOS) and multipath propagation. Experimental results show that the proposed calibration and filtering method is able to achieve metre-level ranging accuracy in case of line-of-sight by using large bandwidth. Estimation results also show that the proposed Wi-Fi ranging model provides an accurate ranging performance in NLOS and multipath contained indoor environment; the final positioning error is less than 2·2 m with a stable output frequency of 3 Hz.
Optimising the case-crossover design for use in shared exposure settings
Authors: Braeye T. , Hens N.
Published: May 2020

With a case-crossover design, a case's exposure during a risk period is compared to the case's exposures at referent periods. The selection of referents for this self-controlled design is determined by the referent selection strategy (RSS). Previous research mainly focused on systematic bias associated with the RSS. We additionally focused on how RSS determines the number of referents per risk, sensitivity to overdispersion and time-varying confounding.

We illustrated the consequences of different RSS using a simulation study informed by data on meteorological variables and Legionnaires’ disease. By randomising the events and exposure time series, we explored statistical power associated with time-stratified and fixed bidirectional RSS and their susceptibility to systematic bias and confounding bias. In addition, we investigated how a high number of events on the same date (e.g. outbreaks) affected coefficient estimation. As illustrated by our work, referent selection alone can be insufficient to control for a time-varying confounding bias. In contrast to systematic bias, confounding bias can be hard to detect. We studied potential solutions: varying the model parameters and link-function, outlier-removal and aggregating the input-data over smaller areas. Our simulation study offers a framework for researchers looking to detect and to avoid bias in case-crossover studies.
Chronic illness in childhood and early adolescence: A longitudinal exploration of co-occurring mental illness
Authors: Brady Ann Marie , Deighton Jessica , Stansfeld Stephen
Published: May 2020

Chronic health conditions are hypothesized to disrupt the typical trajectory of child and adolescent development, and subsequently lead to increased levels of mental illness. However, due to methodological limitations in existing studies, this theory remains to be fully substantiated by empirical research. This study aimed to more thoroughly test hypotheses in the field. This study used data from the Avon Longitudinal Study of Parents and Children to examine the co-occurrence of mental illness among children with chronic illness in late childhood into early adolescence and explore mediating factors in these outcomes. Children with chronic health problems presented with a disproportionate rate of psychiatric illness at 10 years, and these chronic health problems continued to be associated with poor mental health outcomes at 13 years and 15 years. These outcomes were mediated by high levels of peer victimization and health-related school absenteeism. This study suggests that chronic illness may impact on functioning and social development in early adolescence, and consequently lead to increased rates of mental illness. Examining rates of school absenteeism and peer victimization may be key to identifying children at risk over time.
Validation of Spring Wheat Responses to Elevated CO2, Irrigation, and Nitrogen Fertilization in the Community Land Model 4.5
Authors: Lu Yaqiong , Kimball Bruce A.
Published: May 2020

The Community Land Model (CLM) started to incorporate crop growth models since version 4.0 in 2012. Since then, the crop model in CLM has been evolved remarkably, but some of the key crop growth responses to environmental conditions (such as the elevated CO2) have not been well validated. Here, we set up single point simulations with CLM (version 4.5) and validated spring wheat growth response against the Maricopa spring wheat Free Air CO2 Enrichment (FACE) experiment that consisted of multiyear paired treatments to understand the growth response to elevated CO2, irrigation, nitrogen fertilization, and their interactions. Overall, CLM showed too positive growth response to elevated CO2 but insufficient growth response to irrigation. The overestimated growth response to elevated CO2 may be due to ignoring factors (e.g., leaf traits) that will limit crop growth under elevated CO2. The insufficient response to irrigation is due to CLM simulating lower latent heat flux during April and May, which resulted in higher soil moisture. In response to nitrogen fertilization, CLM underestimated leaf area index increase but overestimated grain yield increase. In terms of energy fluxes, CLM showed decreased latent heat flux in response to elevated CO2 but increased latent heat flux in response to nitrogen fertilization, but the response magnitude was much smaller than the observations. Based on these validations, we summarized further model developments for CLM to better simulate crop growth process.
Soil Uptake of Volatile Organic Compounds: Ubiquitous and Underestimated?
Authors: Rinnan Riikka , Albers Christian N.
Published: May 2020

Volatile organic compound (VOC) emissions from ecosystems to the atmosphere have been widely studied, and the importance of soil contributions to VOC fluxes has received increasing attention. We suggest that while soil VOC emissions may be important in some situations, soil uptake of VOCs by microbial degradation is likely an omnipresent process, as also recently suggested by Trowbridge et al. (2020, https://doi.org/10.1029/2019JG005479). To be able to model net VOC fluxes, we need to be able to estimate both soil release and uptake processes and their drivers.
Transpressive Deformation in the Southern European Variscan Belt: New Insights From the Aiguilles Rouges Massif (Western Alps)
Authors: Simonetti M. , Carosi R. , Montomoli C. , Cottle J. M. , Law R. D.
Published: May 2020

Despite the Mediterranean sector of the Variscan Belt being fragmented and reworked during Alpine orogenesis, evidence for the activity of a right‐lateral strike‐slip shear zone has been reported in Paleozoic fragments of the belt such as the Sardinian Variscan Basement, the Maures Massif of southern France, and in the Western Alps. To improve this correlation with new structural data, we performed a structural and microstructural analysis incorporating study of the kinematics of flow and petrochronology of a high‐strain zone in the Aiguilles Rouges Massif (External Crystalline Massifs, Western Alps). The results higlight a dextral pure‐shear dominated transpression initiated under amphibolite‐facies metamorphic conditions (~630°C, 0.4 GPa) during Variscan time. The structural evolution of the high‐strain zone is similar to the Ferriere‐Mollières shear zone in the Argentera Massif; both are transpressive shear zones active at the same time (~320 Ma) under similar metamorphic conditions. These two high‐strain zones represent well‐preserved segments of a system of ductile shear zones in the External Crystalline Massifs. The data presented in this study provide improved constraints on the extent, kinematics, and timing of the East Variscan Shear Zone in the Variscan basement of the Western Alps, with implications for refining the correlation between structures in fragments of the southern Variscan Belt. The data also better constrain a segment of a major pre‐Alpine shear zone which may have played an important role during post‐Variscan tectonics as an inherited discontinuity.
Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter
Authors: Bentea Eduard , Villers Agnès , Moore Cynthia , Funk Adam J. , O’Donovan Sinead M. , Verbruggen Lise , Lara Olaya , Janssen Pauline , De Pauw Laura , Declerck Noemi B. , DePasquale Erica A. K. , Churchill Madeline J. , Sato Hideyo , Hermans Emmanuel , Arckens Lutgarde , Meshul Charles K. , Ris Laurence , McCullumsmith Robert E. , Massie Ann
Published: May 2020

The astrocytic cystine/glutamate antiporter system xc− represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system xc−, xCT (xCT−/− mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT−/− mice. A proteomic and kinomic screen of the striatum of xCT−/− mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT−/− mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system xc− plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior.
Breaking through the glioblastoma micro-environment via extracellular vesicles
Authors: Simon Thomas , Jackson Ellen , Giamas Georgios
Published: May 2020

Glioblastoma (GBM) is the most common and most aggressive brain tumour. Prognosis remains poor, despite the combined treatment of radio- and chemotherapy following surgical removal. GBM cells coexist with normal non-neoplastic cells, including endothelial cells, astrocytes and immune cells, constituting a complex and dynamic tumour micro-environment (TME). Extracellular vesicles (EVs) provide a critical means of bidirectional inter-cellular communication in the TME. Through delivery of a diverse range of genomic, lipidomic and proteomic cargo to neighbouring and distant cells, EVs can alter the phenotype and function of the recipient cell. As such, EVs have demonstrated their role in promoting angiogenesis, immune suppression, invasion, migration, drug resistance and GBM recurrence. Moreover, EVs can reflect the phenotype of the cells within the TME. Thus, in conjunction with their accessibility in biofluids, they can potentially serve as a biomarker reservoir for patient prognosis, diagnosis and predictive therapeutic response as well as treatment follow-up. Furthermore, together with the ability of EVs to cross the blood–brain barrier undeterred and through the exploitation of their cargo, EVs may provide an effective mean of drug delivery to the target site. Unveiling the mechanisms by which EVs within the GBM TME are secreted and target recipient cells may offer an indispensable understanding of GBM that holds the potential to provide a better prognosis and overall quality of life for GBM patients.
MiR-93 is related to poor prognosis in pancreatic cancer and promotes tumor progression by targeting microtubule dynamics
Authors: Vila-Navarro Elena , Fernandez-Castañer Elena , Rovira-Rigau Maria , Raimondi Giulia , Vila-Casadesus Maria , Lozano Juan Jose , Soubeyran Philippe , Iovanna Juan , Castells Antoni , Fillat Cristina , Gironella Meritxell
Published: May 2020

Biomarkers and effective therapeutic agents to improve the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) are urgently required. We aimed to analyze the prognostic value and mechanistic action of miR-93 in PDAC. Correlation of miR-93 tumor levels from 83 PDAC patients and overall survival (OS) was analyzed by Kaplan–Meier. MiR-93 depletion in PANC-1 and MIA PaCa-2 cells was achieved by CRISPR/Cas9 and miR-93 overexpression in HPDE cells by retroviral transduction. Cell proliferation, migration and invasion, cell cycle analysis, and in vivo tumor xenografts in nude mice were assessed. Proteomic analysis by mass spectrometry and western-blot was also performed. Finally, miR-93 direct binding to candidate mRNA targets was evaluated by luciferase reporter assays. High miR-93 tumor levels are significantly correlated with a worst prognosis in PDAC patients. MiR-93 abolition altered pancreatic cancer cells phenotype inducing a significant increase in cell size and a significant decrease in cell invasion and proliferation accompanied by a G2/M arrest. In vivo, lack of miR-93 significantly impaired xenograft tumor growth. Conversely, miR-93 overexpression induced a pro-tumorigenic behavior by significantly increasing cell proliferation, migration, and invasion. Proteomic analysis unveiled a large group of deregulated proteins, mainly related to G2/M phase, microtubule dynamics, and cytoskeletal remodeling. CRMP2, MAPRE1, and YES1 were confirmed as direct targets of miR-93. MiR-93 exerts oncogenic functions by targeting multiple genes involved in microtubule dynamics at different levels, thus affecting the normal cell division rate. MiR-93 or its direct targets (CRMP2, MAPRE1, or YES1) are new potential therapeutic targets for PDAC.
A standardized patient-centered characterization of the phenotypic spectrum of PCDH19 girls clustering epilepsy
Authors: Kolc Kristy L. , Sadleir Lynette G. , Depienne Christel , Marini Carla , Scheffer Ingrid E. , Møller Rikke S. , Trivisano Marina , Specchio Nicola , Pham Duyen , Kumar Raman , Roberts Rachel , Gecz Jozef
Published: May 2020

Protocadherin-19 (PCDH19) pathogenic variants cause an early-onset seizure disorder called girls clustering epilepsy (GCE). GCE is an X-chromosome disorder that affects heterozygous females and mosaic males, however hemizygous (“transmitting”) males are spared. We aimed to define the neuropsychiatric profile associated with PCDH19 pathogenic variants and determine if a clinical profile exists for transmitting males. We also examined genotype- and phenotype–phenotype associations. We developed an online PCDH19 survey comprising the following standardized assessments: The Behavior Rating Inventory of Executive Function; the Social Responsiveness Scale, 2nd edition; the Strengths and Difficulties Questionnaire; and the Dimensional Obsessive-Compulsive Scale. Genetic, seizure, and developmental information were also collected. The survey was completed by patients or by caregivers on behalf of patients. Of the 112 individuals represented (15 males), there were 70 unique variants. Thirty-five variants were novel and included a newly identified recurrent variant Ile781Asnfs*3. There were no significant differences in phenotypic outcomes between published and unpublished cases. Seizures occurred in clusters in 94% of individuals, with seizures resolving in 28% at an average age of 17.5 years. Developmental delay prior to seizure onset occurred in 18% of our cohort. Executive dysfunction and autism spectrum disorder (ASD) occurred in approximately 60% of individuals. The ASD profile included features of attention-deficit hyperactivity disorder. In addition, 21% of individuals met criteria for obsessive-compulsive disorder that appeared to be distinct from ASD. There were no phenotypic differences between heterozygous females and mosaic males. We describe a mosaic male and two hemizygous males with atypical clinical profiles. Earlier seizure onset age and increased number of seizures within a cluster were associated with more severe ASD symptoms (p = 0.001), with seizure onset also predictive of executive dysfunction (p = 4.69 × 10−4) and prosocial behavior (p = 0.040). No clinical profile was observed for transmitting males. This is the first patient-derived standardized assessment of the neuropsychiatric profile of GCE. These phenotypic insights will inform diagnosis, management, and prognostic and genetic counseling.
Prognostic factors, therapeutic approaches, and distinct immunobiologic features in patients with primary mediastinal large B-cell lymphoma on long-term follow-up
Authors: Zhou Hui , Xu-Monette Zijun Y. , Xiao Ling , Strati Paolo , Hagemeister Fredrick B. , He Yizi , Chen Huan , Li Yajun , Manyam Ganiraju C. , Li Yong , Montes-Moreno Santiago , Piris Miguel A. , Young Ken H.
Published: May 2020

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL) without prognostic factors or a single standard of treatment clearly defined. In this study we performed retrospective analysis for clinical outcomes of 166 patients with PMBCL. In overall PMBCL, higher International Prognostic Index, stage, Ki-67 proliferation index, and positron emission tomography (PET) maximum standardized uptake values (SUVmax) at diagnosis were significantly associated with poorer survival, whereas MUM1 expression and higher peripheral blood lymphocyte/monocyte ratios were significantly associated with better survival. Patients who received R-HCVAD or R-EPOCH had better clinical outcome than did those who received the standard treatment R-CHOP. Treatment response and end-of-treatment PET SUVmax had remarkable correlations with survival outcome. In patients with refractory or relapsed PMBCL, stem cell transplant significantly improved overall survival. PMBCL had distinct gene expression signatures compared with overall DLBCL–NOS but not with DLBCL with PD-L1/PD-L2 amplification. PMBCL also showed higher PD-L2 expression in B-cells, lower PD-1 expression in T-cells, and higher CTLA-4 expression in T-cells and distinct miRNA signatures compared with DLBCL-NOS. The prognostic factors, effectiveness of treatment, transcriptional and epigenetic signatures, and immunologic features revealed by this study enrich our understanding of PMBCL biology and support future treatment strategy.
Characteristics and outcomes of patients with therapy-related acute myeloid leukemia with normal karyotype
Authors: Samra Bachar , Richard-Carpentier Guillaume , Kadia Tapan M. , Ravandi Farhad , Daver Naval , DiNardo Courtney D. , Issa Ghayas C. , Bose Prithviraj , Konopleva Marina Y. , Yilmaz Musa , Ohanian Maro , Borthakur Gautam , Garcia-Manero Guillermo , Pierce Sherry , Cortes Jorge E. , Kantarjian Hagop , Short Nicholas J.
Published: May 2020

Normal karyotype in therapy-related acute myeloid leukemia (t-AML) is rare and the relative contribution of prior exposure to chemotherapy or radiotherapy to outcomes in these patients remains uncertain. We performed a retrospective study of 742 patients with newly diagnosed AML and normal karyotype (t-AML, n = 61, and non-t-AML, n = 681). Patients with t-AML were older but had a similar mutational profile compared to those with non-t-AML. Overall survival (OS) and relapse-free survival (RFS) were significantly worse for patients with t-AML (P < 0.01 and P = 0.02, respectively). Patients with t-AML had a higher cumulative incidence of death in remission (51% versus 16%, P < 0.01), but not higher cumulative incidence of relapse (42% versus 56%, respectively, P = 0.21). Both intensive induction and allogeneic hematopoietic stem cell transplantation in first remission were associated with improved OS and RFS in non-t-AML but not in t-AML. Overall, although disease biology appears similar between t-AML and non-t-AML with normal karyotype as indicated by similar risks of relapse, death in remission is the main driver of inferior outcome in t-AML. Careful therapeutic decisions are required to mitigate potential treatment-related toxicity in this rare subgroup of patients with t-AML and normal karyotype.
Evaluation of medical and surgical decompression in patients with dysthyroid optic neuropathy
Authors: Garip Kuebler Aylin , Wiecha Caroline , Reznicek Lukas , Klingenstein Annemarie , Halfter Kathrin , Priglinger Siegfried , Hintschich Christoph
Published: May 2020

Purpose

To evaluate the effectiveness of steroid-pulse therapy and three-wall orbital decompression in patients with dysthyroid optic neuropathy (DON).

Methods

Twenty-five patients (46 eyes) with a diagnosis of DON between 2008 and 2015 were included in the study. The first group (7 patients, 16 eyes) consisted of patients with a steroid-pulse treatment only and the second group (18 patients, 30 eyes) included patients with medical and surgical decompression.

Results

Twenty patients were female; five patients were male. After the diagnosis of DON, all patients were treated with steroid-pulse treatment (intravenous 500 mg prednisolon twice/week for 4 weeks, 250 mg twice/week for 2 weeks) as a first-line treatment (medical decompression). In 30 eyes (18 patients) out of 46 eyes, (25 patients) an orbital decompression was needed to preserve the optic nerve function. In those therapy-resistant cases (surgical decompression group), the orbital decompression led to statistically significant improvements in best-corrected visual acuity (BCVA), protan and tritan value of the color vision (p = 0.007, p < 0.0001, p = 0.019, respectively, comparison of first visit to last visit).

Conclusion

According to our data, the mild cases of DON with better initial visual acuity (in our case series mean: 0.3 logMAR) seem to respond well to steroid treatment. However, therapy-resistant cases with an impaired initial BCVA (in our case series, mean: 0.6 logMAR) seem to need the surgery to preserve the optic nerve function. In conclusion, this retrospective study confirms the effectiveness of surgical decompression in therapy-resistant cases of DON.
Nucleoplasmic signals promote directed transmembrane protein import simultaneously via multiple channels of nuclear pores
Authors: Mudumbi Krishna C. , Czapiewski Rafal , Ruba Andrew , Junod Samuel L. , Li Yichen , Luo Wangxi , Ngo Christina , Ospina Valentina , Schirmer Eric C. , Yang Weidong
Published: May 2020

Roughly 10% of eukaryotic transmembrane proteins are found on the nuclear membrane, yet how such proteins target and translocate to the nucleus remains in dispute. Most models propose transport through the nuclear pore complexes, but a central outstanding question is whether transit occurs through their central or peripheral channels. Using live-cell high-speed super-resolution single-molecule microscopy we could distinguish protein translocation through the central and peripheral channels, finding that most inner nuclear membrane proteins use only the peripheral channels, but some apparently extend intrinsically disordered domains containing nuclear localization signals into the central channel for directed nuclear transport. These nucleoplasmic signals are critical for central channel transport as their mutation blocks use of the central channels; however, the mutated proteins can still complete their translocation using only the peripheral channels, albeit at a reduced rate. Such proteins can still translocate using only the peripheral channels when central channel is blocked, but blocking the peripheral channels blocks translocation through both channels. This suggests that peripheral channel transport is the default mechanism that was adapted in evolution to include aspects of receptor-mediated central channel transport for directed trafficking of certain membrane proteins.
Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells
Authors: Lucas Beth , White Andrea J. , Cosway Emilie J. , Parnell Sonia M. , James Kieran D. , Jones Nick D. , Ohigashi Izumi , Takahama Yousuke , Jenkinson William E. , Anderson Graham
Published: May 2020

The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTβR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTβR controls CD104+CCL21+ mTEClow that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues.
Encoding quantized fluorescence states with fractal DNA frameworks
Authors: Li Jiang , Dai Jiangbing , Jiang Shuoxing , Xie Mo , Zhai Tingting , Guo Linjie , Cao Shuting , Xing Shu , Qu Zhibei , Zhao Yan , Wang Fei , Yang Yang , Liu Lei , Zuo Xiaolei , Wang Lihua , Yan Hao , Fan Chunhai
Published: May 2020

Signal amplification in biological systems is achieved by cooperatively recruiting multiple copies of regulatory biomolecules. Nevertheless, the multiplexing capability of artificial fluorescent amplifiers is limited due to the size limit and lack of modularity. Here, we develop Cayley tree-like fractal DNA frameworks to topologically encode the fluorescence states for multiplexed detection of low-abundance targets. Taking advantage of the self-similar topology of Cayley tree, we use only 16 DNA strands to construct n-node (n = 53) structures of up to 5 megadalton. The high level of degeneracy allows encoding 36 colours with 7 nodes by site-specifically anchoring of distinct fluorophores onto a structure. The fractal topology minimises fluorescence crosstalk and allows quantitative decoding of quantized fluorescence states. We demonstrate a spectrum of rigid-yet-flexible super-multiplex structures for encoded fluorescence detection of single-molecule recognition events and multiplexed discrimination of living cells. Thus, the topological engineering approach enriches the toolbox for high-throughput cell imaging.
Author Correction: Velocity and density characteristics of subducted oceanic crust and the origin of lower-mantle heterogeneities
Authors: Wang Wenzhong , Xu Yinhan , Sun Daoyuan , Ni Sidao , Wentzcovitch Renata , Wu Zhongqing
Published: May 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection
Authors: Adland Emily , Millar Jane , Bengu Nomonde , Muenchhoff Maximilian , Fillis Rowena , Sprenger Kenneth , Ntlantsana Vuyokasi , Roider Julia , Vieira Vinicius , Govender Katya , Adamson John , Nxele Nelisiwe , Ochsenbauer Christina , Kappes John , Mori Luisa , van Lobenstein Jeroen , Graza Yeney , Chinniah Kogielambal , Kapongo Constant , Bhoola Roopesh , Krishna Malini , Matthews Philippa C. , Poderos Ruth Penya , Lluch Marta Colomer , Puertas Maria C. , Prado Julia G. , McKerrow Neil , Archary Moherndran , Ndung’u Thumbi , Groll Andreas , Jooste Pieter , Martinez-Picado Javier , Altfeld Marcus , Goulder Philip
Published: May 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.