bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and temperature dependence of 60% and 85% formic acid treatment against Varroa destructor
Authors: STEUBE Xenia , BEINERT Patricia , KIRCHNER Wolfgang H.
Published: April 2021

The ectoparasitic mite Varroa destructor is considered one of the main threats to the western honey bee (Apis mellifera). Efficient pest management is crucial, and the evaporation of formic acid (FA) is an active principle that could be adopted. However, the usage of FA has an extreme variable efficacy depending on several conditions, ambient temperature among them. Cooler conditions, as they usually occur in Central Europe in late summer and autumn, can negatively affect treatment success. Our study aims to evaluate factors that influence the efficacy of different FA treatments. Over a period of 8 years, we investigated the effect of ambient temperature, hive size and dispenser type on the treatment success with 60% and 85% FA and consolidated those factors in a linear regression model. Treatment with 60% FA shows higher variability, and often lowered efficacy, especially in double brood chamber hives. In contrast, 85% FA treatment achieves higher efficacy and lower variability and shows significantly diminished dependence on ambient temperature.
Glacier Retreat in Iceland Mapped from Space: Time Series Analysis of Geodata from 1941 to 2018
Authors: Hauser Sarah , Schmitt Andreas
Published: April 2021

In recent decades, glaciers outside Greenland and Antarctica have shown increasingly rapid rates of mass loss and retreat of the ice front, which is associated with climatic and oceanic warming. Due to their maritime location, Icelandic glaciers are sensitive to short-term climate fluctuations and have shown rapid rates of retreat and mass loss over the last decade. In this study, historical maps (1941–1949) of the US Army Map Service (AMS series C762) and optical satellite imagery (Landsat 1, Landsat 5, Landsat 7, Landsat 8, and Sentinel-2) are used to study the Langjökull, Hofsjökull and Vatnajökull ice caps. By the help of the Normalized Difference Snow Index (NDSI), the glacier terminus fluctuations of the ice caps from 1973 to 2018 and the Equilibrium Line Altitude (ELA) from 1973 to 2018 are analyzed. The results are compared with climate data, especially with mean summer temperatures and winter precipitation. Due to the negative temperature gradient with increasing altitude, bivariate histograms are generated, showing the glaciated area per altitude zone and time, and providing a prediction of the future development until 2050 and beyond. The results indicate that Langjökull, Hofsjökull and Vatnajökull are retreating and advancing over the study period in correlation with the mean summer temperature, with a steady decrease over time being the clearest and most significant trend. The lower parts of the glaciers, thus, will probably disappear during the next decades. This behaviour is also evident by an exceptional increase of the ELA observed on all three glaciers, which leads to a reduction of the accumulation zone.
Proton Exchange Membrane (PEM) Fuel Cells with Platinum Group Metal (PGM)-Free Cathode
Authors: Du Lei , Zhang Gaixia , Sun Shuhui
Published: April 2021

Proton exchange membrane (PEM) fuel cells have gained increasing interest from academia and industry, due to its remarkable advantages including high efficiency, high energy density, high power density, and fast refueling, also because of the urgent demand for clean and renewable energy. One of the biggest challenges for PEM fuel cell technology is the high cost, attributed to the use of precious platinum group metals (PGM), e.g., Pt, particularly at cathodes where sluggish oxygen reduction reaction takes place. Two primary ways have been paved to address this cost challenge: one named low-loading PGM-based catalysts and another one is non-precious metal-based or PGM-free catalysts. Particularly for the PGM-free catalysts, tremendous efforts have been made to improve the performance and durability—milestones have been achieved in the corresponding PEM fuel cells. Even though the current status is still far from meeting the expectations. More efforts are thus required to further research and develop the desired PGM-free catalysts for cathodes in PEM fuel cells. Herein, this paper discusses the most recent progress of PGM-free catalysts and their applications in the practical membrane electrolyte assembly and PEM fuel cells. The most promising directions for future research and development are pointed out in terms of enhancing the intrinsic activity, reducing the degradation, as well as the study at the level of fuel cell stacks.
Novel Radiographic Indexes for Elbow Stability Assessment: Part B—Preliminary Clinical Study
Authors: Luceri Francesco , Cucchi Davide , Rosagrata Enrico , Zaolino Carlo Eugenio , Menon Alessandra , Radici Mattia , Zagarella Andrea , Catapano Michele , Gallazzi Mauro Battista , Arrigoni Paolo Angelo , Randelli Pietro Simone
Published: April 2021

Introduction

The coronoid process plays a key-role in preserving elbow stability. Currently, there are no radiographic indexes conceived to assess the intrinsic elbow stability and the joint congruency. The aim of this study is to present new radiological parameters, which will help assess the intrinsic stability of the ulnohumeral joint and to define normal values of these indexes in a normal, healthy population.

Methods

Four independent observers (two orthopaedic surgeons and two radiologists) selected lateral view X-rays of subjects with no history of upper limb disease or surgery. The following radiographic indexes were defined: trochlear depth index (TDI); anterior coverage index (ACI); posterior coverage index (PCI); olecranon–coronoid angle (OCA); radiographic coverage angle (RCA). Inter-observer and intra-observer reproducibility were assessed for each index.

Results

126 subjects were included. Standardized lateral elbow radiographs (62 left and 64 right elbows) were obtained and analysed. The mean TDI was 0.46 ± 0.06 (0.3–1.6), the mean ACI was 2.0 ± 0.2 (1.6–3.1) and the mean PCI was 1.3 ± 0.1 (1.0–1.9). The mean RCA was 179.6 ± 8.3° (normalized RCA: 49.9 ± 2.3%) and the mean OCA was 24.6 ± 3.7°. The indexes had a high-grade of inter-observer and intra-observer reliability for each of the four observers. Significantly higher values were found for males for TDI, ACI, PCI and RCA.

Conclusion

The novel radiological parameters described are simple, reliable and easily reproducible. These features make them a promising tool for radiographic evaluation both for orthopaedic surgeons and for radiologists in the emergency department setting or during outpatient services.

Level of evidence

Basic Science Study (Case Series).

Clinical relevance

The novel radiological parameters described are reliable, easily reproducible and become handy for orthopaedic surgeons as well as radiologists in daily clinical practice.
A spatial study of quality of life in the USA
Authors: Amin Raid W. , Rivera-Muñiz Bradly , Guttmann Rodney P.
Published: April 2021

This study's main goal was to develop a comprehensive Quality of Life (QoL) Index based on 31 demographic variables for the 3108 counties in the contiguous USA. Counties were ranked worst in QoL to best, and spatial cluster analysis is used to identify counties with significant low/high QoL clusters. GIS-based mapping was used to create informative heat maps with significant clusters shown. The rate of African Americans, diversity in a race within counties, and upward mobility were studied in a regression analysis in which QoL was predicted from these three covariates. The QoL Index was adjusted for the covariates, and a new spatial heat map with clusters is obtained. It was concluded that as the rate of African Americans increases in a county, the QoL decreases, while the QoL increases when diversity or upward mobility increases.
Advancing the Circular Economy in Public Sector Organisations: Employees’ Perspectives on Practices
Authors: Klein Natacha , Ramos Tomás B. , Deutz Pauline
Published: April 2021

Circular economy (CE) is a concept that is gaining attention as an approach to help accelerate the transition towards sustainability. Research has focused on the adoption of CE practices in the business sector while the adoption within public sector organisations has been relatively overlooked. Examining CE adoption in the public sector through the perceptive of employees is crucial because of their expertise in the organisation where they work. The main aim of this study is to identify what public employees perceive as suitable CE practices for their organisations and their critical role in implementation. As the adoption of CE practices is influenced by social and material configurations, this research has taken a case study approach, focused on the Portuguese Central Public Administration. Semi-structured interviews were conducted with public employees working on CE and sustainability issues, and a complementary analysis was undertaken of governmental reports and legislative documents. The results show that public employees view the existence and potential of CE practices mainly in the area of public procurement but also in resource efficiency and optimisation, dematerialisation and in practices related to the R-hierarchy including reduce and reuse. Both technical-oriented practices aimed to achieve traditional resource efficiency, and human-centred practices targeted at reducing consumption and sharing resources have been identified. This research provides insights into how a specific group of stakeholders envisions CE activities for their sector. Identification of practices for central public sector has the potential to assist decision-makers in the process of defining priorities for CE planning, implementation and monitoring. This study focusing on CE practices in central public sector organisations contributes to the calls for an inclusion of human/socially-based practices centred around consumption reduction, sharing and dematerialisation activities to enhance the transformative and innovative potential of CE.
Pathogenesis of overactive bladder and surgical treatment according to the Integral Theory Paradigm
Authors: Petros Peter
Published: April 2021

Overactive bladder (OAB is a definition by the International Continence Society (ICS). It comprises three symptoms, urge, frequency and nocturia. OAB is a major problem for up to 30% of women, more so for elderly women. OAB is generally assumed to be a paradigm, but it cannot meet the criteria of a paradigm, as its causation is said to be “idiopathic” (unknown) and is said to have no known treatment. In 1993, it was demonstrated that the sequence of events in urodynamically diagnosed detrusor overactivity (now “DO”) was identical with what occurred in normal micturition, which led to the conclusion that frequency, urgency, nocturia were in effect, an uncontrolled but otherwise normal micturition. Data from a 1997 experiment indicated the control mechanism of the bladder was binary, either closed or open, regulated by a peripheral musculoligamentous system under cortical control. The Integral Theory paradigm's view of OAB is based on and is compatible with, ICS definitions and descriptions. The Integral Theory paradigm (ITP) views OAB pathogenesis as anatomical, caused by defects anywhere along the control mechanism pathway, but mainly damage in its weakest link, collagen defects in the peripheral musculoligamentous system. Specific tests to prove causation consist of mechanically supporting suspensory ligaments, pubourethral ligament (PUL) or uterosacral ligament (USL), “simulated operations”; PUL support prevents urine loss on coughing; USL support by inserting the lower blade of a bivalve speculum into the vagina diminishes urge and pain. The ITP specifies treatment of correctible causes: squatting-based exercises to strengthen the reflex pelvic muscles, ligament repair by plication for premenopausal women, slings for postmenopausal women.
Focus on Form
Authors: Benati Alessandro
Published: April 2021

This Cambridge Element examines the role and nature of focus on form in second language acquisition. An overall assessment of the role of instruction and the nature of language is provided. Instruction might have a facilitative role in the rate of acquisition. The Element briefly reviews empirical research examining the relative effects of different types of focus on form and presents some of the key implications for second language learning and teaching. An effective focus on form type is one that is input and meaning oriented. Manipulating input to facilitate language processing and form-meaning connections might enhance second language acquisition.
Swimming training combined with chitosan supplementation reduces the development of obesity and oxidative stress in high-fat diet-fed mice
Authors: Zalaqi Zahra , Ghazalian Farshad , Khodayar Mohammad Javad , Raesi Vanani Atefeh , Khorsandi Layasadat , Shushizadeh Mohammad Reza
Published: April 2021

Obesity is often introduced as one of the metabolic disorders caused by imbalance between energy consumption and metabolisable energy intake. Experts in the field considered obesity as one of the robust risk factors for the lifestyle-associated diseases. The present research examined interventional effects of marine chitosan (CS), swimming training (ST) and combination of CS and ST (CS + ST) in the mice fed with high-fat diets (HFD). In this study, sample size was considered more than three in groups. Forty mice were randomly divided into five groups (n8 per group) including control group (received the standard diet), HFD group (received high-fat food with 20 % fat), HFD + CS group (treated with high-fat food with 5 % CS), HFD + ST group (treated with HFD and ST) and HFD + CS + ST group (treated with high-fat food with 5 % CS and ST). After 8 weeks, the blood glucose, oxidative stress (OS) and lipid profile were measured. The results showed that CS + ST group has more effects in the control of body weight with the increased concentration of HDL-cholesterol, OS inhibition via enhancing the body antioxidant capacity in comparison with the ST or CS alone in HFD-fed mice. Moreover, lipid profile was improved in CS + ST-treated mice compared with HFD-treated mice, and OS inhibition correlated with the greater activities of the antioxidant enzyme enhances the lipid oxidation, cholesterol and fatty acid homoeostasis. The results suggested that a dietary intervention with a combined ST and CS can be a feasible supplementary for human prevention of obesity.
Oat (Avena sativa) yield and grain fill responses to varying agronomic and weather factors
Authors: McCabe C. P. , Burke J. I.
Published: April 2021

Factorial experiments were carried out on spring- and winter-sown oat crops in Ireland in 2016–2019 to identify plant responses in yield formation and grain filling procedures. Two cultivars (Husky and Keely), three seed rates (250, 350 and 450 seeds/m2), six applied nitrogen (N) rates (40, 70, 100, 130, 160 and 190 kg N/ha) with a plant growth regulator (PGR) were examined in spring and winter sowings, using the same cultivars at five rates of applied N (80, 110, 140, 170 and 200 kg N/ha). The applied N rate and seed rate significantly (P < 0.05) modified the yield components determining grains/m2 in spring- and winter-sown crops with increases in panicle number of key importance. Increases were also observed in the proportion of primary grain by weight (0.9–1.6%) and number (0.7–1.4%) ratios in spring-sown crops in response to applied N rate, with winter-sown crops exhibiting a more consistent pattern of grain fill. Seed rate and PGR application had minor effects on yield components and panicle conformation. Grain fill procedures played an important role in the maximization of grain yield under seasonal conditions. Significant positive correlations were observed between the number of aborted grain sites and yield under drought conditions (0.22), with negative associations observed in near-optimal conditions (−0.22 to −0.41). Agronomic effects on grain site abortion were minimal in comparison with seasonal effects. In seasons characterized by cool, consistent conditions, grain yield was maximized by the utilization of all available grain sites. Where assimilate shortages were encountered during grain fill the abortion of grains sites was positively associated with grain yield.
Stiffness modulation of a cable-driven leg exoskeleton for effective human–robot interaction
Authors: Sanjeevi N. S. S. , Vashista Vineet
Published: April 2021

With the widespread development of leg exoskeletons to provide external force-based repetitive training for gait rehabilitation, the prospect of undesired movement adaptation due to applied forces and imposed constraints require adequate investigation. A cable-driven leg exoskeleton, CDLE, presents a lightweight, flexible, and redundantly actuated architecture that enables the possibility of system parameters modulation to alter human–robot interaction while applying the desired forces. In this work, multi-joint stiffness performance of CDLE is formulated to systematically analyze human–CDLE interaction. Further, potential alterations in CDLE architecture are presented to tune human–CDLE interaction that favors the desired human leg movement during a gait rehabilitation paradigm.
Protective effects of health insurance against disasters: an insight from the Great East Japan Earthquake
Authors: Yuda Michio , Lee Jinkook
Published: April 2021

The Great East Japan Earthquake of March 2011 and it's massive tidal waves wreaked devastating damage on residences and communities along 400 km of the Pacific coast in Japan. Using the panel data from the Japanese Study of Aging and Retirement, we estimate the effects of this disaster on individual health, finding a significant negative impact on the health of those in the area. In addition, we exploit a discontinuous decrease in copayments for medical care at the age of 70 years and find that the reduction in copayment increased medical and long-term care utilization and significantly reduced health deterioration after the earthquake.
Some reasons why evidence from educational research is not particularly popular among (pre-service) teachers: A discussion
Authors: Fischer Frank
Published: April 2021

Abstract. This discussion first highlights novel aspects that the individual articles contribute to the special issue on (future) teachers' choice, use, and evaluation of (non-)scientific information sources about educational topics. Among these highlights are the conceptualizations of epistemic goals and the type of pedagogical task as moderators of the selection and use of scientific evidence. The second part raises overarching questions, including the following: How inclusive do we want the concept of evidence to be? How should teachers use research evidence in their pedagogical problem-solving and decision-making? To what extent is multidisciplinary teacher education contributing to epistemological confusion, possibly leading to (pre-service) teachers' low appreciation of educational research?
Riverine Carbon Cycling Over the Past Century in the Mid‐Atlantic Region of the United States
Authors: Yao Yuanzhi , Tian Hanqin , Pan Shufen , Najjar Raymond G. , Friedrichs Marjorie A. M. , Bian Zihao , Li Hong‐Yi , Hofmann Eileen E.
Published: April 2021

The lateral transport and degassing of carbon in riverine ecosystems is difficult to quantify on large spatial and long temporal scales due to the relatively poor representation of carbon processes in many models. Here, we coupled a scale‐adaptive hydrological model with the Dynamic Land Ecosystem Model to simulate key riverine carbon processes across the Chesapeake and Delaware Bay Watersheds from 1900 to 2015. Our results suggest that throughout this time period riverine CO2 degassing and lateral dissolved inorganic carbon fluxes to the coastal ocean contribute nearly equally to the total riverine carbon outputs (mean ± standard deviation: 886 ± 177 Gg C·yr−1 and 883 ± 268 Gg C·yr−1, respectively). Following in order of decreasing importance are the lateral dissolved organic carbon flux to the coastal ocean (293 ± 81 Gg C·yr−1), carbon burial (118 ± 32 Gg C·yr−1), and lateral particulate organic carbon flux (105 ± 35 Gg C·yr−1). In the early 2000s, carbon export to the coastal ocean from both the Chesapeake and Delaware Bay watersheds was only 15%–20% higher than it was in the early 1900s (decade), but it showed a twofold increase in standard deviation. Climate variability (changes in temperature and precipitation) explains most (225 Gg C·yr−1) of the increase since 1900, followed by changes in atmospheric CO2 (82 Gg C·yr−1), atmospheric nitrogen deposition (44 Gg C·yr−1), and applications of nitrogen fertilizer and manure (27 Gg C·yr−1); in contrast, land conversion has resulted in a 188 Gg C·yr−1 decrease in carbon export.
Climate Change Impact Studies: Should We Bias Correct Climate Model Outputs or Post‐Process Impact Model Outputs?
Authors: Chen Jie , Arsenault Richard , Brissette François P. , Zhang Shaobo
Published: April 2021

The inter‐variable dependence of climate variables is usually not considered in many bias correction methods, even though it has been deemed important for various impact studies. Another possible approach is to forgo the bias correction of climate model outputs, and instead, post‐process the outputs of the impact model. This has the advantage of circumventing the difficulties associated with correcting the inter‐variable dependence of climate variables. Using a hydrological impact study as an example, this study investigates the feasibility of bias correcting impact model outputs by comparing the performance of the pre‐processing and post‐processing of hydrological model simulations when using bias correction methods. The performance over calibration and validation periods was used to assess the transferability of both approaches. The results show that both the pre‐processing and post‐processing procedures are capable of significantly reducing the bias of simulated streamflow time series for most global climate models (GCMs), even though their performances depend on GCM simulations, hydrological models, streamflow metrics and watersheds. Both approaches were likely to perform badly over the validation period when bias correction factors have a strong seasonal variability and are therefore sensitive to bias nonstationarity of climate model outputs and/or streamflow between the calibration and validation periods. This problem is found to be more acute for the post‐processing method because streamflows often have a seasonal pattern with more abrupt changes than precipitation and temperature. For this reason, pre‐processing is recommended as it is less likely to suffer from this problem.
Adjoint‐State Traveltime Tomography: Eikonal Equation‐Based Methods and Application to the Anza Area in Southern California
Authors: Tong Ping
Published: April 2021

Ray tracing is avoidable in seismic traveltime tomography. In this study, seismic traveltime tomography is reformulated as an eikonal equation‐constrained optimization problem solved by the ray‐free adjoint‐state method. The resultant approach is called adjoint‐state traveltime tomography. For completeness, an eikonal equation‐based earthquake location method is developed to locate the hypocenters of earthquakes when necessary. The multiple‐grid model parameterization is adopted to discretize the relative slowness perturbation . The step‐size‐controlled gradient descent method, which has an effect of damping regularization, is used to find optimal earthquake hypocenters and velocity models. The performances of the earthquake location and adjoint‐state traveltime tomography methods are tested in the source area of the 2020 Mw 4.9 Anza earthquake, a seismologically active place in southern California. The obtained high‐resolution P‐wave velocity model demonstrates that the 2020 Mw 4.9 Anza earthquake and other historic moderate‐sized Anza earthquakes occurred near or at the boundaries of low VP rocks, a typical seismogenic environment for moderate to large crustal earthquakes. Meanwhile, the source zone of the Anza earthquakes is characterized by high VP/VS, indicating the possible existence of crustal fluids as well as the critical role of fluids in the occurrence of those moderated‐sized Anza earthquakes. On the whole, the well‐performed eikonal equation‐based earthquake location method and adjoint‐state traveltime tomography method provide competent and attractive tools for hypocenter and tomographic inversions.
Tumor-derived exosomal circPSMA1 facilitates the tumorigenesis, metastasis, and migration in triple-negative breast cancer (TNBC) through miR-637/Akt1/β-catenin (cyclin D1) axis
Authors: Yang Su-jin , Wang Dan-dan , Zhong Shan-liang , Chen Wen-quan , Wang Feng-liang , Zhang Jian , Xu Wen-xiu , Xu Di , Zhang Qian , Li Jian , Zhang He-da , Hou Jun-chen , Mao Ling , Tang Jin-hai
Published: April 2021

Circular RNAs (circRNAs) are increasingly gaining importance and attention due to their diverse potential functions and their value as diagnostic biomarkers (disease specific). This study aims to explore the novel mechanisms by which exosome-contained circRNAs promote tumor development and metastasis in TNBC. We identified increased circRNA circPSMA1 in TNBC cells, their exosomes, and serum exosomes samples from TNBC patients. The overexpression of circPSMA1 promoted TNBC cell proliferation, migration, and metastasis both in vitro and in vivo. Moreover, we investigated the tumor-infiltrating immune cells (TICs) or stromal components in immune microenvironment (IME), and identified the significant differences in the immune cells between TNBC and non-TNBC samples. Mechanistically, circPSMA1 acted as a “miRNAs sponge” to absorb miR-637; miR-637 inhibited TNBC cell migration and metastasis by directly targeted Akt1, which recognized as a key immune-related gene and affected downstream genes β-catenin and cyclin D1. Subsequent co-culture experiments also demonstrated that exosomes from TNBC carrying large amounts of circPSMA1 could transmit migration and proliferation capacity to recipient cells. Kaplan–Meier plots showed that high expression of Akt1 and low expression of mir-637 are highly correlated with poor prognosis in patients with lymph node metastasis of TNBC. Collectively, all these results reveal that circPSMA1 functions as a tumor promoter through the circPSMA1/miR-637/Akt1-β-catenin (cyclin D1) regulatory axis, which can facilitate the tumorigenesis, metastasis, and immunosuppression of TNBC. Our research proposes a fresh perspective on novel potential biomarkers and immune treatment strategies for TNBC.
CRISPR-edited CART with GM-CSF knockout and auto secretion of IL6 and IL1 blockers in patients with hematologic malignancy
Authors: Yi Yan , Chai Xiaoshan , Zheng Liping , Zhang Yongjing , Shen Jiankai , Hu Biliang , Tao Guangshi
Published: April 2021

Revolutionary CART therapy still faces the challenge of severe cytokine release syndrome (CRS). While IL6 and IL1 have been demonstrated as essential contributors, GM-CSF is one of the most abundant inflammatory cytokines secreted by CART and has also been suggested in contributing to CRS. To minimize GM-CSF production from CART to reduce its associated toxicity, we conducted a pilot study (ChiCTR2000032124) of CRISPR-edited GM-CSF knockout (KO) in CART secreting anti-IL6 scFv and IL1RA, with additional TCR KO for tracing edited CART. The initial results of three patients (1 Non-Hodgkin lymphoma (NHL) and 2 multiple myelomas (MMs)) are summarized as: 3/3 complete response, 2/3 none CRS, 1/3 grade 2 CRS, and 0/3 neurotoxicity. The analysis revealed low levels of GM-CSF, IL6 and IL1B at the time of interferon-gamma (IFNG) peaks, and elevated IL1RA. We also observed significant expansion of CD3– CART during treatment and no aberrant expansion of CD3– CART in the follow-up. Re-expansion of CD3– CART was observed in two patients while recurring CD19+ cells were eradicated in the patient with NHL. In summary, our study supported the safety and durable potency of CRISPR-edited CART in patients, providing a novel platform for developing autologous or allogeneic CART to minimize GM-CSF-associated toxicity in addition to autonomous IL6/IL1 blockade.
How do non-geneticist physicians deal with genetic tests? A qualitative analysis
Authors: Pasquier Laurent , Minguet Guy , Moisdon-Chataigner Sylvie , Jarno Pascal , Denizeau Philippe , Volf Ginette , Odent Sylvie , Moutel Grégoire
Published: April 2021

Genetic testing is accepted to be a common practice in many medical specialties. These genetic tests raise issues such as respect for basic rights, how to handle results and uncertainty and how to balance concerns for medical confidentiality with the rights of third parties. Physicians need help to deal with the rapid development of genomic medicine as most of them have received no specific training on the medical, ethical, and social issues involved. Analyzing how these professionals integrate genetic testing into the patient-provider relationship is essential to paving the way for a better use of genomics by all. We conducted a qualitative study comprising a series of focus groups with 21 neurologists and endocrinologists about their genetic testing practices in the western part of France. The interviews were transcribed and analyzed for major themes. We identified an automated care management procedure of genetic testing that affects patient autonomy. The simple fact of having a written consent cannot justify a genetic test given the stakes associated with the results. We also suggest orienting practices toward a systemic approach using a multidisciplinary team or network to provide resources for dealing with uncertainties in interpreting results or situations that require additional technical or clinical skills and, if necessary, to allow for joint consultations with both a geneticist and a non-geneticist medical specialist.
Nanoscale electric-field imaging based on a quantum sensor and its charge-state control under ambient condition
Authors: Bian Ke , Zheng Wentian , Zeng Xianzhe , Chen Xiakun , Stöhr Rainer , Denisenko Andrej , Yang Sen , Wrachtrup Jörg , Jiang Ying
Published: April 2021

Nitrogen-vacancy (NV) centers in diamond can be used as quantum sensors to image the magnetic field with nanoscale resolution. However, nanoscale electric-field mapping has not been achieved so far because of the relatively weak coupling strength between NV and electric field. Here, using individual shallow NVs, we quantitatively image electric field contours from a sharp tip of a qPlus-based atomic force microscope (AFM), and achieve a spatial resolution of ~10 nm. Through such local electric fields, we demonstrated electric control of NV’s charge state with sub-5 nm precision. This work represents the first step towards nanoscale scanning electrometry based on a single quantum sensor and may open up the possibility of quantitatively mapping local charge, electric polarization, and dielectric response in a broad spectrum of functional materials at nanoscale.
Recurrent deletions in clonal hematopoiesis are driven by microhomology-mediated end joining
Authors: Feldman Tzah , Bercovich Akhiad , Moskovitz Yoni , Chapal-Ilani Noa , Mitchell Amanda , Medeiros Jessie J. F. , Biezuner Tamir , Kaushansky Nathali , Minden Mark D. , Gupta Vikas , Milyavsky Michael , Livneh Zvi , Tanay Amos , Shlush Liran I.
Published: April 2021

The mutational mechanisms underlying recurrent deletions in clonal hematopoiesis are not entirely clear. In the current study we inspect the genomic regions around recurrent deletions in myeloid malignancies, and identify microhomology-based signatures in CALR, ASXL1 and SRSF2 loci. We demonstrate that these deletions are the result of double stand break repair by a PARP1 dependent microhomology-mediated end joining (MMEJ) pathway. Importantly, we provide evidence that these recurrent deletions originate in pre-leukemic stem cells. While DNA polymerase theta (POLQ) is considered a key component in MMEJ repair, we provide evidence that pre-leukemic MMEJ (preL-MMEJ) deletions can be generated in POLQ knockout cells. In contrast, aphidicolin (an inhibitor of replicative polymerases and replication) treatment resulted in a significant reduction in preL-MMEJ. Altogether, our data indicate an association between POLQ independent MMEJ and clonal hematopoiesis and elucidate mutational mechanisms involved in the very first steps of leukemia evolution.
Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection
Authors: Wheatley Rachel , Diaz Caballero Julio , Kapel Natalia , de Winter Fien H. R. , Jangir Pramod , Quinn Angus , del Barrio-Tofiño Ester , López-Causapé Carla , Hedge Jessica , Torrens Gabriel , Van der Schalk Thomas , Xavier Basil Britto , Fernández-Cuenca Felipe , Arenzana Angel , Recanatini Claudia , Timbermont Leen , Sifakis Frangiscos , Ruzin Alexey , Ali Omar , Lammens Christine , Goossens Herman , Kluytmans Jan , Kumar-Singh Samir , Oliver Antonio , Malhotra-Kumar Surbhi , MacLean Craig
Published: April 2021

It is well established that antibiotic treatment selects for resistance, but the dynamics of this process during infections are poorly understood. Here we map the responses ofPseudomonas aeruginosato treatment in high definition during a lung infection of a single ICU patient. Host immunity and antibiotic therapy with meropenem suppressedP. aeruginosa, but a second wave of infection emerged due to the growth ofoprDandwbpMmeropenem resistant mutants that evolved in situ. Selection then led to a loss of resistance by decreasing the prevalence of low fitnessoprDmutants, increasing the frequency of high fitness mutants lacking the MexAB-OprM efflux pump, and decreasing the copy number of a multidrug resistance plasmid. Ultimately, host immunity suppressedwbpMmutants with high meropenem resistance and fitness. Our study highlights how natural selection and host immunity interact to drive both the rapid rise, and fall, of resistance during infection.
IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion
Authors: Lin Hong , Yan Yuan , Luo Yifan , So Wing Yan , Wei Xiayun , Zhang Xiaozhe , Yang Xiaoli , Zhang Jun , Su Yang , Yang Xiuyan , Zhang Bobo , Zhang Kangjun , Jiang Nan , Chow Billy Kwok Chong , Han Weiping , Wang Fengchao , Rao Feng
Published: April 2021

COP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1–CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2WT/K70E mice with partially disrupted binding of IP6, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4COP1 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4COP1 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2WT/K70E, high-fat diet-treated, and ob/ob mice. The CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4COP1-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP6-assisted CSN-COP1 competition. Deregulation of the IP6-CSN-CRL4COP1-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.
A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics
Authors: Knox Jessica , Joly Nicolas , Linossi Edmond M. , Carmona-Negrón José A. , Jura Natalia , Pintard Lionel , Zuercher William , Roy Peter J.
Published: April 2021

Over one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.
Extracellular vesicles derived from ascitic fluid enhance growth and migration of ovarian cancer cells
Authors: Mitra Aparna , Yoshida-Court Kyoko , Solley Travis N. , Mikkelson Megan , Yeung Chi Lam Au , Nick Alpa , Lu Karen , Klopp Ann H.
Published: April 2021

Ovarian cancer is associated with a high mortality rate due to diagnosis at advanced stages. Dissemination often occurs intraperitoneally within the ascites fluid. The microenvironment can support dissemination through several mechanisms. One potential ascites factor which may mediate dissemination are EVs or extracellular vesicles that can carry information in the form of miRNAs, proteins, lipids, and act as mediators of cellular communication. We present our observations on EVs isolated from ascitic supernatants from patients diagnosed with high grade serous ovarian carcinoma in augmenting motility, growth, and migration towards omental fat. MicroRNA profiling of EVs from malignant ascitic supernatant demonstrates high expression of miR 200c-3p, miR18a-5p, miR1246, and miR1290 and low expression of miR 100- 5p as compared to EVs isolated from benign ascitic supernatant. The migration of ovarian cancer spheroids towards omental fat is enhanced in the presence of malignant ascitic EVs. Gene expression of these cells showed increased expression of ZBED2, ZBTB20, ABCC3, UHMK1, and low expression of Transgelin and MARCKS. We present evidence that ovarian ascitic EVs increase the growth of ovarian cancer spheroids through miRNAs.
Stress-induced differential gene expression in cardiac tissue
Authors: de Carvalho Ana Elisa T. S. , Cordeiro Marco A. , Rodrigues Luana S. , Ortolani Daniela , Spadari Regina C.
Published: April 2021

The stress response is adaptive and aims to guarantee survival. However, the persistence of a stressor can culminate in pathology. Catecholamines released as part of the stress response over activate beta adrenoceptors (β-AR) in the heart. Whether and how stress affects the expression of components of the intracellular environment in the heart is still, however, unknown. This paper used microarray to analyze the gene expression in the left ventricle wall of rats submitted to foot shock stress, treated or not treated with the selective β2-AR antagonist ICI118,551 (ICI), compared to those of non-stressed rats also treated or not with ICI, respectively. The main findings were that stress induces changes in gene expression in the heart and that β2-AR plays a role in this process. The vast majority of genes disregulated by stress were exclusive for only one of the comparisons, indicating that, in the same stressful situation, the profile of gene expression in the heart is substantially different when the β2-AR is active or when it is blocked. Stress induced alterations in the expression of such a large number of genes seems to be part of stress-induced adaptive mechanism.
Real-world outcomes of first-line pembrolizumab plus pemetrexed-carboplatin for metastatic nonsquamous NSCLC at US oncology practices
Authors: Velcheti Vamsidhar , Hu Xiaohan , Piperdi Bilal , Burke Thomas
Published: April 2021

Evidence from real-world clinical settings is lacking with regard to first-line immunotherapy plus chemotherapy for the treatment of non-small cell lung cancer (NSCLC). Our aim was to describe outcomes for patients treated with first-line pembrolizumab-combination therapy for metastatic nonsquamous NSCLC in US oncology practices. Using an anonymized, nationwide electronic health record-derived database, we identified patients who initiated pembrolizumab plus pemetrexed-carboplatin in the first-line setting (May 2017 to August 2018) after diagnosis of metastatic nonsquamous NSCLC that tested negative for EGFR and ALK genomic aberrations. Eligible patients had ECOG performance status of 0–1. An enhanced manual chart review was used to collect outcome information. Time-to-event analyses were performed using the Kaplan–Meier method. Of 283 eligible patients, 168 (59%) were male; median age was 66 years (range 33–84); and the proportions of patients with PD-L1 tumor proportion score (TPS) of ≥ 50%, 1–49%, < 1%, and unknown were 28%, 27%, 28%, and 17%, respectively. At data cutoff on August 31, 2019, median patient follow-up was 20.3 months (range 12–28 months), and median real-world times on treatment (rwToT) with pembrolizumab and pemetrexed were 5.6 (95% CI 4.5–6.4) and 2.8 months (95% CI 2.2–3.5), respectively. Median overall survival (OS) was 16.5 months (95% CI 13.2–20.6); estimated 12-month survival was 59.5% (95% CI 53.3–65.0); rwProgression-free survival was 6.4 months (95% CI 5.4–7.8); and rwTumor response rate (complete or partial response) was 56.5% (95% CI 50.5–62.4). Median OS was 20.6, 16.3, 13.2, and 13.7 months for patient cohorts with PD-L1 TPS ≥ 50%, 1–49%, < 1%, and unknown, respectively. These findings demonstrate the effectiveness of pembrolizumab plus pemetrexed-carboplatin by describing clinical outcomes among patients with metastatic nonsquamous NSCLC who were treated at US oncology practices.
Central administration of afzelin extracted from Ribes fasciculatum improves cognitive and memory function in a mouse model of dementia
Authors: Oh So-Young , Jang Min Jun , Choi Yun-Hyeok , Hwang Hongik , Rhim Hyewhon , Lee Bonggi , Choi Chun Whan , Kim Min Soo
Published: April 2021

Neurodegenerative disorders are characterized by the decline of cognitive function and the progressive loss of memory. The dysfunctions of the cognitive and memory system are closely related to the decreases in brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) signalings. Ribes fasciculatum, a medicinal plant grown in diverse countries, has been reported to pharmacological effects for autoimmune diseases and aging recently. Here we found that afzelin is a major compound in Ribes fasciculatum. To further examine its neuroprotective effect, the afzelin (100 ng/µl, three times a week) was administered into the third ventricle of the hypothalamus of C57BL/6 mice for one month and scopolamine was injected (i.p.) to these mice to impair cognition and memory before each behavior experiment. The electrophysiology to measure long-term potentiation and behavior tests for cognitive and memory functions were performed followed by investigating related molecular signaling pathways. Chronic administration of afzelin into the brain ameliorated synaptic plasticity and cognitive/memory behaviors in mice given scopolamine. Studies of mice’s hippocampi revealed that the response of afzelin was accountable for the restoration of the cholinergic systems and molecular signal transduction via CREB-BDNF pathways. In conclusion, the central administration of afzelin leads to improved neurocognitive and neuroprotective effects on synaptic plasticity and behaviors partly through the increase in CREB-BDNF signaling.
An analytic solution of full-sky spherical geometry for satellite relative motions
Authors: Lee Soung Sub , Hall Christopher D.
Published: April 2021

Herein, an exact and efficient analytic solution for an unperturbed satellite relative motion was developed using a direct geometrical approach. The derivation of the relative motion geometrically interpreted the projected Keplerian orbits of the satellites on a sphere (Earth and celestial spheres) using the solutions of full-sky spherical triangles. The results were basic and computationally faster than the vector and plane geometry solutions owing to the advantages of the full-sky spherical geometry. Accordingly, the validity of the proposed solution was evaluated by comparing it with other analytic relative motion theories in terms of modeling accuracy and efficiency. The modeling accuracy showed an equivalent performance with Vadali’s nonlinear unit sphere approach, which is essentially equal to the Yan–Alfriend nonlinear theory. Moreover, the efficiency was demonstrated by the lowest computational cost compared with other models. In conclusion, the proposed modeling approach illustrates a compact and efficient closed-form solution for satellite relative motion dynamics.
Saccharomyces boulardii modulates oxidative stress and renin angiotensin system attenuating diabetes-induced liver injury in mice
Authors: Barssotti Leticia , Abreu Isabel C. M. E. , Brandão Ana Beatriz P. , Albuquerque Raquel C. M. F. , Ferreira Fabiana G. , Salgado Miguel A. C. , Dias Danielle D. S. , De Angelis Kátia , Yokota Rodrigo , Casarini Dulce E. , Souza Lívia B. , Taddei Carla R. , Cunha Tatiana S.
Published: April 2021

Type 1 diabetes (T1DM) is a chronic disease characterized by hyperglycemia due to a deficiency in endogenous insulin production, resulting from pancreatic beta cell death. Persistent hyperglycemia leads to enhanced oxidative stress and liver injury. Several studies have evaluated the anti-diabetic and protective effects of probiotic strains in animal models. In the present study, we investigated, through histopathological and biochemical analyses, the effects of eight weeks of administration of Saccharomyces boulardii (S. boulardii) yeast on the liver of streptozotocin (STZ) induced diabetic C57BL/6 mice. Our results demonstrated that S. boulardii attenuates hepatocytes hydropic degeneration and hepatic vessels congestion in STZ-induced diabetic mice. The treatment attenuated the oxidative stress in diabetic mice leading to a reduction of carbonylated protein concentration and increased activity of antioxidant enzymes superoxide dismutase and glutathione peroxidase, compared to untreated diabetic animals. The results also show the beneficial influence of S. boulardii in regulating the hepatic concentration of renin angiotensin system (RAS) peptides. Therefore, our results demonstrated that S. boulardii administration to STZ-induced diabetic mice reduces oxidative stress and normalizes the concentration of RAS peptides, supporting the hypothesis that this yeast may have a role as a potential adjunctive therapy to attenuate diabetes-induced liver injury.
Microanchored borehole fiber optics allows strain profiling of the shallow subsurface
Authors: Zhang Cheng-Cheng , Shi Bin , Zhang Song , Gu Kai , Liu Su-Ping , Gong Xu-Long , Wei Guang-Qing
Published: April 2021

Vertical deformation profiles of subterranean geological formations are conventionally measured by borehole extensometry. Distributed strain sensing (DSS) paired with fiber-optic cables installed in the ground opens up possibilities for acquiring high-resolution static and quasistatic strain profiles of deforming strata, but it is currently limited by reduced data quality due to complicated patterns of interaction between the buried cables and their surroundings, especially in upper soil layers under low confining pressures. Extending recent DSS studies, we present an improved approach using microanchored fiber-optic cables—designed to optimize ground-to-cable coupling at the near surface—for strain determination along entire lengths of vertical boreholes. We proposed a novel criterion for soil–cable coupling evaluation based on the geotechnical bearing capacity theory. We applied this enhanced methodology to monitor groundwater-related vertical motions in both laboratory and field experiments. Corroborating extensometer recordings, acquired simultaneously, validated fiber optically determined displacements, suggesting microanchored DSS as an improved means for detecting and monitoring shallow subsurface strain profiles.