bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of genetic variation and base modifications at base-pair resolution on both DNA and RNA
Authors: Wang Zhen , Maluenda Jérôme , Giraut Laurène , Vieille Thibault , Lefevre Andréas , Salthouse David , Radou Gaël , Moulinas Rémi , Astete Sandra , D’Avezac Pol , Smith Geoff , André Charles , Allemand Jean-François , Bensimon David , Croquette Vincent , Ouellet Jimmy , Hamilton Gordon 
Published: January 2021

AbstractAccurate decoding of nucleic acid variation is critical to understand the complexity and regulation of genome function. Here we use a single-molecule magnetic tweezer (MT) platform to identify sequence variation and map a range of important epigenetic base modifications with high sensitivity, specificity, and precision in the same single molecules of DNA or RNA. We have also developed a highly specific amplification-free CRISPR-Cas enrichment strategy to isolate genomic regions from native DNA. We demonstrate enrichment of DNA from both E. coli and the FMR1 5’UTR coming from cells derived from a Fragile X carrier. From these kilobase-length enriched molecules we could characterize the differential levels of adenine and cytosine base modifications on E. coli, and the repeat expansion length and methylation status of FMR1. Together these results demonstrate that our platform can detect a variety of genetic, epigenetic, and base modification changes concomitantly within the same single molecules.
SARS-CoV-2 specific antibody and neutralization assays reveal the wide range of the humoral immune response to virus
Authors: Dogan Mikail , Kozhaya Lina , Placek Lindsey , Gunter Courtney , Yigit Mesut , Hardy Rachel , Plassmeyer Matthew , Coatney Paige , Lillard Kimberleigh , Bukhari Zaheer , Kleinberg Michael , Hayes Chelsea , Arditi Moshe , Klapper Ellen , Merin Noah , Liang Bruce Tsan-Tang , Gupta Raavi , Alpan Oral , Unutmaz Derya 
Published: January 2021

AbstractDevelopment of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n = 115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.
Hallmarks of primary neurulation are conserved in the zebrafish forebrain
Authors: Werner Jonathan M. , Negesse Maraki Y. , Brooks Dominique L. , Caldwell Allyson R. , Johnson Jafira M. , Brewster Rachel M. 
Published: January 2021

AbstractPrimary neurulation is the process by which the neural tube, the central nervous system precursor, is formed from the neural plate. Incomplete neural tube closure occurs frequently, yet underlying causes remain poorly understood. Developmental studies in amniotes and amphibians have identified hingepoint and neural fold formation as key morphogenetic events and hallmarks of primary neurulation, the disruption of which causes neural tube defects. In contrast, the mode of neurulation in teleosts has remained highly debated. Teleosts are thought to have evolved a unique mode of neurulation, whereby the neural plate infolds in absence of hingepoints and neural folds, at least in the hindbrain/trunk where it has been studied. Using high-resolution imaging and time-lapse microscopy, we show here the presence of these morphological landmarks in the zebrafish anterior neural plate. These results reveal similarities between neurulation in teleosts and other vertebrates and hence the suitability of zebrafish to understand human neurulation.
Mutational burden and chromosomal aneuploidy synergistically predict survival from radiotherapy in non-small cell lung cancer
Authors: Jia Qingzhu , Chu Qian , Zhang Anmei , Yu Jing , Liu Fangfang , Qian Kaiyu , Xiao Yu , Wang Xue , Yang Ying , Zhao Yi , He Ji , Li Guanghui , Wan Yisong Y. , Xie Conghua , Zhu Bo 
Published: January 2021

AbstractTherapeutic radiation can result in substantially different survival outcomes for patients with non-small cell lung cancer (NSCLC). Measures for identification of patients who can benefit most throughout radiotherapy remain limited. In this retrospective study, survival analysis was performed based on a discovery cohort from TCGA and a validation cohort from three independent hospitals. Tumor mutational burden (TMB) and chromosomal aneuploidy (ANE) were derived from the whole exome sequencing (WES) data from treatment-naïve tumors. Integrated risk scores were derived from TMB and ANE by a multivariate Cox proportional hazards model. TCGA reveal that TMB and ANE are associated positively and negatively, respectively, with survival throughout radiotherapy. Additionally, the synergistically predictive significance of these two genomic alterations, in differing responders and non-responders to radiotherapy is identified. These biomarkers may have clinical potential to improve personalized treatment management by rationally identifying highly likely responders to therapeutic radiation in patients with NSCLC.
The level of oncogenic Ras determines the malignant transformation of Lkb1 mutant tissue in vivo
Authors: Rackley Briana , Seong Chang-Soo , Kiely Evan , Parker Rebecca E. , Rupji Manali , Dwivedi Bhakti , Heddleston John M. , Giang William , Anthony Neil , Chew Teng-Leong , Gilbert-Ross Melissa 
Published: January 2021

AbstractThe genetic and metabolic heterogeneity of RAS-driven cancers has confounded therapeutic strategies in the clinic. To address this, rapid and genetically tractable animal models are needed that recapitulate the heterogeneity of RAS-driven cancers in vivo. Here, we generate a Drosophila melanogaster model of Ras/Lkb1 mutant carcinoma. We show that low-level expression of oncogenic Ras (RasLow) promotes the survival of Lkb1 mutant tissue, but results in autonomous cell cycle arrest and non-autonomous overgrowth of wild-type tissue. In contrast, high-level expression of oncogenic Ras (RasHigh) transforms Lkb1 mutant tissue resulting in lethal malignant tumors. Using simultaneous multiview light-sheet microcopy, we have characterized invasion phenotypes of Ras/Lkb1 tumors in living larvae. Our molecular analysis reveals sustained activation of the AMPK pathway in malignant Ras/Lkb1 tumors, and demonstrate the genetic and pharmacologic dependence of these tumors on CaMK-activated Ampk. We further show that LKB1 mutant human lung adenocarcinoma patients with high levels of oncogenic KRAS exhibit worse overall survival and increased AMPK activation. Our results suggest that high levels of oncogenic KRAS is a driving event in the malignant transformation of LKB1 mutant tissue, and uncovers a vulnerability that may be used to target this aggressive genetic subset of RAS-driven tumors.
Synergistic impacts of global warming and thermohaline circulation collapse on amphibians
Authors: Velasco Julián A. , Estrada Francisco , Calderón-Bustamante Oscar , Swingedouw Didier , Ureta Carolina , Gay Carlos , Defrance Dimitri 
Published: January 2021

AbstractImpacts on ecosystems and biodiversity are a prominent area of research in climate change. However, little is known about the effects of abrupt climate change and climate catastrophes on them. The probability of occurrence of such events is largely unknown but the associated risks could be large enough to influence global climate policy. Amphibians are indicators of ecosystems’ health and particularly sensitive to novel climate conditions. Using state-of-the-art climate model simulations, we present a global assessment of the effects of unabated global warming and a collapse of the Atlantic meridional overturning circulation (AMOC) on the distribution of 2509 amphibian species across six biogeographical realms and extinction risk categories. Global warming impacts are severe and strongly enhanced by additional and substantial AMOC weakening, showing tipping point behavior for many amphibian species. Further declines in climatically suitable areas are projected across multiple clades, and biogeographical regions. Species loss in regional assemblages is extensive across regions, with Neotropical, Nearctic and Palearctic regions being most affected. Results underline the need to expand existing knowledge about the consequences of climate catastrophes on human and natural systems to properly assess the risks of unabated warming and the benefits of active mitigation strategies.
Multimodal in vivo recording using transparent graphene microelectrodes illuminates spatiotemporal seizure dynamics at the microscale
Authors: Driscoll Nicolette , Rosch Richard E. , Murphy Brendan B. , Ashourvan Arian , Vishnubhotla Ramya , Dickens Olivia O. , Johnson A. T. Charlie , Davis Kathryn A. , Litt Brian , Bassett Danielle S. , Takano Hajime , Vitale Flavia 
Published: January 2021

AbstractNeurological disorders such as epilepsy arise from disrupted brain networks. Our capacity to treat these disorders is limited by our inability to map these networks at sufficient temporal and spatial scales to target interventions. Current best techniques either sample broad areas at low temporal resolution (e.g. calcium imaging) or record from discrete regions at high temporal resolution (e.g. electrophysiology). This limitation hampers our ability to understand and intervene in aberrations of network dynamics. Here we present a technique to map the onset and spatiotemporal spread of acute epileptic seizures in vivo by simultaneously recording high bandwidth microelectrocorticography and calcium fluorescence using transparent graphene microelectrode arrays. We integrate dynamic data features from both modalities using non-negative matrix factorization to identify sequential spatiotemporal patterns of seizure onset and evolution, revealing how the temporal progression of ictal electrophysiology is linked to the spatial evolution of the recruited seizure core. This integrated analysis of multimodal data reveals otherwise hidden state transitions in the spatial and temporal progression of acute seizures. The techniques demonstrated here may enable future targeted therapeutic interventions and novel spatially embedded models of local circuit dynamics during seizure onset and evolution.
Glacial melt disturbance shifts community metabolism of an Antarctic seafloor ecosystem from net autotrophy to heterotrophy
Authors: Braeckman Ulrike , Pasotti Francesca , Hoffmann Ralf , Vázquez Susana , Wulff Angela , Schloss Irene R. , Falk Ulrike , Deregibus Dolores , Lefaible Nene , Torstensson Anders , Al-Handal Adil , Wenzhöfer Frank , Vanreusel Ann 
Published: January 2021

AbstractClimate change-induced glacial melt affects benthic ecosystems along the West Antarctic Peninsula, but current understanding of the effects on benthic primary production and respiration is limited. Here we demonstrate with a series of in situ community metabolism measurements that climate-related glacial melt disturbance shifts benthic communities from net autotrophy to heterotrophy. With little glacial melt disturbance (during cold El Niño spring 2015), clear waters enabled high benthic microalgal production, resulting in net autotrophic benthic communities. In contrast, water column turbidity caused by increased glacial melt run-off (summer 2015 and warm La Niña spring 2016) limited benthic microalgal production and turned the benthic communities net heterotrophic. Ongoing accelerations in glacial melt and run-off may steer shallow Antarctic seafloor ecosystems towards net heterotrophy, altering the metabolic balance of benthic communities and potentially impacting the carbon balance and food webs at the Antarctic seafloor.
Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure
Authors: Furihata Takaaki , Takada Shingo , Kakutani Naoya , Maekawa Satoshi , Tsuda Masaya , Matsumoto Junichi , Mizushima Wataru , Fukushima Arata , Yokota Takashi , Enzan Nobuyuki , Matsushima Shouji , Handa Haruka , Fumoto Yoshizuki , Nio-Kobayashi Junko , Iwanaga Toshihiko , Tanaka Shinya , Tsutsui Hiroyuki , Sabe Hisataka , Kinugawa Shintaro 
Published: January 2021

AbstractHeart failure (HF) occurs frequently among older individuals, and dysfunction of cardiac mitochondria is often observed. We here show the cardiac-specific downregulation of a certain mitochondrial component during the chronological aging of mice, which is detrimental to the heart. MitoNEET is a mitochondrial outer membrane protein, encoded by CDGSH iron sulfur domain 1 (CISD1). Expression of mitoNEET was specifically downregulated in the heart and kidney of chronologically aged mice. Mice with a constitutive cardiac-specific deletion of CISD1 on the C57BL/6J background showed cardiac dysfunction only after 12 months of age and developed HF after 16 months; whereas irregular morphology and higher levels of reactive oxygen species in their cardiac mitochondria were observed at earlier time points. Our results suggest a possible mechanism by which cardiac mitochondria may gradually lose their integrity during natural aging, and shed light on an uncharted molecular basis closely related to age-associated HF.
Hadal trenches are dynamic hotspots for early diagenesis in the deep sea
Authors: Glud Ronnie N. , Berg Peter , Thamdrup Bo , Larsen Morten , Stewart Heather A. , Jamieson Alan J. , Glud Anni , Oguri Kazumasa , Sanei Hamed , Rowden Ashley A. , Wenzhöfer Frank 
Published: January 2021

AbstractThe deepest part of the global ocean, hadal trenches, are considered to act as depocenters for organic material. Relatively high microbial activity has been demonstrated in the deepest sections of some hadal trenches, but the deposition dynamics are thought to be spatially and temporally variable. Here, we explore sediment characteristics and in-situ benthic oxygen uptake along two trenches with contrasting surface primary productivity: the Kermadec and Atacama trenches. We find that benthic oxygen consumption varies by a factor of about 10 between hadal sites but is in all cases intensified relative to adjacent abyssal plains. The benthic oxygen uptake of the two trench regions reflects the difference in surface production, whereas variations within each trench are modulated by local deposition dynamics. Respiratory activity correlates with the sedimentary inventories of organic carbon and phytodetrital material. We argue that hadal trenches represent deep sea hotspots for early diagenesis and are more diverse and dynamic environments than previously recognized.
Design and analysis of different cooling schemes of a flux‐modulated permanent magnet in‐wheel motor for electric vehicle applications
Authors: Li Longnv , Zhu Gaojia , Zhao Yishuang , Jia Nan , Xue Ming , Li Yanbing 
Published: January 2021

AbstractThe flux‐modulated permanent magnet (FMPM) in‐wheel motor has provided a promising solution to drive electric vehicles (EVs) because of its salient features such as tight structure, high power (torque) density, and high transmission efficiency. But it easily causes excessive temperature rise and limits the torque output due to the poor heat dissipation capacity inside the in‐wheel cavity. In this regard, a 3D fluidic‐thermal coupled model integrating computational fluid dynamics and numerical heat transfer is proposed and validated by experimental results on a 2.1 kW, 1800 rpm PM motor prototype. The temperature rise distribution of a 22.6 kW, 600 rpm FMPM in‐wheel motor under an existing natural cooling structure is then numerically investigated. It is revealed that it is difficult to satisfy the thermal requirements of the motor using only natural cooling approach. Consequently, a self‐ventilated cooling system and a non‐contact lead‐in (NCLI) system are used to maintain the temperature rise. In addition, to further improve the heat dissipation capacity, the NCLI structure is modified with water cooling channels separated by orifice plates to limit the excessive motor temperature rise. The motor temperature rises under different cooling schemes are analyzed to verify the effectiveness of the proposed cooling structures.
Spontaneous Preterm Birth: Is Prevention with Aspirin Possible?
Authors: Berger Richard , Kyvernitakis Ioannis , Maul Holger 
Published: January 2021

Abstract
Background The rate of preterm births in Germany is 8.6%, which is very high compared to other European countries. As preterm birth contributes significantly to perinatal morbidity and mortality rates, the existing prevention strategies need to be optimized and expanded further. About ⅔ of all women with preterm birth have preterm labor or premature rupture of membranes. They are bracketed together under the term “spontaneous preterm birth” as opposed to iatrogenic preterm birth, for example as a consequence of preeclampsia or fetal growth retardation. Recent studies suggest that low-dose aspirin does not just reduce the rate of iatrogenic preterm births but can also further reduce the rate of spontaneous preterm births. This review article presents the current state of knowledge.
Method A selective literature search up until April 2020 was done in PubMed, using the terms “randomized trial”, “randomized study”, “spontaneous preterm birth”, and “aspirin”.
Results Secondary analyses of prospective randomized studies on the prevention of preeclampsia with low-dose aspirin show that this intervention also significantly reduced the rate of spontaneous preterm births in both high-risk and low-risk patient populations. The results of the ASPIRIN trial, a prospective, randomized, double-blinded multicenter study carried out in six developing countries, also point in this direction, with the figures showing that the daily administration of 81 mg aspirin starting before 14 weeks of gestation lowered the preterm birth rate of nulliparous women without prior medical conditions by around 11% (11.6 vs. 13.1%; RR 0.89; 95% CI: 0.81 – 0.98, p = 0.012).
Conclusion Further studies on this issue are urgently needed. If these confirm the currently available results, then it would be worth discussing whether general aspirin prophylaxis for all pregnant women starting at the latest in 12 weeks of gestation is indicated.
Choice of Continuous Glucose Monitoring Systems May Affect Metrics: Clinically Relevant Differences in Times in Ranges
Authors: Freckmann Guido , Pleus Stefan , Schauer Sebastian , Link Manuela , Jendrike Nina , Waldenmaier Delia , Haug Cornelia , Stuhr Andreas 
Published: January 2021

Abstract
Background Continuous glucose monitoring-derived parameters are becoming increasingly important in the treatment of people with diabetes. The aim of this study was to assess whether these parameters, as calculated from different continuous glucose monitoring systems worn in parallel, are comparable. In addition, clinical relevance of differences was investigated.
Methods A total of 24 subjects wore a FreeStyle Libre (A) and a Dexcom G5 (B) sensor in parallel for 7 days. Mean glucose, coefficient of variation, glucose management indicator and time spent in different glucose ranges were calculated for each system. Pairwise differences between the two different continuous glucose monitoring systems were computed for these metrics.
Results On average, the two CGM systems indicated an identical time in range (67.9±10.2 vs. 67.9±11.5%) and a similar coefficient of variation; both categorized as unstable (38.1±5.9 vs. 36.0±4.8%). In contrast, the mean time spent below and above range, as well as the individual times spent below, in and above range differed substantially. System A indicated about twice the time spent below range than system B (7.7±7.2 vs. 3.8±2.7%, p=0.003). This could have led to different therapy recommendations in approximately half of the subjects.
Discussion The differences in metrics found between the two continuous glucose monitoring systems may result in different therapy recommendations. In order to make adequate clinical decisions, measurement performance of CGM systems should be standardized and all available information, including the HbA1c, should be utilized.
Performance of Diagnostic Scores in Thrombotic Microangiopathy Patients in the Intensive Care Unit: A Monocentric Study
Authors: Mariotte Eric , Zafrani Lara , Fadlallah Jehane , Galicier Lionel , Ghrenassia Etienne , Kerhuel Lionel , Calvet Laure , Jong Audrey De , Lemiale Virginie , Valade Sandrine , Joly Bérangère S. , Stepanian Alain , Azoulay Elie , Darmon Michael 
Published: January 2021

AbstractEarly thrombotic thrombocytopenic purpura (TTP) recognition is critical as this disease is almost always lethal if not treated promptly with therapeutic plasma exchanges. Currently, as ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity is not widely available in emergency, scores have been developed to help differentiating TTP from other thrombotic microangiopathies (TMAs). The aim of this work was to study the accuracy of these diagnostic scores in the intensive care unit (ICU) setting. Performance of both Coppo and PLASMIC scores was studied in a cohort of adult TMA patients requiring admission to one university hospital ICU from 2006 to 2017. Receiver operating characteristic (ROC) curves were established, and confidence intervals of the area under the curve (AUC) were determined. Multivariate logistic regression analysis was performed to identify parameters specifically associated with TTP, to compare diagnostic scores and to elaborate more accurate diagnostic models. During the study period, 154 TMA patients required ICU admission, including 99 (64.2%) TTP and 55 (35.7%) non-TTP patients. AUC under the ROC curve in predicting TTP was 0.86 (95% confidence interval [CI]: 0.81–0.92) for the Coppo score, 0.67 (95% CI: 0.58–0.76) for the PLASMIC score, and 0.86 (95% CI: 0.81–0.92) for platelet count alone. Platelet count ≤20 G/L, determined as the best cut-off rate for thrombocytopenia, performed similarly to the Coppo score and better than the PLASMIC score to differentiate TTP from non-TTP patients, both using AUC ROC curve and logistic regression. In a monocentric cohort of TMA patients requiring ICU admission, the PLASMIC score had limited performance for the diagnosis of TTP. The performance of the Coppo score was good but similar to a single highly discriminant item: platelet count ≤20 G/L at admission.