bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimental erosion of microbial diversity decreases soil CH4consumption rates
Authors: Schnyder Elvira , Bodelier Paul L.E. , Hartmann Martin , Henneberger Ruth , Niklaus Pascal A. 
Published: March 2020

AbstractBiodiversity-ecosystem functioning (BEF) experiments have predominantly focused on communities of higher organisms, in particular plants, with comparably little known to date about the relevance of biodiversity for microbially-driven biogeochemical processes. Methanotrophic bacteria play a key role in Earth’s methane (CH4) cycle by removing atmospheric CH4and reducing emissions from methanogenesis in wetlands and landfills. Here, we used a dilution-to-extinction approach to simulate diversity loss in a methanotrophic landfill cover soil community. Combining analyses of CH4flux and community structure, we found a linear decrease of CH4oxidation rates with the number of taxonomic units lost. This effect was independent of community size, consistent over the three-month study, and occurred in relatively diverse communities, challenging the notion of high functional redundancy mediating high resistance to diversity erosion in natural microbial systems. The effects we report resemble the ones for higher organisms, suggesting that BEF-relationships are universal across taxa and spatial scales.
Computational simulations reveal the binding dynamics between human ACE2 and the receptor binding domain of SARS-CoV-2 spike protein
Authors: Lupala Cecylia S. , Li Xuanxuan , Lei Jian , Chen Hong , Qi Jianxun , Liu Haiguang , Su Xiao-dong 
Published: March 2020

AbstractA novel coronavirus (the SARS-CoV-2) has been identified in January 2020 as the causal pathogen for COVID-19 pneumonia, an outbreak started near the end of 2019 in Wuhan, China. The SARS-CoV-2 was found to be closely related to the SARS-CoV, based on the genomic analysis. The Angiotensin converting enzyme 2 protein (ACE2) utilized by the SARS-CoV as a receptor was found to facilitate the infection of SARS-CoV-2, initiated by the binding of the spike protein to the human ACE2. Using homology modeling and molecular dynamics (MD) simulation methods, we report here the detailed structure of the ACE2 in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The predicted model is highly consistent with the experimentally determined complex structures. Besides the binding interface reported in the crystal structures, new plausible binding poses were revealed from all-atom MD simulations. The simulation data helped identify critical residues at the complex interface and provided more details about the interactions between the SARS-CoV-2 RBD and human ACE2. Two mutants mimicking rat ACE2 were modeled to study the mutation effects on RBD binding to ACE2. The simulations showed that the N-terminal helix and the K353 are very important for the tight binding of the complex, the mutants were found to alter the binding modes of the CoV2-RBD to ACE2.
A competency-based approach to pass/fail decisions in an objective structured clinical examination: An observational study
Authors: Alkhateeb Nazdar Ezzaddin , Al-Dabbagh Ali , Mohammed Yaseen Omar , Ibrahim Mohammed 
Published: March 2020

BackgroundAny high-stakes assessment that leads to an important decision requires careful consideration in determining whether a student passes or fails. This observational study conducted in Erbil, Iraq, in June 2018 proposes a defensible pass/fail decision based on the number of failed competencies.MethodsResults were obtained for 150 medical students on their final objective structured clinical examination. Cutoff scores and pass/fail decisions were calculated using the modified Angoff, borderline, borderline-regression and holistic methods. The results were compared with each other and with a new competency method using Cohen’s kappa. Rasch analysis was used to compare the consistency of competency data with Rasch model estimates.ResultsThe competency method resulted in 40 (26.7%) students failing, compared with 76 (50.6%), 37 (24.6%), 35 (23.3%) and 13 (8%) for the modified Angoff, borderline, borderline regression and holistic methods, respectively. The competency method demonstrated a sufficient degree of fit to the Rasch model (mean outfit and infit statistics of 0.961 and 0.960, respectively).Conclusionsthe competency method was more stringent in determining pass/fail, compared with other standard-setting methods, except for the modified Angoff method. The fit of competency data to the Rasch model provides evidence for the validity and reliability of pass/fail decisions.
A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Authors: Zhou Ying , Yang Zhen , Guo Yanan , Geng Shuang , Gao Shan , Ye Shenglan , Hu Yi , Wang Yafei 
Published: March 2020

AbstractBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan, Hubei, China. This study sought to elucidate a novel predictor of disease severity in patients with coronavirus disease-19 (COVID-19) cased by SARS-CoV-2.MethodsPatients enrolled in this study were all hospitalized with COVID-19 in the Central Hospital of Wuhan, China. Clinical features, chronic comorbidities, demographic data, and laboratory and radiological data were reviewed. The outcomes of patients with severe pneumonia and those with non-severe pneumonia were compared using the Statistical Package for the Social Sciences (IBM Corp., Armonk, NY, USA) to explore clinical characteristics and risk factors. The receiver operating characteristic curve was used to screen optimal predictors from the risk factors and the predictive power was verified by internal validation.ResultsA total of 377 patients diagnosed with COVID-19 were enrolled in this study, including 117 with severe pneumonia and 260 with non-severe pneumonia. The independent risk factors for severe pneumonia were age [odds ratio (OR): 1.059, 95% confidence interval (CI): 1.036–1.082; p < 0.001], N/L (OR: 1.322, 95% CI: 1.180–1.481; p < 0.001), CRP (OR: 1.231, 95% CI: 1.129–1.341; p = 0.002), and D-dimer (OR: 1.059, 95% CI: 1.013–1.107; p = 0.011). We identified a product of N/L*CRP*D-dimer as having an important predictive value for the severity of COVID-19. The cutoff value was 5.32. The negative predictive value of less than 5.32 for the N/L*CRP*D-dimer was 93.75%, while the positive predictive value was 46.03% in the test sets. The sensitivity and specificity were 89.47% and 67.42%. In the training sets, the negative and positive predictive values were 93.80% and 41.32%, respectively, with a specificity of 70.76% and a sensitivity of 89.87%.ConclusionsA product of N/L*CRP*D-dimer may be an important predictor of disease severity in patients with COVID-19.
Structural Disconnection of the Tool Use Network After Left Hemisphere Stroke Predicts Limb Apraxia Severity
Authors: Garcea Frank E. , Greene Clint , Grafton Scott T. , Buxbaum Laurel J. 
Published: March 2020

AbstractProducing a tool use gesture is a complex process drawing upon the integration of stored knowledge of tools and their associated actions with sensory-motor mechanisms supporting the planning and control of hand and arm actions. Understanding how sensory-motor systems in parietal cortex interface with semantic representations of actions and objects in the temporal lobe remains a critical issue, and is hypothesized to be a key determinant of the severity of limb apraxia, a deficit in producing skilled action after left hemisphere stroke. We used voxel-based and connectome-based lesion symptom mapping with data from 57 left hemisphere stroke participants to assess the lesion sites and structural disconnection patterns associated with poor tool use gesturing. We found that structural disconnection between the left inferior parietal lobule, lateral temporal lobe (left middle temporal gyrus) and ventral temporal cortex (left medial fusiform gyrus) predicted the severity of tool use gesturing performance. Control analyses demonstrated that reductions in right-hand grip strength were associated with motor system disconnection, bypassing regions supporting tool use gesturing. Our findings provide causal evidence that limb apraxia may arise, in part, from disconnection of conceptual representations in the temporal lobe from mechanisms enabling skilled action production in the inferior parietal lobule.
Precise replacement ofSaccharomyces cerevisiaeproteasome genes with human orthologs by an integrative targeting method
Authors: Yellman Christopher M. 
Published: March 2020

ABSTRACTArtificial induction of a chromosomal double-strand break inSaccharomyces cerevisiaeenhances the frequency of integration of homologous DNA fragments into the broken region by up to several orders of magnitude. The process of homologous repair can be exploited to integrate, in principle, any foreign DNA into a target site, provided the introduced DNA is flanked at both the 5’ and 3’ ends by sequences homologous to the region surrounding the double-strand break. We have developed a tool set that requires a minimum of steps to induce double-strand breaks at chromosomal target sites with the meganuclease I-SceI and select integration events at those sites. We demonstrate this method in two different applications. First, the introduction of site-specific single-nucleotide phosphorylation site mutations into theS. cerevisiaegeneSPO12. Second, the precise chromosomal replacement of elevenS. cerevisiaeproteasome genes with their human orthologs. Placing the human genes underS. cerevisiaetranscriptional control allowed us to update our of model of functional replacement. Our experience suggests that using native promoters may be a useful general strategy for the coordinated expression of foreign genes inS. cerevisiae. We provide an integrative targeting toolset that will facilitate a variety of precision genome engineering applications.
Dynamics of gaze control during prey capture in freely moving mice
Authors: Michaiel Angie M. , Abe Elliott T.T. , Niell Cristopher M. 
Published: March 2020

ABSTRACTMany studies of visual processing are conducted in unnatural conditions, such as head- and gaze-fixation. As this radically limits natural exploration of the visual environment, there is much less known about how animals actively use their sensory systems to acquire visual information in natural, goal-directed contexts. Recently, prey capture has emerged as an ethologically relevant behavior that mice perform without training, and that engages vision for accurate orienting and pursuit. However, it is unclear how mice target their gaze during such natural behaviors, particularly since, in contrast to many predatory species, mice have a narrow binocular field and lack foveate vision that would entail fixing their gaze on a specific point in the visual field. Here we measured head and bilateral eye movements in freely moving mice performing prey capture. We find that the majority of eye movements are compensatory for head movements, thereby acting to stabilize the visual scene. During head turns, however, these periods of stabilization are interspersed with non-compensatory saccades that abruptly shift gaze position. Analysis of eye movements relative to the cricket position shows that the saccades do not preferentially select a specific point in the visual scene. Rather, orienting movements are driven by the head, with the eyes following in coordination to sequentially stabilize and recenter the gaze. These findings help relate eye movements in the mouse to other species, and provide a foundation for studying active vision during ethological behaviors in the mouse.
Combining Information from Crosslinks and Monolinks in the Modelling of Protein Structures
Authors: Sinnott M. , Malhotra S. , Madhusudhan M.S. , Thalassinos K. , Topf M. 
Published: March 2020

SUMMARYMonolinks are produced in a Chemical Crosslinking Mass Spectrometry experiment and are more abundant than crosslinks. They convey residue exposure information, but so far have not been used in the modelling of protein structures. Here we present the Monolink Depth Score (MoDS), for assessing structural models based on the depth of monolinked residues, corresponding to their distance to the nearest bulk water. Using simulated and reprocessed experimental data from the Proteomic Identification Database, we compare the performance of MoDS to MNXL - our previously-developed score for assessing models based on crosslinking data. Our results show that MoDS can be used to effectively score model structures based on monolinks, and that combining it with MNXL leads to overall higher scoring performance. The work strongly supports the use of monolink data in the context of integrative structure determination. We also present XLM-Tools, a programme to assist in this effort, available at:https://github.com/Topf-Lab/XLM-Tools.
Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis
Authors: Megremis Spyridon , Walker Thomas D. J. , He Xiaotong , O’Sullivan James , Ollier William E.R. , Chinoy Hector , Pendleton Neil , Payton Antony , Hampson Lynne , Hampson Ian , Lamb Janine A. 
Published: March 2020

SummaryWe investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. Increased microbial diversity was observed in dermatomyositis. Viruses were over-represented and species of the Poxviridae family were significantly enriched. The autoantibodies identified recognised a large portion of the human proteome, including interferon regulated proteins; these proteins were clustered in specific biological processes. Apart from TRIM33, autoantibodies against eleven further TRIM proteins, including TRIM21, were identified. Some of these TRIM proteins shared epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a significant role in the pathogenesis of dermatomyositis.
Anti-CD19 CAR T cells potently redirected to kill solid tumor cells
Authors: Ambrose Christine , Su Lihe , Wu Lan , Dufort Fay J. , Sanford Thomas , Birt Alyssa , Hackel Benjamin , Hombach Andreas , Abken Hinrich , Lobb Roy R. , Rennert Paul D. 
Published: March 2020

AbstractSuccessful CAR T cell therapy for the treatment of solid tumors requires exemplary CAR T cell expansion, persistence and fitness, and the ability to target tumor antigens safely. Here we address this constellation of critical attributes for successful cellular therapy by using integrated technologies that simplify development and derisk clinical translation. We have developed a CAR-CD19 T cell that secretes a CD19-anti-Her2 bridging protein. This cell therapy strategy exploits the ability of CD19-targeting CAR T cells to interact with CD19 on normal B cells to drive expansion, persistence and fitness. The secreted bridging protein potently binds to Her2-positive tumor cells, mediating CAR-CD19 T cell cytotoxicityin vitroandin vivo. Because of its short half-life, the secreted bridging protein will selectively accumulate at the site of highest antigen expression, ie. at the tumor. Bridging proteins that bind to multiple different tumor antigens have been created. Therefore, antigen-bridging CAR-CD19 T cells incorporate critical attributes for successful solid tumor cell therapy. This platform can be exploited to attack tumor antigens on any cancer.
Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology
Authors: Bartell Eric , Fujimoto Masanobu , Khoury Jane C. , Khoury Philip R. , Vedantam Sailaja , Hirschhorn Joel , Dauber Andrew 
Published: March 2020

AbstractThe growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 in 839 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels nearIGFBP3andIGFBP5genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, theIGFBP3signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); theIGFBP5signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated SNPs near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.
POMC neurons functional heterogeneity relies on mTORC1 signaling
Authors: Saucisse Nicolas , Mazier Wilfrid , Simon Vincent , Binder Elke , Catania Caterina , Bellocchio Luigi , Romanov Roman A. , Matias Isabelle , Zizzari Philippe , Leon Stephane , Quarta Carmelo , Cannich Astrid , Meece Kana , Gonzales Delphine , Clark Samantha , Becker Julia M. , Yeo Giles S.H. , Merkle Florian T. , Wardlaw Sharon L. , Harkany Tibor , Massa Federico , Marsicano Giovanni , Cota Daniela 
Published: March 2020

AbstractHypothalamic Pro-opiomelanocortin (POMC) neurons are classically known to trigger satiety. However, they encompass heterogeneous subpopulations whose functions are unknown. Here we show that POMC neurons releasing GABA, glutamate or both neurotransmitters possess distinct spatial distribution, molecular signatures and functions. Functional specificity of these subpopulations relies on the energy sensor mechanistic Target of Rapamycin Complex 1 (mTORC1), since pharmacological blockade of mTORC1, by mimicking a cellular negative energy state, simultaneously inhibited POMC/glutamatergic and activated POMC/GABAergic neurons. Chemogenetics and conditional deletion of mTORC1 then demonstrated that mTORC1 blockade in POMC neurons causes hyperphagia. This is due to decreased POMC-derived anorexigenicα-melanocyte-stimulating hormone and the recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Genetic inhibition of glutamate release from POMC neurons also produced hyperphagia, recapitulating the phenotype caused by mTORC1 blockade. Altogether, these findings pinpoint the molecular mechanisms engaged by POMC neurons to oppositely control feeding, thereby challenging conventional views about their functions.
Exploiting prior knowledge about biological macromolecules in cryo-EM structure determination
Authors: Kimanius Dari , Zickert Gustav , Nakane Takanori , Adler Jonas , Lunz Sebastian , Schönlieb Carola-Bibiane , Öktem Ozan , Scheres Sjors H.W. 
Published: March 2020

AbstractThree-dimensional reconstruction of the electron scattering potential of biological macromolecules from electron cryo-microscopy (cryo-EM) projection images is an ill-posed problem. The most popular cryo-EM software solutions to date rely on a regularisation approach that is based on the prior assumption that the scattering potential varies smoothly over three-dimensional space. Although this approach has been hugely successful in recent years, the amount of prior knowledge it exploits compares unfavourably to the knowledge about biological structures that has been accumulated over decades of research in structural biology. Here, we present a regularisation framework for cryo-EM structure determination that exploits prior knowledge about biological structures through a convolutional neural network that is trained on known macromolecular structures. We insert this neural network into the iterative cryo-EM structure determination process through an approach that is inspired by Regularisation by Denoising. We show that the new regularisation approach yields better reconstructions than the current state-of-the-art for simulated data and discuss options to extend this work for application to experimental cryo-EM data.
Selection and suppression of visual information in the macaque prefrontal cortex
Authors: Di Bello F. , Ben Hadj Hassen S. , Astrand E. , Ben Hamed S. 
Published: March 2020

AbstractIn everyday life, we are continuously struggling at focusing on our current goals while at the same time avoiding distractions. Attention is the neuro-cognitive process devoted to the selection of behaviorally relevant sensory information while at the same time preventing distraction by irrelevant information. Visual selection can be implemented by both long-term (learning-based spatial prioritization) and short term (dynamic spatial attention) mechanisms. On the other hand, distraction can be prevented proactively, by strategically prioritizing task-relevant information at the expense of irrelevant information, or reactively, by actively suppressing the processing of distractors. The distinctive neuronal signature of each of these four processes is largely unknown. Likewise, how selection and suppression mechanisms interact to drive perception has never been explored neither at the behavioral nor at the neuronal level. Here, we apply machine-learning decoding methods to prefrontal cortical (PFC) activity to monitor dynamic spatial attention with an unprecedented spatial and temporal resolution. This leads to several novel observations. We first identify independent behavioral and neuronal signatures for learning-based attention prioritization and dynamic attentional selection. Second, we identify distinct behavioral and neuronal signatures for proactive and reactive suppression mechanisms. We find that while distracting task-relevant information is suppressed proactively, task-irrelevant information is suppressed reactively. Critically, we show that distractor suppression, whether proactive or reactive, strongly depends on both learning-based attention prioritization and dynamic attentional selection. Overall, we thus provide a unified neuro-cognitive framework describing how the prefrontal cortex implements spatial selection and distractor suppression in order to flexibly optimize behavior in dynamic environments.