bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coarse-grained Force Fields from the Perspective of Statistical Mechanics: Better Understanding the Origins of a MARTINI Hangover
Authors: Jarin Zack , Newhouse James , Voth Gregory A. 
Published: June 2020

AbstractThe popular MARTINI coarse-grained model is used as a test case to analyze the adherence of top-down coarse-grained molecular dynamics models (i.e., models primarily parameterized to match experimental results) to the known features of statistical mechanics for the underlying all-atom representations. Specifically, the temperature dependence of various pair distribution functions, and hence their underlying potentials of mean force via the reversible work theorem, are compared between MARTINI 2.0, Dry MARTINI, and all-atom simulations mapped onto equivalent coarse-grained sites for certain lipid bilayers. It is found that the MARTINI models do not completely capture the lipid structure seen in atomistic simulations as projected onto the coarse-grained mappings, and that issues of accuracy and temperature transferability arise due to an incorrect enthalpy-entropy decomposition of these potentials of mean force. The potential of mean force for the association of two amphipathic helices in a lipid bilayer is also calculated and, especially at shorter ranges, the MARTINI and all-atom projection results differ substantially. The former is much less repulsive and hence will lead to a higher probability of MARTINI helix association in the MARTINI bilayer than occurs in the actual all-atom case. Additionally, the bilayer height fluctuation spectra are calculated for the MARTINI model and – compared to the all-atom results – it is found that the magnitude of thermally averaged amplitudes at intermediate length scales is quite different, pointing to a number of possible consequences for realistic modeling of membrane processes. Taken as a whole, the results presented here can point the way for future coarse-grained model parameterization efforts that might bring top-down coarse-grained models into better agreement with the statistical mechanics of the actual all-atom systems they aspire to represent.
State-space optimal feedback control of optogenetically driven neural activity
Authors: Bolus M F , Willats A A , Rozell C J , Stanley G B 
Published: June 2020

AbstractObjectiveThe rapid acceleration of tools for recording neuronal populations and targeted optogenetic manipulation has enabled real-time, feedback control of neuronal circuits in the brain. Continuously-graded control of measured neuronal activity poses a wide range of technical challenges, which we address through a combination of optogenetic stimulation and a state-space optimal control framework implemented in the thalamocortical circuit of the awake mouse.ApproachClosed-loop optogenetic control of neurons was performed in real-time via stimulation of channelrhodopsin-2 expressed in the somatosensory thalamus of the head-fixed mouse. A state-space linear dynamical system model structure was used to approximate the light-to-spiking input-output relationship in both single-neuron as well as multi-neuron scenarios when recording from multielectrode arrays. These models were utilized to design state feedback controller gains by way of linear quadratic optimal control and were also used online for estimation of state feedback, where a parameter-adaptive Kalman filter provided robustness to model-mismatchMain resultsThis model-based control scheme proved effective for feedback control of single-neuron firing rate in the thalamus of awake animals. Notably, the graded optical actuation utilized here did not synchronize simultaneously recorded neurons, but heterogeneity across the neuronal population resulted in a varied response to stimulation. Simulated multi-output feedback control provided better control of a heterogeneous population and demonstrated how the approach generalizes beyond single-neuron applicationsSignificanceTo our knowledge, this work represents the first experimental application of state space model-based feedback control for optogenetic stimulation. In combination with linear quadratic optimal control, the approaches here should generalize to future problems involving the control of highly complex neural circuits. More generally, feedback control of neuronal circuits opens the door to adaptively interacting with the dynamics underlying sensory, motor, and cognitive signaling, enabling a deeper understanding of circuit function and ultimately the control of function in injury or disease.
Diagnostic technology for COVID-19: comparative evaluation of antigen and serology-based SARS-CoV-2 immunoassays, and contact tracing solutions for potential use as at-home products
Authors: Jorfi Mehdi , Luo Nell Meosky , Hazra Aditi , Herisson Fanny , Miller Glenn , Toombs James A. , Walt David R. , Bonato Paolo , Ahmad Rushdy ,   COVID-19 Direct-to-Consumer Task Force Investigators
Published: June 2020

AbstractAs the United States prepares to return to work and open up the economy in the midst of the COVID-19 pandemic without an available vaccine or effective therapy, testing and contact tracing are essential to contain and limit the spread of the COVID-19 virus. In response to the urgent public health need for accurate, effective, low-cost, and scalable COVID-19 testing technology, we evaluated and identified diagnostic solutions with potential for use as an at-home product. We conducted a deep horizon scan for antigen and serology-based diagnostics and down-selected to the most promising technologies. A total of 303 candidate products (138 antibody and 44 antigen tests) were identified. Product evaluations were based entirely on company-provided data. 73 serology-based antibody tests passing an initial scoring algorithm based on specificity and sensitivity data were then further evaluated using a second scoring algorithm. This second algorithm included a review of additional technical specifications of the devices, an analysis of supply chain, manufacturing, and distribution capacity of each vendor. 24 potential antibody products met the selection criteria for further direct laboratory evaluation. The performance metrics for selection of these 24 products are currently being evaluated in a Mass General Brigham laboratory. Testing alone might not be sufficient to prevent the spread of a highly contagious disease like COVID-19. Manual contact tracing could complement testing, but it is likely to fail in identifying many individuals who were in contact with a given COVID patient. The proliferation of smartphones in the population has enabled the development of solutions that can provide public health officials with valuable information for rapid and accurate contact tracing. Besides, electronic-based contact tracing solutions can be augmented by symptom self-reports gathered using electronic patient reported outcome (ePRO) platforms and by physiological data collected using wearable sensors. We performed a detailed assessment of 12 ePRO solutions, 27 wearable sensors, and 44 electronic-based contact tracing solutions. These technologies were evaluated using criteria developed to assess their suitability to address the COVID-19 pandemic. We identified a number of solutions that could augment if not provide a more effective alternative to manual contact tracing. Finally, we propose a theoretical framework in which ePRO platforms, wearable sensors, and electronic-based contact tracing solutions would be utilized in combination with molecular and serological tests to identify and isolate COVID-19 cases rapidly.
Highly efficient intercellular spreading of protein misfolding mediated by viral ligand - receptor interactions
Authors: Liu Shu , Hossinger Andre , Hornberger Annika , Buravlova Oleksandra , Müller Stephan , Lichtenthaler Stefan F. , Neumann Manuela , Denner Philip , Vorberg Ina M. 
Published: June 2020

SUMMARYPathological protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble proteins of the same kind. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contributes to the prion-like spreading of protein misfolding is unclear. Exchange of cellular cargo by both direct cell-to-cell contact as well as via EV depends on receptor-ligand interactions and subsequent release of cargo into the cytosol. We hypothesized that enabling these interactions through viral ligands enhances the aggregate-inducing capacity of EV-associated proteopathic seeds. Using different cellular models propagating model prion-like protein aggregates, mouse-adapted prions or pathogenic Tau aggregates, we demonstrate that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase protein aggregate induction by direct cell-to-cell contact or via viral glycoprotein-decorated EV. Thus, receptor-ligand interactions are major determinants of intercellular aggregate dissemination. Further, our data raise the intriguing possibility that acute or latent viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer.HIGHLIGHTSDifferent types of proteopathic seeds are secreted in association with extracellular vesiclesReceptor-ligand interactions are important drivers of direct cell-to-cell and extracellular vesicle-mediated spreading of protein misfoldingViral glycoproteins mediating attachment and membrane fusion strongly enhance aggregate inducing capacity in recipient cellsGRAPHICAL ABSTRACT
Abundance data applied to a novel model invertebrate host sheds new light on parasite community assembly in nature
Authors: Brian Joshua I. , Aldridge David C. 
Published: June 2020

AbstractUnderstanding how environmental drivers influence the construction of parasite communities, in addition to how parasites may interact at an infracommunity level, are fundamental requirements for the study of parasite ecology. Knowledge of how parasite communities are assembled will help to predict the risk of parasitism for hosts, and model how parasite communities may change under variable conditions. However, studies frequently rely on presence-absence data and examine multiple host species or sites, metrics which may be too coarse to characterise nuanced within-host patterns. Here, we utilise a novel host system, the freshwater musselAnodonta anatina, to investigate how both the presence and abundance of 14 parasite taxa correlate with environmental drivers across 720 replicate parasite infracommunities. Using both redundancy analysis and a joint species distribution model, we model the impact of both host-level and environment-level characteristics on parasite structure, as well as parasite-parasite correlations after accounting for all other factors. We demonstrate that both niche- and neutral-based factors are important but to varying degrees across parasite species, suggesting that applying generalities to parasite community construction is too simplistic. Further, we show that presence-absence data fails to capture important density-dependent effects of parasite load for parasites with high abundance. Finally, we highlight that predicted parasite interaction networks vary greatly depending on whether abundance or presence-absence data is used. Our results emphasise the multi-faceted nature of parasite community assembly, and that future studies require careful consideration of the data used to infer community structure.
Ontology-guided segmentation and object identification for developmental mouse lung immunofluorescent images
Authors: Masci Anna Maria , White Scott , Neely Ben , Ardini-Polaske Maryanne , Hill Carol B. , Misra Ravi S , Aronow Bruce , Gaddis Nathan , Wert Susan E. , Palmer Scott M. , Chan Cliburn ,   LungMAP Consortium
Published: June 2020

AbstractBackgroundImmunofluorescent confocal microscopy uses labeled antibodies as probes against specific macromolecules to discriminate between multiple cell types. For images of the developmental mouse lung, these cells are themselves organized into densely packed higher-level anatomical structures. These types of images can be challenging to segment automatically for several reasons, including the relevance of biomedical context, dependence on the specific set of probes used, prohibitive cost of generating labeled training data, as well as the complexity and dense packing of anatomical structures in the image. The use of an application ontology surmounts these challenges by combining image data with its metadata to provide a meaningful biological context, and hence constraining and simplifying the process of segmentation and object identification.ResultsWe propose an innovative approach for the automated analysis of complex and densely packed anatomical structures from immunofluorescent images that utilizes an application ontology to provide a simplified context for image segmentation and object identification. We describe how the logical organization of biological facts in the form of an ontology can provide useful constraints that enhance automatic processing of complex images. We demonstrate the results of ontology-guided segmentation and object identification in mouse developmental lung images from the Bioinformatics REsource ATlas for the Healthy lung (BREATH) database of the Molecular Atlas of Lung Development (LungMAP1) program.ConclusionThe microscopy analysis pipeline library (micap) is available athttps://github.com/duke-lungmap-team/microscopy-analysis-pipeline. Code to reproduce our analysis of LungMAP images is also available athttps://github.com/duke-lungmap-team/lungmap-pipeline. Finally, the application ontology is available athttps://github.com/duke-lungmap-team/lung_ontologyand includes example SPARQL queries.ContactAnna Maria Masci email:annamaria.masci@duke.edu
Baricitinib restrains the immune dysregulation in COVID-19 patients
Authors: Bronte Vincenzo , Ugel Stefano , Tinazzi Elisa , Vella Antonio , De Sanctis Francesco , Canè Stefania , Batani Veronica , Trovato Rosalinda , Fiore Alessandra , Petrova Varvara , Hofer Francesca , Barouni Roza Maria , Musiu Chiara , Caligola Simone , Pinton Laura , Torroni Lorena , Polati Enrico , Donadello Katia , Friso Simonetta , Pizzolo Francesca , Iezzi Manuela , Facciotti Federica , Pelicci Piergiuseppe , Righetti Daniela , Bazzoni Paolo , Rampudda Mariaelisa , Comel Andrea , Mosaner Walter , Lunardi Claudio , Olivieri Oliviero 
Published: June 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing pandemic coronavirus disease 2019 (COVID-19). The majority of patients with COVID-19 have a good prognosis, but variable percentages in different countries develop pneumonia associated with lymphocytopenia and severe inflammatory response due to uncontrolled release of cytokines. These immune mediators are transcriptionally regulated by JAK-STAT molecular pathways, which can be disabled by small molecules. Here, we provide evidences on the efficacy of baricitinib, a JAK1/JAK2 inhibitor, in correcting the immune abnormalities observed in patients hospitalized with COVID-19. Indeed, we demonstrate a significant reduction in serum levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)α, a rapid recovery in circulating T and B cell frequencies and an increased antibody production against SARS-CoV-2 spike protein in baricitinib-treated patients. Moreover, treated patients underwent a rapid reduction in oxygen flow need and progressive increase in the P/F. Our work provides the basis on developing effective treatments against COVID-19 pathogenesis using on-target therapy.
Genomic epidemiology of SARS-CoV-2 in Colombia
Authors: Laiton-Donato Katherine , Villabona-Arenas Christian Julián , Usme-Ciro José A. , Franco-Muñoz Carlos , Álvarez-Díaz Diego A. , Villabona-Arenas Liz Stephany , Echeverría-Londoño Susy , Cucunubá Zulma M. , Franco-Sierra Nicolás D. , Flórez Astrid C. , Ferro Carolina , Ajami Nadim J. , Walteros Diana Marcela , Prieto Franklin , Durán Carlos Andrés , Ospina-Martínez Martha Lucia , Mercado-Reyes Marcela 
Published: June 2020

AbstractCoronavirus disease 2019 (COVID-19) was first diagnosed in Colombia from a traveler arriving from Italy on February 26, 2020. To date, available data on the origins and number or introductions of SARS-CoV-2 into the country are limited. Here, we sequenced SARS-CoV-2 from 43 clinical samples and—together with other 73 genomes sequences available from the country—we investigated the emergence and the routes of importation of COVID-19 into Colombia using epidemiological, historical air travel and phylogenetic observations. Our study provided evidence of multiple introductions, mostly from Europe, with at least 12 lineages being documented. Phylogenetic findings validated the lineage diversity, supported multiple importation events and the evolutionary relationship of epidemiologically-linked transmission chains. Our results reconstruct the early evolutionary history of SARS-CoV-2 in Colombia and highlight the advantages of genome sequencing to complement COVID-19 outbreak investigation.
Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19
Authors: Brunetta Enrico , Folci Marco , Bottazzi Barbara , De Santis Maria , Protti Alessandro , Mapelli Sarah , Leone Roberto , My Ilaria , Bacci Monica , Zanon Veronica , Spata Gianmarco , Gianatti Andrea , Sironi Marina , Angelini Claudio , Garlanda Cecilia , Ciccarelli Michele , Cecconi Maurizio , Mantovani Alberto 
Published: June 2020

ABSTRACTPTX3 is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation. PTX3 plasma levels are associated with poor outcome in systemic inflammatory conditions and vascular pathology. The present study was designed to assess expression and significance of PTX3 in COVID-19. By bioinformatics analysis of public databases PTX3 expression was detected in lung respiratory cell lines exposed to SARS-CoV-2. By analysis at single cell level of COVID-19 circulating mononuclear cells, we found that PTX3 was selectively expressed by monocytes among circulating leukocytes. Moreover, in lung bronchoalveolar lavage fluid, single cell analysis revealed selective expression of PTX3 in neutrophils and macrophages, which play a major role in the pathogenesis of the disease. By immunohistochemistry, PTX3 was expressed by lung myelomocytic cells, type 2 pneumocytes and vascular endothelial cells. PTX3 plasma levels were determined by ELISA in 96 consecutive patients with a laboratory-confirmed diagnosis of COVID-19. Higher PTX3 plasma levels were observed in 52 (54.2%) patients admitted in ICU (median 21.0ng/mL, IQT 15.5-46.3 vs 12.4ng/mL IQT 6.1-20.2 in ward patients; p=0.0017) and in 22 (23%) patients died by 28 days (39.8ng/mL, IQT 20.2-75.7 vs 15.7ng/mL, IQT 8.2-21.6 in survivors; p=0.0001). After determining an optimal PTX3 cut-off for the primary outcome, the Kaplan-Meier curve showed an increased mortality in patients with PTX3>22.25ng/mL (Log-rank tests p<0.0001). In Cox regression model, PTX3>22.25ng/mL showed an adjusted Hazard Ratio (aHR) of 7.6 (95%CI2.45-23.76) in predicting mortality. Performing a multivariate logistic regression including all inflammatory markers (PTX3, ferritin, D-Dimer, IL-6, and CRP), PTX3 was the only marker significantly associated with death (aHR 1.13;95%CI1.02-1.24; p=0.021). The results reported here suggest that circulating and lung myelomonocytic cells are a major source of PTX3 and that PTX3 plasma levels can serve as a strong prognostic indicator of short-term mortality in COVID-19.
Oncogenesis and Aging by Isotopic Functionalizations of the Proteins and Nucleic Acids
Authors: Little Reginald B. , Uziel Orit 
Published: June 2020

AbstractAlthough the dynamics of telomeres during the life expectancy of normal cells have been extensively studied, there are still some unresolved issues regarding this research field. For example, the conditions required for telomere shortening leading to malignant transformations are not fully understood. In this work, we mass analyzed DNA of normal and cancer cells for comparing telomere isotopic compositions of white blood cells and cancer cells. We have found that the 1327 Da and 1672 Da characteristic telomere mass to charges cause differential mass distributions of about 1 Da for determining isotopic variations among normal cells relative to cancer cells. These isotopic differences are consistent with a prior theory that replacing primordial, common isotopes of1H,12C,14N,16O,24Mg,31P and/or32S by nonprimordial, uncommon isotopes of2D,13C,15N,17O,25Mg and/or33S leads to altered enzymatic dynamics for modulating DNA and telomere codons towards transforming normal cells to cancer cells. The prior theory and current data are consistent also with a recently observed non-uniform methylation in DNA of cancer cells relative to more uniform methylation in DNA of normal cells. We observe further evidence of nonprimordial isotopic accelerations of acetylations, methylations, hydroxylations and aminations of nucleosides with alterations of phosphorylations of nucleotides for possibly explaining the induced mutations of DNA, RNA and proteins leading to cancer and more general alterations of DNA associated with aging. The different mass spectra of normal and cancer DNA may be reasoned by different functionalizations and isotopic enrichments as causing different motionally induced atomic and nucleotide orders by different nuclear magnetic moments (NMMs); many motionally induced oligonucleotides causing nanoscale disorder and chaos; and the many such motionally induced nanoscale chaoses of different genes causing order in macroscopic DNA for organelles organizations.
SMARCA4 Mutations in KRAS-mutant Lung Adenocarcinoma: A Multi-cohort Analysis
Authors: Liu Liang , Ahmed Tamjeed , Petty W. Jeffrey , Grant Stefan , Ruiz Jimmy , Lycan Thomas W. , Topaloglu Umit , Chou Ping-Chieh , Miller Lance D. , Hawkins Gregory A. , Alexander-Miller Martha A. , O’Neill Stacey S. , Powell Bayard L. , D’Agostino Ralph B. , Munden Reginald F. , Pasche Boris , Zhang Wei 
Published: June 2020

ABSTRACTBackgroundKRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin-remodeling gene SMARCA4 was co-mutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD.MethodsThe association of SMARCA4 mutations with survival outcomes was interrogated in 4 independent cohorts totaling 564 patients: KRAS-mutant patients with LUAD who received non-immunotherapy treatment from 1) The Cancer Genome Atlas (TCGA) and 2) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from 3) the MSK-IMPACT (MSK-IO) and 4) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts.ResultsOf the patients receiving non-immunotherapy treatment, in the TCGA cohort (n=155), KRAS-mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome (P=6e-04 for disease-free survival (DFS) and .031 for overall survival (OS), respectively), compared to KRAS-TP53 co-mutant (KP) and KRAS-only mutant (K) patients; in the MSK-CT cohort (n=314), KS patients also exhibited shorter OS than KP (P=.03) or K (P=.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression-free survival (PFS; P=.0091) in the MSK-IO (n=77), and the shortest PFS (P=.0026) and OS (P=0.0014) in the WFBCCC (n=18) cohorts, respectively.Conclusionsmutations of SMARCA4 represent a genetic factor that lead to adverse clinical outcome in lung adenocarcinoma treated by either non-immunotherapy or immunotherapy.