bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of SARS-CoV2 antigen in human saliva may be a reliable tool for large scale screening
Authors: Kannian Priya , Lavanya Chandra , Ravichandran Krittika , Jayaraman Bagavad Gita , Mahanathi Pasuvaraj , Ashwini Veeraraghavan , Kumarasamy Nagalingeswaran , Rajan Gunaseelan , Ranganathan Kannan , Challacombe Stephen J. , Webster-Cyriaque Jennifer , Johnson Newell W. 
Published: December 2020

AbstractIntroductionSARS-CoV2, the aetiological agent of the current COVID-19 pandemic, has been detected in saliva and recently implicated in several oral diseases. Collection of nasopharyngeal swabs (NPS) and detection by reverse transcriptase-polymerase chain reaction (RT-PCR) requires medical / technical expertise. A reliable and easy to handle point-of-care (POC) test is highly desirable, especially to curb transmission. Therefore, in this study, we evaluated a commercially available POC rapid antigen test (RAT) for the detection of SARS-CoV2 antigens in the saliva of RT-PCR confirmed positive and negative patients.MethodsThirty saliva samples of 10 saliva RT-PCR negative and 20 saliva RT-PCR positive patients were tested by RAT.ResultsRAT was negative in 10/10 (100%) RT-PCR-negative samples; positive in 9/20 (45%) RT-PCR-positive samples; concordance was 63% (p=0.001). Patients with positive RAT had higher virus copies in their NPS samples compared to the RAT-negative patients. This difference was also statistically significant (p=0.01).ConclusionThus, the POC RAT may be used to detect SARS-CoV2 as a reliable tool for self-testing, large-scale population screening and emergency medical/dental screening. Patients negative by RAT should be confirmed by RT-PCR.
Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers
Authors: Eugene Andy R. 
Published: December 2020

AbstractBackgroundRecent in vitro studies have shown fluoxetine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) pathogen and one clinical study reported fluoxetine exposure at a median dose of 20mg in patients with the SARS-Cov-2 coronavirus disease 2019 (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to conduct in silico population dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-Cov-2 as reported in Calu-3 human lung cells.MethodsPopulation pharmacokinetic parameter estimates for a structural one-compartment model with first-order absorption was used to simulate fluoxetine concentration-time data. A population of 1,000 individuals were simulated at standard fluoxetine doses (20mg/day, 40mg/day, and 60mg/day) to estimate the percentage of the patients achieving a trough level for the EC90 SARS-Cov-2 inhibitory concentration at each day throughout a 10-day treatment period. All analyses were conducted via statistical programming in R.ResultsStandard fluoxetine antidepressant doses resulted in a range of 79% to 97% of the patient population achieving a trough target plasma concentration of 25.1 ng/ml which translates to lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 μM). At a dose of 40mg per day, at least 85% of patients will reach the trough target EC90 concentration within 3-days. The findings of this pharmacokinetic dosing study corroborate both in vitro and observational clinical study findings showing fluoxetine inhibits the SARS-Cov-2 pathogen at commonly treated doses in the practice of psychiatry.
Cell-intrinsic IL4R alpha independence of large intestinal RELMα+ Ym1+ macrophages
Authors: Forman Ruth , Logunova Larisa , Smith Hannah , Wemyss Kelly , Mair Iris , Boon Louis , Allen Judith E. , Muller Werner , Pennock Joanne L. , Else Kathryn J. 
Published: December 2020

ABSTRACTThe balance of pro-inflammatory and anti-inflammatory macrophages is critically important in enabling the development and resolution of inflammatory responses. Anti-inflammatory macrophages have been shown to be activated by IL4 and/or IL13 via the IL4Rα. In the context of type 2 immunity, anti-inflammatory macrophages have been defined by the expression of the signature markers RELMα, CD206 and Ym1, associated with activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, many of which feature unbalanced macrophage activation states, little is known about how large intestinal macrophages are activated. Here, we address this important knowledge gap by using aTrichuris murisinfection model of resolving type 2 intestinal inflammation, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. These models allowed us to interrogate the role of IL4/IL13 in macrophage activation driven by inflammation of the large intestine. We make the unexpected finding that education of large intestinal macrophages towards a RELMα and Ym1 expressing cell type during type 2 inflammation, does not require IL4Rα expression on macrophages. Thus, upregulation of RELMα and Ym1 post infection is independent of macrophage IL4Rα expression. Further, this independence is maintained even when the mice are treated with anti-IFNγ antibody to create a strongly polarised Th2 environment. In contrast to RELMα and Ym1, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These data challenge existing paradigms, evidencing that expression of RELMα and Ym1 by macrophages, typically regarded as having anti-inflammatory functions, do not always rely on IL4/IL13.
A Theory of Synaptic Transmission
Authors: Wang Bin , Dudko Olga K. 
Published: December 2020

AbstractRapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters into the synaptic cleft within just milliseconds of the action potential. Yet neurotransmitter release lacks a theoretical framework that is both phenomenologically accurate and mechanistically realistic. Here, we formulate an analytic theory of the action-potential-triggered neurotransmitter release at a chemical synapse. The theory captures general principles of synaptic transmission while generating concrete predictions for particular synapses. A universal scaling in synaptic transmission is established, and demonstrated through a collapse of experimental data from different synapses onto a universal curve. The theory shows how key characteristics of synaptic function – plasticity, fidelity, and efficacy – emerge from molecular mechanisms of neurotransmitter release machinery.
Human hippocampal neurons track moments in a sequence of events
Authors: Reddy Leila , Zoefel Benedikt , Possel Jessy K. , Peters Judith C. , Dijksterhuis Doris , Poncet Marlene , van Straaten Elisabeth C.W. , Baayen Johannes C. , Idema Sander , Self Matthew W. 
Published: December 2020

AbstractAn indispensable feature of episodic memory is our ability to temporally piece together different elements of an experience into a coherent memory. Hippocampal “time cells” – neurons that represent temporal information – may play a critical role in this process. While these cells have been repeatedly found in rodents, it is still unclear to what extent similar temporal selectivity exists in the human hippocampus. Here we show that temporal context modulates the firing activity of human hippocampal neurons during structured temporal experiences. We recorded neuronal activity in the human brain while patients learned predictable sequences of pictures. We report that human time cells fire at successive moments in this task. Furthermore, time cells also signaled inherently changing temporal contexts during empty 10-second gap periods between trials, while participants waited for the task to resume. Finally, population activity allowed for decoding temporal epoch identity, both during sequence learning and during the gap periods. These findings suggest that human hippocampal neurons could play an essential role in temporally organizing distinct moments of an experience in episodic memory.Significance StatementEpisodic memory refers to our ability to remember the “what, where, and when” of a past experience. Representing time is an important component of this form of memory. Here, we show that neurons in the human hippocampus represent temporal information. This temporal signature was observed both when participants were actively engaged in a memory task, as well as during 10s-long gaps when they were asked to wait before performing the task. Furthermore, the activity of the population of hippocampal cells allowed for decoding one temporal epoch from another. These results suggest a robust representation of time in the human hippocampus.
Sensory modulation of gait characteristics in human locomotion: a neuromusculoskeletal modeling study
Authors: Di Russo Andrea , Stanev Dimitar , Armand Stéphane , Ijspeert Auke 
Published: December 2020

AbstractThe central nervous system of humans and animals is able to modulate the activity in the spinal cord to achieve several locomotion behaviors. Previous neuromechanical models investigated the modulation of human gait changing selected parameters belonging to the CPGs (Central Pattern Generators) feedforward oscillatory structures or to the feedback reflex circuits. CPG-based models could replicate slow and fast walking by changing only the oscillation’s properties. On the other hand, reflex-based models could achieve different behaviors mainly through optimizations of a large dimensional parameter space, but could not identify effectively individual key reflex parameters responsible for the modulation of gait characteristics. This study, investigates which reflex parameters modulate the gait characteristics through neuromechanical simulations. A recently developed reflex-based model is used to perform optimizations with different target behaviors on speed, step length and step duration in order to analyse the correlation between reflex parameters and their influence on these gait characteristics. We identified 9 key parameters that influence the target speed ranging from slow to fast walking (0.48 and 1.71 m/s) as well as a large range of step lengths (0.43 and 0.88 m) and step duration (0.51, 0.98 s). The findings show that specific reflexes during stance have a major effect on step length regulation mainly given by the contribution of positive force feedback on the ankle plantarflexors’ group. On the other hand, stretch reflexes active during swing of iliopsoas and gluteus maximus regulate all the gait characteristics under analysis. Additionally, the results show that the stretch reflex of the hamstring’s group during landing phase is responsible for modulating the step length and step duration. Additional validation studies in simulations demonstrated that the identified reflexes are sufficient to modulate gait in human locomotion. Thus, this study provides an overview of the possible reflexes to control the gait characteristics.Author summary
A unified theory of E/I synaptic balance, quasicritical neuronal avalanches and asynchronous irregular spiking
Authors: Girardi-Schappo Mauricio , Galera Emilio F. , Carvalho Tawan T. A. , Brochini Ludmila , Kamiji Nilton L. , Roque Antonio C. , Kinouchi Osame 
Published: December 2020

AbstractNeuronal avalanches and asynchronous irregular (AI) firing patterns have been thought to represent distinct frameworks to understand the brain spontaneous activity. The former is typically present in systems where there is a balance between the slow accumulation of tension and its fast dissipation, whereas the latter is accompanied by the balance between synaptic excitation and inhibition (E/I). Here, we develop a new theory of E/I balance that relies on two homeostatic adaptation mechanisms: the short-term depression of inhibition and the spike-dependent threshold increase. First, we turn off the adaptation and show that the so-called static system has a typical critical point commonly attributed to self-organized critical models. Then, we turn on the adaptation and show that the network evolves to a dynamic regime in which: (I) E/I synapses balance regardless of any parameter choice; (II) an AI firing pattern emerges; and (III) neuronal avalanches display power laws. This is the first time that these three phenomena appear simultaneously in the same network activity. Thus, we show that the once thought opposing frameworks may be unified into a single dynamics, provided that adaptation mechanisms are in place. In our model, the AI firing pattern is a direct consequence of the hovering close to the critical line where external inputs are compensated by threshold growth, creating synaptic balance for any E/I weight ratio.HighlightsAsynchronous irregular (AI) firing happens together with power-law neuronal avalanches under self-organized synaptic balance.Self-organization towards the critical and balanced state (with AI and power-law avalanches) occur via short-term inhibition depression and firing threshold adaptation.The avalanche exponents match experimental findings.The adaptation time scales drive the self-organized dynamics towards different firing regimes.Author summaryTwo competing frameworks are employed to understand the brain spontaneous activity, both of which are backed by computational and experimental evidence: globally asynchronous and locally irregular (AI) activity arises in excitatory/inhibitory balanced networks subjected to external stimuli, whereas avalanche activity emerge in excitable systems on the critical point between active and inactive states. Here, we develop a new theory for E/I networks and show that there is a state where synaptic balance coexists with AI firing and power-law distributed neuronal avalanches. This regime is achieved through the introducing of short-term depression of inhibitory synapses and spike-dependent threshold adaptation. Thus, the system self-organizes towards the balance point, such that its AI activity arises from quasicritical fluctuations. The need for two independent adaptive mechanisms explains why different dynamical states are observed in the brain.
Dynamic positioning and precision of bistable gene expression boundaries through diffusion and morphogen decay
Authors: Perkins Melinda Liu 
Published: December 2020

1AbstractTraditional models for how morphogen gradients guide embryonic patterning fail to account for experimental observations of temporal refinement in gene expression domains. Dynamic positional information has recently emerged as a framework to address this shortcoming. Here, we explore two central aspects of dynamic positional information—the precision and placement of gene expression boundaries—in bistable genetic networks driven by morphogen gradients. First, we hypothesize that temporal morphogen decay may increase the precision of a boundary by compensating for variation in initial conditions that would otherwise lead neighboring cells with identical inputs to diverge to separate steady states. Second, we explore how diffusion of gene products may play a key role in placing gene expression boundaries. Using an existing model for Hb patterning in embryonic fruit flies, we show that diffusion permits boundaries to act as near-traveling wavefronts with local propagation speed determined by morphogen concentration. We then harness our understanding of near-traveling fronts to propose a method for achieving accurate steady-state boundary placement independent of initial conditions. Our work posits functional roles for temporally varying inputs and cell-to-cell coupling in the regulation and interpretation of dynamic positional information, illustrating that mathematical theory should serve to clarify not just our quantitative, but also our intuitive understanding of patterning processes.2Author SummaryIn many developmental systems, cells interpret spatial gradients of chemical morphogens to produce gene expression boundaries in exact positions. The simplest mathematical models for “positional information” rely on threshold detection, but such models are not robust to variations in the morphogen gradient or initial protein concentrations. Furthermore, these models fail to account for experimental results showing dynamic shifts in boundary placement and increased boundary precision over time. Here, we propose two theoretical mechanisms for enhancing boundary precision and placement using a bistable toggle switch. Distinct from existing research in “dynamic positional information”, this work posits a functional role for temporal decay in morphogen concentration and for diffusion of gene expression products, the latter of which is often omitted in quantitative models. We suggest that future research into dynamic positional information would benefit from perspectives that link local (cellular) and global (patterning) behaviors, as well as from mathematical theory that builds our intuitive understanding alongside more data-driven approaches.
Considerations for performance metrics of metagenomic next generation sequencing analyses
Authors: Kralj Jason G. , Servetas Stephanie L. , Forry Samuel P. , Jackson Scott A. 
Published: December 2020

AbstractEvaluating the performance of metagenomics analyses has proven a challenge, due in part to limited ground-truth standards, broad application space, and numerous evaluation methods and metrics. Application of traditional clinical performance metrics (i.e. sensitivity, specificity, etc.) using taxonomic classifiers do not fit the “one-bug-one-test” paradigm. Ultimately, users need methods that evaluate fitness-for-purpose and identify their analyses’ strengths and weaknesses. Within a defined cohort, reporting performance metrics by taxon, rather than by sample, will clarify this evaluation. An estimated limit of detection, positive and negative control samples, and true positive and negative true results are necessary criteria for all investigated taxa. Use of summary metrics should be restricted to comparing results of similar cohorts and data, and should employ harmonic means and continuous products for each performance metric rather than arithmetic mean. Such consideration will ensure meaningful comparisons and evaluation of fitness-for-purpose.
Poly(ADP-ribose) potentiates ZAP antiviral activity
Authors: Xue Guangai , Braczyk Klaudia , Gonçalves-Carneiro Daniel , Dawidziak Daria M. , Zawada Katarzyna , Ong Heley , Wan Yueping , Zadrozny Kaneil K. , Ganser-Pornillos Barbie K. , Bieniasz Paul D. , Pornillos Owen 
Published: December 2020

AbstractZinc-finger antiviral protein (ZAP), also known as poly(ADP-ribose) polymerase 13 (PARP13), is an antiviral factor that selectively targets viral RNA for degradation. ZAP is active against both DNA and RNA viruses, including important human pathogens such as hepatitis B virus and type 1 human immunodeficiency virus (HIV-1). ZAP selectively binds CpG dinucleotides through its N-terminal RNA-binding domain, which consists of four zinc fingers. ZAP also contains a central region that consists of a fifth zinc finger and two WWE domains. Through structural and biochemical studies, we found that the fifth zinc finger and tandem WWEs of ZAP combine into a single integrated domain that binds to poly(ADP-ribose) (PAR), a cellular polynucleotide. PAR binding is mediated by the second WWE module of ZAP and likely involves specific recognition ofiso(ADP-ribose), a repeating structural unit of PAR. Mutation of the putativeiso(ADP-ribose) binding site in ZAP abrogates the interactionin vitroand diminishes ZAP activity against a CpG-rich HIV-1 reporter virus. In cells, PAR facilitates formation of non-membranous sub-cellular compartments such as DNA repair foci, spindle poles and cytosolic RNA stress granules. Our results suggest that ZAP-mediated viral mRNA degradation is facilitated by PAR, and provides a biophysical rationale for the reported association of ZAP with RNA stress granules.
Do honey bee species differ in the odometer used for the waggle dance?
Authors: George Ebi Antony , Thulasi Neethu , Kohl Patrick L. , Suresh Sachin , Rutschmann Benjamin , Brockmann Axel 
Published: December 2020

AbstractHoney bees estimate distances to food sources using image motion experienced on the flight path and they use this measure to tune the waggle phase duration in their dance communication. Most studies on the relationship between experienced optic flow and the dance-related odometer are based on experiments withApis melliferaforagers trained into a small tunnel with black and white patterns which allowed quantifiable changes in the optic flow. In this study we determined the calibration curves for foragers of the two Asian honey bee species,A. floreaandA. cerana, in two different natural environments with clear differences in the vegetation conditions and hence visual contrast. We found that the dense vegetation condition (with higher contrast) elicited a more rapid increase in the waggle phase duration with distance than the sparse vegetation inA. floreabut not inA. cerana. Visual contrast did not affect the perception of the food reward, measured as the number of dance circuits produced per distance, in both species. Our findings suggest that contrast sensitivity of the waggle dance odometer, or other aspects of flight behaviour, might vary among honey bee species.
Genome architecture shapes evolutionary adaptation to DNA replication stress
Authors: Fumasoni Marco , Murray Andrew W. 
Published: December 2020

ABSTRACTIn haploid budding yeast, evolutionary adaptation to constitutive DNA replication stress alters three genome maintenance modules: DNA replication, the DNA damage checkpoint, and sister chromatid cohesion. We asked how these trajectories depend on a population’s genome architecture by comparing the adaptation of haploids to that diploids and recombination deficient haploids. In all three genome architectures, adaptation happens within 1000 generations at rates that are linearly correlated with the initial fitness defect of the ancestors. Mutations in individual genes are selected at different frequencies in different architectures, but the benefits these mutations confer are similar in all three architectures, and combinations of these mutations reproduce the fitness gains of evolved populations. Despite the differences in the selected mutations, the evolutionary trajectories target the same three functional modules in all architectures revealing a common evolutionary response to DNA replication stress.
Quantitative cross-species translators of cardiac myocyte electrophysiology: model training, experimental validation, and applications
Authors: Morotti Stefano , Liu Caroline , Hegyi Bence , Ni Haibo , Iseppe Alex Fogli , Wang Lianguo , Ripplinger Crystal M. , Bers Donald M. , Edwards Andrew G. , Grandi Eleonora 
Published: December 2020

AbstractAnimal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds. However, inter-species differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology, and undermine the assessment of drugs’ efficacy and safety. Here, we built a suite of translators for quantitatively mapping electrophysiological responses in ventricular myocytes across species. We trained these statistical operators using a broad dataset obtained by simulating populations of our biophysically detailed computational models of action potential and Ca2+transient in mouse, rabbit, and human. We then tested our translators against experimental data describing the response to stimuli, such as ion channel block, change in beating rate, and β-adrenergic challenge. We demonstrate that this approach is well suited to predicting the effects of perturbations across different species or experimental conditions, and suggest its integration into mechanistic studies and drug development pipelines.