bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comparative Analysis of Clinical Stage 3 COVID-19 Vaccines using Knowledge Representation
Authors: Burgos-Salcedo Javier 
Published: March 2021

AbstractThe emergence of a novel SARS-CoV-2 coronavirus at the end of 2019 and its accelerated spread worldwide to become a pandemic has had, from the medical biotechnology point of view, an unprecedented global response, to the point that there are currently 176 vaccine candidates in preclinical stage, 66 in clinical stage, of which 19 are in phase 3, and 5 of these are massively applied worldwide. The purpose of the present work is to elaborate a hierarchical landscape of the current status of phase 3 vaccines, taking into account their attributes of technological platform, safety and efficacy. The methodology used was that of conceptual knowledge representation, resulting in, firstly, an appropriate classification of stage 3 vaccines, The Conceptual Lattice for COVID-19 vaccines, constructed according to how they relate to each other with respect to the set of their attributes. Secondly, the approach used allows proposing rational strategies for the design of heterologous vaccination schemes, which are urgently needed to control the pandemic.
Role of IL-23 neutralization in psoriasis – insights from a mechanistic PK/PD model and meta-analysis of clinical data
Authors: Kapitanov Georgi I. 
Published: March 2021

AbstractBlocking of IL-23 has shown a profound effect on patient outcomes in psoriasis. The current IL-23 binding monoclonal antibodies show differences in dosing regimens, pharmacokinetics, affinity for the target, and efficacy outcomes in the clinic. The goal of the current work is to use a mechanistic pharmacokinetics/pharmacodynamics mathematical model to estimate projected free IL-23 neutralization for the different therapeutic molecules and connect it to clinical efficacy outcomes. The meta-analysis indicates a sigmoid-like relationship and suggests that the best current anti-IL23 antibodies are close to saturating the efficacy that can be achieved by this pathway in psoriasis.
Predicting vaccine hesitancy from area-level indicators: A machine learning approach
Authors: Carrieri Vincenzo , Lagravinese Raffele , Resce Giuliano 
Published: March 2021

AbstractVaccine hesitancy (VH) might represent a serious threat to the next COVID-19 mass immunization campaign. We use machine-learning algorithms to predict communities at a high risk of VH relying on area-level indicators easily available to policymakers. We illustrate our approach on data from child immunization campaigns for seven non-mandatory vaccines carried out in 6408 Italian municipalities in 2016. A battery of machine learning models is compared in terms of area under the Receiver Operating Characteristics (ROC) curve. We find that the Random Forest algorithm best predicts areas with a high risk of VH improving the unpredictable baseline level by 24% in terms of accuracy. Among the area-level indicators, the proportion of waste recycling and the employment rate are found to be the most powerful predictors of high VH. This can support policy makers to target area-level provaccine awareness campaigns.
Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations
Authors: Singh Uday , Saito Kenji , Toth Brandon A. , Dickey Jacob E. , Rodeghiero Samuel R. , Deng Yue , Deng Guorui , Xue Baojian , Zhu Zhiyong , Jiang Jingwei , Zingman Leonid V. , Cui Huxing 
Published: March 2021

ABSTRACTObjectiveThe paraventricular nucleus of hypothalamus (PVN) is an integrative center in the brain orchestrating a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is undoubtedly involved in feeding regulation, the neuroanatomical organization of PVNMC4R+pathway and its role in diverse physiological and behavioral regulations have not been fully understood. Here we aimed to better characterize the input-output organization of PVNMC4R+neurons and further test their potential functional roles beyond feeding.MethodsUsing a combination of viral tools, we performed a comprehensive mapping of PVNMC4R+circuits and tested the effects of chemogenetic activation of PVNMC4R+neurons on thermogenesis, cardiovascular control and other behavioral regulations beyond feeding.ResultsWe found that PVNMC4R+neurons broadly innervate many different brain regions known to be important not only for feeding but also for neuroendocrine and autonomic control of thermogenesis and cardiovascular function, including but not limited to preoptic area, median eminence, parabrachial nucleus, locus coeruleus, nucleus of solitary tract, ventrolateral medulla and thoracic spinal cord. Contrary to broad efferent projections, PVNMC4R+neurons receive monosynaptic inputs from limited brain regions, including medial preoptic nucleus, arcuate and dorsomedial hypothalamic nuclei, and supraoptic nucleus. Consistent with broad efferent projections, chemogenetic activation of PVNMC4R+neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure and brown adipose tissue thermogenesis. Strikingly, these physiological changes accompanied an unexpected repetitive bedding-removing behavior followed by hypoactivity and resting-like behavior.ConclusionsOur results clarify the neuroanatomical organization of PVNMC4R+circuits and shed new light on the roles of PVNMC4R+pathways in autonomic control of thermogenesis, cardiovascular function and other behavioral regulations.
Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistantS. pseudintermedius
Authors: O’Neill Alan M. , Worthing Kate A. , Kulkarni Nikhil , Li Fengwu , Nakatsuji Teruaki , Mills Robert H. , Cheng Joyce Y. , Gonzalez David J. , Norris Jacqueline M. , Gallo Richard L. 
Published: March 2021

ABSTRACTMethicillin-resistantStaphylococcus pseudintermedius(MRSP) is an important emerging zoonotic pathogen that causes severe skin infections. To combat infections from drug-resistant bacteria, the transplantation of commensal antimicrobial bacteria as a therapeutic has shown clinical promise. We screened a collection of diverse staphylococcus species from domestic dogs and cats for antimicrobial activity against MRSP. A unique strain (S. felisC4) was isolated from feline skin that inhibited MRSP and multiple gram-positive pathogens. Competition experiments in mice showed thatS. felissignificantly reduced MRSP skin colonization and an antimicrobial extract fromS. felissignificantly reduced necrotic skin injury from MRSP infection. Fluorescence and electron microscopy revealed thatS. felisantimicrobials disrupted bacterial but not eukaryotic cell membranes. LC/MS identified severalS. felisphenol-soluble modulin beta (PSMβ) peptides that exhibited antimicrobial and anti-inflammatory activity. These findings indicate a feline commensal bacterium that could be utilized in bacteriotherapy against difficult-to-treat animal and human skin infections.
Self-healing codes: how stable neural populations can track continually reconfiguring neural representations
Authors: Rule M. E. , O’Leary T. 
Published: March 2021

As an adaptive system, the brain must retain a faithful representation of the world while continuously integrating new information. Recent experiments have measured population activity in cortical and hippocampal circuits over many days, and found that patterns of neural activity associated with fixed behavioral variables and percepts change dramatically over time. Such “representational drift” raises the question of how malleable population codes can interact coherently with stable long-term representations that are found in other circuits, and with relatively rigid topographic mappings of peripheral sensory and motor signals. We explore how known plasticity mechanisms can allow single neurons to reliably read out an evolving population code without external error feedback. We find that interactions between Hebbian learning and single-cell homeostasis can exploit redundancy in a distributed population code to compensate for gradual changes in tuning. Recurrent feedback of partially stabilized readouts could allow a pool of readout cells to further correct inconsistencies introduced by representational drift. This shows how relatively simple, known mechanisms can stabilize neural tuning in the short term, and provides a plausible explanation for how plastic neural codes remain integrated with consolidated, long-term representations.SignificanceThe brain is capable of adapting while maintaining stable long-term memories and learned skills. Recent experiments show that neural responses are highly plastic in some circuits, while other circuits maintain consistent responses over time, raising the question of how these circuits interact coherently. We show how simple, biologically motivated Hebbian and homeostatic mechanisms in single neurons can allow circuits with fixed responses to continuously track a plastic, changing representation without reference to an external learning signal.
Laminar-specific interhemispheric connectivity mapping with bilateral line-scanning fMRI
Authors: Choi Sangcheon , Chen Yi , Zeng Hang , Biswal Bharat , Yu Xin 
Published: March 2021

ABSTRACTDespite extensive studies detecting blood-oxygen-level-dependent (BOLD) fMRI signals across two hemispheres to present cognitive processes in normal and diseased brains, the role of corpus callosum (CC) to mediate interhemispheric functional connectivity remains controversial. Several studies show maintaining low-frequency fluctuation of resting-state (rs)-fMRI signals in homotopic brain areas of acallosal humans and post-callosotomy animals, raising the question: how can we specify the circuit-specific rs-fMRI signal fluctuation from other sources? To address this question, we have developed a bilateral line-scanning fMRI (BiLS) method to detect bilateral laminar BOLD fMRI signals from symmetric cortical regions with high spatial (100 μm) and temporal (100 ms) resolution in rodents under anesthesia. In addition to ultra-slow oscillation (0.01-0.02 Hz) patterns across all cortical layers, a layer-specific bilateral coherence pattern was observed with a peak at Layer (L)2/3, where callosal projection neurons are primarily located and reciprocal transcallosal projections are received. In particular, the L2/3-specific coherence pattern showed a peak at 0.05 Hz based on the stimulation paradigm, depending on the interhemispheric CC activation. Meanwhile, the L2/3-specific rs-fMRI coherence was peaked at 0.08-0.1Hz which was independent of the varied ultra-slow oscillation patterns (0.01-0.02 Hz) presumably involved with global neuromodulation. This work provides a unique laminar fMRI mapping scheme to characterize the CC-mediated evoked fMRI and frequency-dependent rs-fMRI responses, presenting crucial evidence to distinguish the circuit-specific fMRI signal fluctuations across two hemispheres.Significance statementLaminar fMRI is a promising method to better understand neuronal circuit contribution to functional connectivity (FC) across cortical layers. Here, we developed a bilateral line-scanning fMRI method, allowing the detection of laminar-specific BOLD-fMRI signals from homologous cortical regions in rodents with high spatial and temporal resolution. Laminar coherence patterns of both evoked and rs-fMRI signals revealed that CC-dependent interhemispheric FC is significantly strong at Layer 2/3, where callosal projection neurons are primarily located. The Layer 2/3-specific rs-fMRI coherence is independent of ultra-slow oscillation based on global neuromodulation, distinguishing the circuit-specific rs-fMRI signal fluctuation from different regulatory sources.
A H3K9me2-Binding Protein AGDP3 Limits DNA Methylation and Transcriptional Gene Silencing in Arabidopsis
Authors: Zhou Xuelin , Wei Mengwei , Nie Wenfeng , Xi Yue , Du Xuan , Peng Li , Zheng Qijie , Tang Kai , Satheesh Viswanathan , Wang Yuhua , Luo Jinyan , Liu Rui , Yang Zhenlin , Zhong Yingli , An Guo-Yong , Zhu Jian-Kang , Du Jiamu , Lei Mingguang 
Published: March 2021

AbstractDNA methylation is critical for tuning gene expression to prevent potentially deleterious gene-silencing. The Arabidopsis DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1) initiates active DNA demethylation and is required for the prevention of DNA hypermethylation at thousands of genomic loci. However, the mechanism recruiting ROS1 to specific loci is not well understood. Here, we report the discovery of Arabidopsis AGENET Domain Containing Protein 3 (AGDP3) as a cellular factor required for ROS1-mediated DNA demethylation, and targets ROS1 to specific loci. We found that AGDP3 could bind to the H3K9me2 mark by its AGD12 cassette. The crystal structure of the AGDP3 AGD12 in complex with an H3K9me2 peptide reveals the molecular basis for the specific recognition, that the dimethylated H3K9 and unmodified H3K4 are specifically anchored into two different surface pockets. Interestingly, a histidine residue located in the methylysine binding aromatic cage enables AGDP3 pH-dependent H3K9me2 binding capacity. Considering the intracellular pH correlates with the histone acetylation status, our results provide the molecular mechanism for the regulation of ROS1 DNA demethylase by the gene silencing H3K9me2 mark and the potential crosstalk with active histone acetylation mark.
Short duration overnight cattle kraaling in natural rangelands: does time after kraal use affect their utilization by wildlife and above ground grass parameters?
Authors: Huruba Rangarirai , Nemera Servious , Ngute Faith , Sahomba Meshack , Mundy Peter J. , Sebata Allan , MacFadyen Duncan N. 
Published: March 2021

AbstractShort duration overnight cattle kraaling in natural rangelands creates nutrients hotspots attractive to a diverse suite of large mammalian herbivores. However, few studies have determined the use of these sites by large mammalian herbivores. We determined the number of animal sightings per day from camera traps and used them as proxies for use of these newly created nutrient hotspots of varying ages (1, 2, 3 and 4 years) and surrounding vegetation. Six mammalian herbivores of different sizes belonging to three feeding guilds viz. grazers (Burchell’s zebra Equus quagga burchelli and warthog Phacochoerus africanus), mixed feeders (impala Aepyceros melampus and African savanna elephant Loxodonta africana africana) and browsers (northern giraffe Giraffa camelopardalis giraffa and greater kudu Tragelaphus strepsiceros) frequently used these nutrient hotspots. The number of sightings per day of mammalian herbivores was determined during three periods of the year (January – wet season; June – early dry season; October – late dry season) to ascertain their use of these nutrient hotspots. In addition, above ground grass biomass and height was measured and related to grazer sightings. Furthermore, we tested if repeated grazing in the newly created nutrient hotspots stimulated grass compensatory growth. All the mammalian herbivores used the newly created nutrient hotspots similarly throughout the year, with impala the most active users. Grazer and browser use of nutrient hotspots was not influenced by their age, while mixed feeders mostly used the one year old sites. Grazer use of nutrient hotspots was not influenced by aboveground grass biomass and height. Repeated clipping (proxy for grazing) resulted in compensatory aboveground grass biomass growth in nutrient hotspots. Impala benefited the most and zebra the least from the creation of nutrient hotspots in natural rangelands. We conclude that creation of nutrients hotspots through short duration overnight kraaling results in rangeland heterogeneity that improves availability of herbivore foraging sites.
Noradrenergic circuit control of non-REM sleep substates
Authors: Osorio-Forero Alejandro , Cardis Romain , Vantomme Gil , Guillaume-Gentil Aurélie , Katsioudi Georgia , Fernandez Laura M.J. , Lüthi Anita 
Published: March 2021

SummaryOne promising approach towards understanding what makes sleep vulnerable in disease is to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is inhibited during non-REM sleep (NREMS). However, many mammalian species, including humans, show recurrent moments of sleep fragility during which sensory reactivity is elevated. Wake-related neuronal activity could thus remain active in NREMS, but its roles in dynamic variations of sensory reactivity remain unknown. Here, we demonstrate that mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the ∼50-seconds time-scale. These fluctuations occurred around mean noradrenaline levels greater than the ones of quiet wakefulness, while they declined steeply in REMS. They coincided with a clustering of sleep spindle rhythms in the forebrain and with heart rate variations. We addressed the origins of these fluctuations by using closed-loop optogenetic locus coeruleus (LC) activation or inhibition timed to moments of low and high spindle activity during NREMS. We could suppress, lock or entrain sleep spindle clustering or heart rate variations, demonstrating that both fore- and hindbrain-projecting LC neurons show synchronized infraslow activity variations in natural NREMS. Noradrenergic modulation of thalamic but not cortical circuits was required for sleep spindle clustering and involved noradrenaline release into primary sensory and reticular thalamic nuclei that activated both α1- and β-adrenergic receptors to cause slowly decaying membrane depolarizations. Noradrenergic signaling by LC, primarily known for attention promotion in wakefulness, renders mammalian NREMS more ‘wake-like’ on the close-to-minute-time scale through sustaining thalamocortical and autonomic sensory arousability.
Estimating Ectopic Beat Probability with Simplified Statistical Models that Account for Experimental Uncertainty
Authors: Jin Qingchu , Greenstein Joseph L. , Winslow Raimond L. 
Published: March 2021

AbstractEctopic beats (EBs) are cellular arrhythmias that can trigger lethal arrhythmias. Simulations using biophysically-detailed cardiac myocyte models can reveal how model parameters influence the probability of these cellular arrhythmias, however such analyses can pose a huge computational burden. Here, we develop a simplified approach in which logistic regression models (LRMs) are used to define a mapping between the parameters of complex cell models and the probability of EBs (P(EB)). As an example, in this study, we build an LRM for P(EB) as a function of diastolic cytosolic Ca2+concentration ([Ca2+]i), sarcoplasmic reticulum (SR) Ca2+load, and kinetic parameters of the inward rectifier K+current (IK1) and ryanodine receptor (RyR). This approach, which we refer to as arrhythmia sensitivity analysis, allows for evaluation of the relationship between these arrhythmic event probabilities and their associated parameters. This LRM is also used to demonstrate how uncertainties in experimentally measured values determine the uncertainty in P(EB). In a study of the role of [Ca2+]SRuncertainty, we show a special property of the uncertainty in P(EB), where with increasing [Ca2+]SRuncertainty, P(EB) uncertainty first increases and then decreases. Lastly, we demonstrate that IK1suppression, at the level that occurs in heart failure myocytes, increases P(EB).Author summaryAn ectopic beat is an abnormal cellular electrical event which can trigger dangerous arrhythmias in the heart. Complex biophysical models of the cardiac myocyte can be used to reveal how cell properties affect the probability of ectopic beats. However, such analyses can pose a huge computational burden. We develop a simplified approach that enables a highly complex biophysical model to be reduced to a rather simple statistical model from which the functional relationship between myocyte model parameters and the probability of an ectopic beat is determined. We refer to this approach as arrhythmia sensitivity analysis. Given the efficiency of our approach, we also use it to demonstrate how uncertainties in experimentally measured myocyte model parameters determine the uncertainty in ectopic beat probability. We find that, with increasing model parameter uncertainty, the uncertainty in probability of ectopic beat first increases and then decreases. In general, our approach can efficiently analyze the relationship between cardiac myocyte parameters and the probability of ectopic beats and can be used to study how uncertainty of these cardiac myocyte parameters influences the ectopic beat probability.
Differential effects on neuromuscular physiology betweenSodloss-of-function mutation and paraquat-induced oxidative stress inDrosophila
Authors: Ueda Atsushi , Iyengar Atulya , Wu Chun-Fang 
Published: March 2021

AbstractOxidative stress is thought to be a major contributor to aging processes. Here, we report differential effects on neurotransmission caused by loss-of-function mutations ofSuperoxide dismutase(Sod) and by paraquat (PQ) feeding inDrosophila. We demonstrated alterations inSodmutants; the larval neuromuscular junction displayed supernumerary discharges and the adult giant-fiber escape pathway showed increased latency and poor response to repetitive high-frequency stimulation. Even though the concentrations used led to motor coordination defects and lethality, PQ feeding failed to reproduce such performance deficits in these larval and adult preparations, indicating mechanistic distinctions between genetic and pharmacological manipulation of oxidative stress.
Comparative phylogeography of the freshwater mussels of the southeastern United States: reconstructing historic drainages using molecular data
Authors: Small Scott T. , Wares John P. 
Published: March 2021

AbstractKnowledge of species ages and their distribution enhance our understanding of processes that create and maintain species diversity at both local and regional levels. The largest family of freshwater mussels (Unionidae), reach their highest species diversity in drainages of the southeastern united states. By sequencing multiple loci from mussel species distributed throughout the drainages in this region, we attempt to uncover historical patterns of divergence and determine the role of vicariance events on the species formation in mussels and extend our hypothesis to freshwater animals in general. We analyzed 346 sequences from five genera encompassing 37 species. Species were sampled across 12 distinct drainages ending either in the Atlantic Ocean or the Gulf of Mexico. Overall the topologies of the different genera returned phylogenetic trees that were congruent with geographically contiguous drainages. The most common pattern was the grouping between the Atlantic slope and gulf coast drainages, however the Tennessee drainage was often the exception to this pattern grouping with the Atlantic slope. Most mussel species find a most recent common ancestor within a drainage before finding an ancestor between drainages. This supports the hypothesis of allopatric divergence followed by later burst of speciation within a drainage. Our estimated divergence times for the Atlantic-Gulf split agree with other studies estimating vicariance in fish species of the Atlantic and gulf coast.