bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesicles
Authors: Mohamud Yusuf A , Hagemann N , Zhang X , Zafar M , Hussner T , Bromkamp C , Martiny C , Tertel T , Börger V , Schumacher F , Solari FA , Hasenberg M , Kleinschnitz C , Doeppner TR , Kleuser B , Sickmann A , Gunzer M , Giebel B , Kolesnick R , Gulbins E , Hermann DM 
Published: March 2021

AbstractFunctional inhibitors of acid sphingomyelinase are clinically used as anti-depressants since ∼60 years. Here, we show that acid sphingomyelinase inhibition by the antidepressants amitriptyline, fluoxetine and desipramine protects from ischemia/reperfusion and elicits a profound brain remodeling response with increased angiogenesis, improved blood-brain barrier integrity, reduced brain leukocyte infiltration and increased neuronal survival. Angiogenesis is promoted by small extracellular vesicles withbona fidecharacteristics of exosomes, which are released from endothelial cells and which constitute an elegant target for the amplification of stroke recovery.
CD47 as a potential biomarker for the early diagnosis of severe COVID-19
Authors: McLaughlin Katie-May , Bojkova Denisa , Bechtel Marco , Kandler Joshua D. , Reus Philipp , Le Trang , Wagner Julian U. G. , Ciesek Sandra , Wass Mark N. , Michaelis Martin , Cinatl Jindrich 
Published: March 2021

AbstractThe coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. Antiviral interventions are only effective prior to the onset of hyperinflammation. Hence, biomarkers are needed for the early identification and treatment of high-risk patients. Here, we show in a range of model systems and data from post mortem samples that SARS-CoV-2 infection results in increased levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells. Systematic literature searches also indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions which may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, CD47 is a candidate biomarker for severe COVID-19. Further research will have to show whether CD47 is a reliable diagnostic marker for the early identification of COVID-19 patients requiring antiviral therapy.
Acetylcholine boosts dendritic NMDA spikes in a CA3 pyramidal neuron model
Authors: Humphries Rachel , Mellor Jack R. , O’Donnell Cian 
Published: March 2021

AbstractAcetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca2+influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of acetylcholine on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca2+-activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles.Highlights-Using biophysical computational models of CA3 pyramidal neurons we estimated the quantitative effects of acetylcholine on nonlinear synaptic integration.-Nonlinear NMDA spikes can be triggered by fewer synapses in distal dendrites due to increased local input resistance.-Acetylcholine broadly reduces the number of synapses needed to trigger NMDA spikes, but the magnitude of the effect varies across dendrite branches within a single neuron.-No single potassium channel type is the dominant mediator of the excitability effects of acetylcholine.
Non-canonical Hedgehog signaling through L-type voltage gated Ca2+channels controls CD8+T cell killing
Authors: Hanna Joachim , Kapeni Chrysa , O’Brien Louise , Carbonaro Valentina , Beke Flavio , Chilamakuri Chandra , de la Roche Maike 
Published: March 2021

ABSTRACTCytotoxic CD8+T lymphocytes (CTLs) are critical to the immune response against intracellular pathogens and cancer and act by eliminating infected and malignant cells through targeted secretion of cytotoxic granules. Hedgehog (Hh) signaling has been shown to be critical for CTL killing. Interestingly, Hh signaling in CD8+T cells is not induced by extracellular Hh ligands but is initiated upon T cell receptor (TCR) engagement. How the TCR induces the Hh pathway independently of extracellular Hh ligands is unknown. Here we show that the Hh transcription factor Gli1 is essential for efficient CTL function and is induced downstream of the TCR by an extracellular Ca2+influx selectively controlled by L-type voltage gated Ca2+channels localized at the plasma membrane. We demonstrate that this novel mode of Hh signaling induction is independent of the canonical Hh pathway and represents the primary mechanism of Gli1 induction in naïve CD8+T cells, while CTLs can also activate Gli1 via MAP Kinase signaling. Importantly, we show that this L-type voltage gated Ca2+channel-controlled Gli1 induction is functionally required for CTL killing in mice and humans. Gli inhibitors are currently in clinical trials against various cancers and our observations indicate that they likely inhibit the anti-tumor response.Significance statementCytotoxic CD8+T cells (CTLs) kill infected and malignant cells by targeted secretion of cytotoxic granules. Hedgehog signaling is critical for effective CTL killing and is activated by the T cell receptor (TCR) independently of exogenous Hedgehog ligands. This study shows that Hedgehog transcription factor Gli1 is required for CTL killing and identifies L-type voltage gated Ca2+channels (Cav1) as essential regulators of CTL killing in mouse and human, by virtue of their ability to activate Gli1 downstream of the TCR. This Cav1-Gli1 axis operates independently of canonical Hedgehog signaling. Our work suggests that caution is required when using Gli inhibitors, currently in trials as anti-cancer therapeutics, since they may dampen the anti-tumor response.
Interaction of thyroid hormones and gonadotropin inhibitory hormone in the multifactorial control of zebrafish (Danio rerio) spermatogenesis
Authors: Rodrigues Maira S. , Fallah Hamideh P. , Zanardini Maya , Habibi Hamid R. , Nóbrega Rafael H. 
Published: March 2021

ABSTRACTReproduction is under multifactorial control of neurohormones, pituitary gonadotropins, as well as a number of gonadal hormones including sex steroids and growth factors. Gonadotropin-inhibitory hormone (Gnih), a novel RFamide neuropeptide, was shown to be involved in the control of pituitary gonadotropin production, as well as being involved as a paracrine factor in the regulation of gonadal function. In this context, recent studies have demonstrated that Gnih inhibited gonadotropin-induced spermatogenesis in the zebrafish testicular explants. Thyroid hormones are known to interact with the reproductive axis, and are, in particular, involved in the regulation of testicular function. Based on this background, we investigated the interaction between Gnih and thyroid hormones in the control of zebrafish spermatogenesis. To this end, zebrafish adult males were treated with the goitrogen methimazole (1mM for 21 days) in order to generate a hypothyroid model organism. Subsequently, a factorial design using anex vivotestis culture system in combination with histomorphometrical and FACScan cell cycle analyses were adopted. Our results showed that methimazole treatment affected both basal and gonadotropin-induced spermatogenesis, in particular, meiosis and spermiogenesis. Moreover, the goitrogen treatment nullified the inhibitory actions of Gnih on the gonadotropin-induced spermatogenesis, specifically in the haploid cell population. We have demonstrated that thyroid hormones interaction with gonadotropin and Gnih are important components for the regulation of zebrafish spermatogenesis. The results provide a support for the hypothesis that thyroid hormones are important contributors in multifactorial control of spermatogenesis in zebrafish.
The spatiotemporal organization of experience dictates hippocampal involvement in primary visual cortical plasticity
Authors: Finnie Peter S. B. , Komorowski Robert W. , Bear Mark F. 
Published: March 2021

AbstractThe hippocampus and neocortex are theorized to be crucial partners in the formation of long-term memories. Here, we assess hippocampal involvement in two related forms of experience-dependent plasticity in the primary visual cortex (V1) of mice. Like control animals, those with hippocampal lesions exhibit potentiation of visually evoked potentials following passive daily exposure to a phase reversing oriented grating stimulus, which is accompanied by long-term habituation of a reflexive behavioral response. Thus, low-level recognition memory is formed independently of the hippocampus. However, response potentiation resulting from daily exposure to a fixed sequence of four oriented gratings is severely impaired in mice with hippocampal damage. A feature of sequence plasticity in V1 of controls, but absent in lesioned mice, is generation of predictive responses to an anticipated stimulus element when it is withheld or delayed. Thus, hippocampus is involved in encoding temporally structured experience, even in primary sensory cortex.
Deciphering enhancer sequence using thermodynamics-based models and convolutional neural networks
Authors: Dibaeinia Payam , Sinha Saurabh 
Published: March 2021

AbstractDeciphering the sequence-function relationship encoded in enhancers holds the key to interpreting non-coding variants and understanding mechanisms of transcriptomic variation. Several quantitative models exist for predicting enhancer function and underlying mechanisms; however, there has been no systematic comparison of these models characterizing their relative strengths and shortcomings. Here, we interrogated a rich data set of neuroectodermal enhancers inDrosophila, representing cis- and trans- sources of expression variation, with a suite of biophysical and machine learning models. We performed rigorous comparisons of thermodynamics-based models implementing different mechanisms of activation, repression, and cooperativity. Moreover, we developed a convolutional neural network (CNN) model, called CoNSEPT, that learns enhancer “grammar” in an unbiased manner. CoNSEPT is the first general-purpose CNN tool for predicting enhancer function in varying conditions, and we show that such complex models can suggest interpretable mechanisms. We found model-based evidence for mechanisms previously established for the studied system, including cooperative activation and short-range repression. The data also favored one hypothesized activation mechanism over another and suggested an intriguing role for a direct, distance-independent repression mechanism. Our modeling shows that while fundamentally different models can yield similar fits to data, they vary in their utility for mechanistic inference. CoNSEPT is freely available at:https://github.com/PayamDiba/CoNSEPT.
Modeling of Deformable Cell Separation in a Microchannel with Sequenced Pillars
Authors: Hymel Scott J. , Fujioka Hideki , Khismatullin Damir B. 
Published: March 2021

AbstractEmbedded pillar microstructures are an efficient approach for controlling and sculpting shear flow in a microchannel but have not yet demonstrated to be effective for deformability-based cell separation and sorting. Although simple pillar configurations (lattice, line sequence) worked well for size-based separation of rigid particles, they had a low separation efficiency for circulating cells. The objective of this study was to optimize sequenced microstructures for separation of deformable cells. This was achieved by numerical analysis of pairwise cell migration in a microchannel with multiple pillars, which size, longitudinal spacing, and lateral location as well as the cell elasticity and size varied. This study revealed two basic pillar configurations optimized for deformability-based separation: 1) “duplet” that consists of two closely spaced pillars positioned far below the centerline and above the centerline halfway to the wall; and 2) “triplet” composed of three widely-spaced pillars located below, above and at the centerline, respectively. The duplet configuration is well suited for deformable cell separation in short channels, while the triplet or a combination of duplets and triplets provides even better separation in long channels. These optimized pillar microstructures can dramatically improve microfluidic methods for sorting and isolation of blood and rare circulating tumor cells.
On the emergence of orientational order in folded proteins with implications for allostery
Authors: Chakraborty Debayan , Mugnai Mauro Lorenzo , Thirumalai D. 
Published: March 2021

AbstractThe beautiful structures of single and multi-domain proteins are clearly ordered in some fashion but cannot be readily classified using group theory methods that are successfully used to describe periodic crystals. For this reason, protein structures are considered to be aperiodic, and may have evolved this way for functional purposes, especially in instances that require a combination of softness and rigidity within the same molecule. By analyzing the solved protein structures, we show that orientational symmetry is broken in the aperiodic arrangement of the secondary structural elements (SSEs), which we deduce by calculating the nematic order parameter,P2. We find that the folded structures are nematic droplets with a broad distribution ofP2. We argue that non-zero values ofP2, leads to an arrangement of the SSEs that can resist external stresses forces, which is a requirement for allosteric proteins. Such proteins, which resist mechanical forces in some regions while being flexible in others, transmit signals from one region of the protein to another (action at a distance) in response to binding of ligands (oxygen, ATP or other small molecules).
Rattus economicus: A neural model for rational regulation of water-seeking effort in rodents
Authors: Reinagel Pamela 
Published: March 2021

AbstractIn the laboratory, animals’ motivation to work tends to be positively correlated with reward magnitude. But in nature, rewards earned by work are essential to survival (e.g., working to find water), and the payoff of that work can vary on long timescales (e.g., seasonally). Under these constraints, the strategy of working less when rewards are small could be fatal. We found that instead, rats in a closed economy did more work for water rewards when the rewards were stably smaller, a phenomenon also observed in human labor supply curves. Like human consumers, rats also showed elasticity of demand, consuming far more water per day when its price in effort was lower. The neural mechanisms underlying such “rational” market behaviors remain largely unexplored. We propose a dynamic utility maximization model that can account for the dependence of rat labor supply (trials/day) on the wage rate (ml/trial), and also predict the temporal dynamics of when rats work. Based on data from mice, we hypothesize that SFOGLUTneurons inlamina terminaliscontinuously compute the instantaneous marginal utility of voluntary work for water reward, and causally determine the amount and timing of work.
Institutional pressures and cluster firms’ ambidextrous innovation: the mediating role of strategic cognition
Authors: Song Bo , Zhao Zhonghua 
Published: March 2021

Purpose
How do institutional pressures influence the cluster firm’s innovation? Institutional pressure consists of regulative, normative and cognitive pressures; most scholars have only focused on the influence of regulative pressure as institutional environment on innovation. In addition, the nature of strategic cognition, as the mediator act on innovation strategy, remains underexplored in the literature. Based on institution theory and ambidextrous innovation theory, this study aims to propose a framework to examine the mechanism of institutional pressures acting on ambidextrous innovation through the moderated mediating role of strategic cognition in clusters.

Design/methodology/approach
Using survey data collected from 422 sampled firms in China, regression models were used to test hypotheses from the mediating role of strategic cognition between institutional pressures and cluster firm’s ambidextrous innovation.

Findings
The results showed that regulative, cognitive pressures and, especially, normative pressures have significant positive effects on cluster firms’ ambidextrous innovation. Strategic cognition presented by prospector and analyzer mediates the relationship between institutional pressure and ambidextrous innovation except defender; dynamic environment positively moderates the mediating effects of prospector cognition on explorative innovation, and negatively moderates the mediating effects of analyzer cognition on exploitative innovation.

Originality/value
The findings of this study have some implications that strategic cognition played a partially meditating role between the institutional pressure and ambidextrous innovation. Government should construct a dynamic innovation policy system according to the resource endowment in different regions; furthermore, classification support system to cluster firms with different strategic cognition should be built.
Evaluating a bystander intervention to disrupt interpersonal violence/abuse
Authors: Roberts Nicola , Marsh Heaven 
Published: March 2021

Purpose
It is recommended that universities implement bystander interventions to disrupt the interpersonal violence and abuse that students experience in this context. Yet, there are few evaluations of bystander interventions in the UK. Building on an existing evaluation carried out on a bystander intervention at a university in 2017/18, the purpose of this research was to evaluate the intervention.

Design/methodology/approach
Using a one-way repeated measures design, analysis of variance was used to analyse pre- and post-intervention data gathered from 121 students, during 2018/19.

Findings
As the aims of the session were met, it can be inferred individuals who participate in the bystander intervention have the potential to disrupt interpersonal violence and abuse.

Research limitations/implications
The small sample size and design of the survey limited the research. Further evaluations of bystander interventions are needed in the UK that utilises large samples and a validated survey.

Practical implications
This paper notes the importance of engaging many students in a cohort to participate on a bystander intervention.

Originality/value
This study adds to the paucity of evaluations of bystander interventions in the UK. Knowing that the intervention has the potential to disrupt interpersonal violence and abuse builds the momentum for other similarly designed interventions to be implemented in universities in the UK.
Linking Data on Constituent Health with Elected Officials’ Opinions: Associations Between Urban Health Disparities and Mayoral Officials’ Beliefs About Health Disparities in Their Cities
Authors: PURTLE JONATHAN , JOSHI RENNIE , LÊ‐SCHERBAN FÉLICE , HENSON ROSIE MAE , DIEZ ROUX ANA V. 
Published: March 2021

Policy Points
Mayoral officials’ opinions about the existence and fairness of health disparities in their city are positively associated with the magnitude of income‐based life expectancy disparity in their city.
Associations between mayoral officials’ opinions about health disparities in their city and the magnitude of life expectancy disparity in their city are not moderated by the social or fiscal ideology of mayoral officials or the ideology of their constituents.
Highly visible and publicized information about mortality disparities, such as that related to COVID‐19 disparities, has potential to elevate elected officials’ perceptions of the severity of health disparities and influence their opinions about the issue.
ContextA substantive body of research has explored what factors influence elected officials’ opinions about health issues. However, no studies have assessed the potential influence of the health of an elected official's constituents. We assessed whether the magnitude of income‐based life expectancy disparity within a city was associated with the opinions of that city's mayoral official (i.e., mayor or deputy mayor) about health disparities in their city.MethodsThe independent variable was the magnitude of income‐based life expectancy disparity in US cities. The magnitude was determined by linking 2010‐2015 estimates of life expectancy and median household income for 8,434 census tracts in 224 cities. The dependent variables were mayoral officials’ opinions from a 2016 survey about the existence and fairness of health disparities in their city (n = 224, response rate 30.3%). Multivariable logistic regression was used to adjust for characteristics of mayoral officials (e.g., ideology) and city characteristics.FindingsIn cities in the highest income‐based life expectancy disparity quartile, 50.0% of mayoral officials “strongly agreed” that health disparities existed and 52.7% believed health disparities were “very unfair.” In comparison, among mayoral officials in cities in the lowest disparity quartile 33.9% “strongly agreed” that health disparities existed and 22.2% believed the disparities were “very unfair.” A 1‐year‐larger income‐based life expectancy disparity in a city was associated with 25% higher odds that the city's mayoral official would “strongly agree” that health disparities existed (odds ratio [OR] = 1.25; P = .04) and twice the odds that the city's mayoral official would believe that such disparities were “very unfair” (OR = 2.24; P <.001).ConclusionsMayoral officials’ opinions about health disparities in their jurisdictions are generally aligned with, and potentially influenced by, information about the magnitude of income‐based life expectancy disparities among their constituents.
Responding to Activist Short Sellers: Allegations, Firm Responses, and Outcomes
Authors: Brendel Janja , Ryans James 
Published: March 2021

ABSTRACTThis study provides descriptive evidence on how firms respond to activist short seller reports and how these responses are associated with outcomes for the targeted firms. We show that the frequency of these reports has grown substantially in recent years. Although we find that firms respond only 31% of the time, this rate increases substantially when the report is accompanied by significantly negative abnormal returns and when the report contains new evidence. Not responding is associated with a less negative stock price response at report release and fewer adverse outcomes. Firms that launch internal investigations following the report release have significantly higher subsequent rates of stock exchange delisting and SEC enforcement actions, and lower rates of being acquired. Overall, our results highlight the impact of activist short sellers on target firms and that firm responses are associated with material outcomes.