bluuebunny/crossref_metadata_2025_split huggingface dataset:
T cell stiffness is enhanced upon formation of immunological synapse
Authors: Jung Philipp , Zhou Xiangda , Bischoff Markus , Qu Bin 
Published: January 2021

AbstractT cells are activated by cognate target cells via an intimate contact, termed immunological synapse (IS). Cellular mechanical properties, especially stiffness, are essential to regulate cell functions, T cell stiffness at a subcellular level at the IS still remains largely elusive. In this work, we established an atomic force microscopy (AFM)-based elasticity mapping method on whole T cells to obtain an overview of the stiffness with a resolution of ~ 60 nm. Using Jurkat T-cells and primary human CD4+T cells, we show that in the T cells in contact with functionalized surfaces, the lamellipodia are stiffer than the cell body. Upon IS formation, T cell stiffness is substantially enhanced both at the lamellipodia and in cell body. Chelation of intracellular Ca2+abolishes IS-induced stiffening at the lamellipodia but has no influence on cell body-stiffening, suggesting different regulatory mechanism of IS-induced stiffening between the lamellipodia and the cell body.
A single- and paired-pulse TMS-EEG investigation of the N100 and long interval cortical inhibition in autism spectrum disorder
Authors: Kirkovski Melissa , Hill Aron T. , Rogasch Nigel C , Saeki Takashi , Fitzgibbon Bernadette M. , Yang Joel , Do Michael , Donaldson Peter H , Albein-Urios Natalia , Fitzgerald Paul B , Enticott Peter G 
Published: January 2021

AbstractBackgroundThere is evidence to suggest a disruption of gamma-aminobutyric acid (GABA) in autism spectrum disorder (ASD), but findings are mixed. Concurrent electroencephalography and transcranial magnetic stimulation (TMS-EEG) provides a novel method by which to probe GABA-mediated cortical inhibition.MethodsWith a particular focus on GABAB-ergic mechanisms, we investigated the N100 peak of the TMS evoked potential (TEP), as well as long interval cortical inhibition (LICIEEG) in adults with ASD (n = 23; 12 female) without intellectual disability, and a neurotypical comparison group (n =22; 12 female) matched for age, sex, and IQ. Seventy-five single-(spTMS) and 75 paired-(ppTMS; 100 ms inter-stimulus-interval) pulses were applied to the right primary motor cortex (M1), right temporoparietal junction (TPJ), and right dorsolateral prefrontal cortex (DLPFC) while EEG was recorded from 20 scalp electrodes. Additionally, electromyography (EMG) was used to investigate corticospinal inhibition following ppTMS to M1 (LICIEMG).ResultsThere were no group differences in the N100 amplitude or latency following spTMS. LICI outcomes following ppTMS, as measured by either EEG or EMG, also did not differ between groups. These findings were further supported by Bayesian analyses, which provided weak-moderate support for the null hypothesis.LimitationsData presented here reflect adults without intellectual disability, and the generalisability of these results is therefore limited.ConclusionsThe findings of this study argue against GABAB-ergic impairment in adults with ASD without intellectual disability, at least at the cortical regions examined. Further research investigating these mechanisms in ASD at various ages, with varying degrees of symptomatology, and at different brain sites is an important factor in understating the role of GABA in the neuropathophysiology of ASD.
Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons
Authors: Biane Célia , Rückerl Florian , Abrahamsson Therese , Saint-Cloment Cécile , Mariani Jean , Shigemoto Ryuichi , DiGregorio David A. , Sherrard Rachel M. , Cathala Laurence 
Published: January 2021

AbstractSynaptic transmission, connectivity, and dendritic morphology mature in parallel during brain development and are often disrupted in neurodevelopmental disorders. Yet how these changes influence the neuronal computations necessary for normal brain function are not well understood. To identify cellular mechanisms underlying the maturation of synaptic integration in interneurons, we combined patch-clamp recordings of excitatory inputs in cerebellar stellate cells (SCs), 3D-reconstruction of SC morphology with excitatory synapse location, and biophysical modeling. We found that, during development, synaptic strength was homogeneously reduced along the somato-dendritic axis, but that dendritic integration was always sublinear. However, dendritic branching increased without changes in synapse density, leading to a substantial gain in distal inputs. Thus, changes in synapse distribution, rather than dendrite cable properties, are the dominant mechanism underlying the maturation of neuronal computation. These mechanisms favor the emergence of a spatially compartmentalized two-stage integration model promoting location-dependent integration within dendritic subunits.
IRGM/Irgm1 Aggravates Progression of Atherosclerosis by Inducing Macrophage Apoptosis through the MAPK Signaling Pathway
Authors: Fang Shaohong , Sun Song , Cai Hengxuan , Hao Xinran , Zou Xiaoyi , Wan Xin , Tian Jiangtian , Li Zhaoying , Wang Shanjie , He Zhongze , Huang Wei , Liang Chenchen , Zhang Zhenming , Yang Liming , Tian Jinwei , Yu Bo , Sun Bo 
Published: January 2021

AbstractAimsAtherosclerosis underlies most cardiovascular diseases, among which acute coronary syndrome (ACS) caused by plaque rupture (PR) often leads to death. Immune-related GTPases (IRGM/Irgm1) have been extensively studied in inflammatory diseases, but their role in atherosclerosis is unclear. Determining how IRGM/Irgm1 promotes atherosclerotic plaque vulnerability will provide information for new biomarkers and/or therapeutic targets.Methods and resultsWe identified ruptured and unruptured plaques by optical coherence tomography, and found that serum IRGM was highly expressed in patients with ST-segment elevation myocardial infarction in PR. We used ApoE-/-Irgm1+/+, ApoE-/-Irgm1+/-mice and chimeric mice to establish a model of advanced atherosclerosis. The results of pathological experiments showed that Irgm1 caused plaque necrosis. The ratio of neutral lipids and cholesterol crystals increases, while the content of collagen fibers decreases, aggravating the destabilization of atherosclerotic plaques. In vitro, we used multiple approaches to confirm that Irgm1 promotes macrophage apoptosis by promoting the production of reactive oxygen species and activating the MAPK signaling pathway.ConclusionsIRGM may be a potential risk factor for PR. Mechanistic studies have shown that IRGM/Irgm1 contributes to the formation and rupture of fragile plaques. This is partly mediated by the induction of macrophage apoptosis via the MAPK signaling pathway. IRGM may offer new strategies for early treatment of ACS.Translation viewOur findings indicate that IRGM/Irgm1 contributes to formation and rupture of vulnerable plaques. It suggests that IRGM may provide a new target for the early treatment of ACS.
Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy
Authors: Pérez Malena M. , Pimentel Vinícius E. , Fuzo Carlos A. , da Silva-Neto Pedro V. , Toro Diana M. , Souza Camila O. S. , Fraga-Silva Thais F. C. , Gardinassi Luiz Gustavo , de Carvalho Jonatan C. S. , Neto Nicola T. , Carmona-Garcia Ingryd , Oliveira Camilla N. S. , Milanezi Cristiane M. , Takahashi Viviani Nardini , De Leo Thais Canassa , Rodrigues Lilian C. , Dias Cassia F. S. L. , Xavier Ana C. , Porcel Giovanna S. , Guarneri Isabelle C. , Zaparoli Kamila , Garbato Caroline T. , Argolo Jamille G. M. , Júnior Ângelo A. F. , Feitosa Marley R. , Parra Rogerio S. , da Rocha José J. R. , Feres Omar , Vilar Fernando C. , Gaspar Gilberto G. , da Silva Rafael C. , Constant Leticia F. , Ostini Fátima M. , de Amorim Alessandro P. , Degiovani Augusto M. , da Silva Dayane P. , Nepomuceno Debora C. , Barbieri Rita C. C. , Santos Isabel K. F. M. , Maruyama Sandra R. C. , Russo Elisa M. S. , Viana Angelina L. , Fernandes Ana P. M. , Bonato Vânia L. D. , Cardoso Cristina R. B. , Sorgi Carlos A. , Dias-Baruffi Marcelo , Faccioli Lúcia H. 
Published: January 2021

AbstractCytokine storms and hyperinflammation, potentially controlled by glucocorticoids, occur in COVID-19; the roles of lipid mediators and acetylcholine (ACh) and how glucocorticoid therapy affects their release in Covid-19 remain unclear. Blood and bronchoalveolar lavage (BAL) samples from SARS-CoV-2- and non-SARS-CoV-2-infected subjects were collected for metabolomic/lipidomic, cytokines, soluble CD14 (sCD14), and ACh, and CD14 and CD36-expressing monocyte/macrophage subpopulation analyses. Transcriptome reanalysis of pulmonary biopsies was performed by assessing coexpression, differential expression, and biological networks. Correlations of lipid mediators, sCD14, and ACh with glucocorticoid treatment were evaluated. This study enrolled 190 participants with Covid-19 at different disease stages, 13 hospitalized non-Covid-19 patients, and 39 healthy-participants. SARS-CoV-2 infection increased blood levels of arachidonic acid (AA), 5-HETE, 11-HETE, sCD14, and ACh but decreased monocyte CD14 and CD36 expression. 5-HETE, 11-HETE, cytokines, ACh, and neutrophils were higher in BAL than in circulation (fold-change for 5-HETE 389.0; 11-HETE 13.6; ACh 18.7, neutrophil 177.5, respectively). Only AA was higher in circulation than in BAL samples (fold-change 7.7). Results were considered significant at P<0.05, 95%CI. Transcriptome data revealed a unique gene expression profile associated with AA, 5-HETE, 11-HETE, ACh, and their receptors in Covid-19. Glucocorticoid treatment in severe/critical cases lowered ACh without impacting disease outcome. We first report that pulmonary inflammation and the worst outcomes in Covid-19 are associated with high levels of ACh and lipid mediators. Glucocorticoid therapy only reduced ACh, and we suggest that treatment may be started early, in combination with AA metabolism inhibitors, to better benefit severe/critical patients.
Comparing the age and sex trajectories of SARS-CoV-2 morbidity with other respiratory pathogens points to potential immune mechanisms
Authors: Metcalf C. Jessica E. , Paireau Juliette , O’Driscoll Megan , Pivette Mathilde , Hubert Bruno , Pontais Isabelle , Cummings Derek , Cauchemez Simon , Salje Henrik 
Published: January 2021

AbstractComparing age and sex differences in SARS-CoV-2 hospitalization and mortality with influenza and other health outcomes opens the way to generating hypotheses as to the underlying mechanisms, building on the extraordinary advances in immunology and physiology that have occurred over the last year. Notable departures in health outcomes starting around puberty suggest that burdens associated with influenza and other causes are reduced relative to the two emergent coronaviruses over much of adult life. Two possible hypotheses could explain this: protective adaptive immunity for influenza and other infections, or greater sensitivity to immunosenescence in the coronaviruses. Comparison of sex differences suggest an important role for adaptive immunity; but immunosenescence might also be relevant, if males experience faster immunosenescence. Involvement of the renin-angiotensin-system in SARS-CoV-2 infection might drive high sensitivity to disruptions of homeostasis. Overall, these results highlight the long tail of vulnerability in the age profile relevant to the emergent coronaviruses, which more transmissible variants have the potential to uncover at the younger end of the scale, and aging populations will expose at the other end of the scale.
Computational modelling of EEG and fMRI paradigms reveals a consistent loss of pyramidal cell synaptic gain in schizophrenia
Authors: Adams Rick A , Pinotsis Dimitris , Tsirlis Konstantinos , Unruh Leonhardt , Mahajan Aashna , Horas Ana Montero , Convertino Laura , Summerfelt Ann , Sampath Hemalatha , Du Xiaoming Michael , Kochunov Peter , Ji Jie Lisa , Repovs Grega , Murray John D , Friston Karl J , Hong L Elliot , Anticevic Alan 
Published: January 2021

AbstractDiminished synaptic gain – the sensitivity of postsynaptic responses to neural inputs – may be a fundamental synaptic pathology in schizophrenia. Evidence for this is indirect, however. Furthermore, it is unclear whether pyramidal cells or interneurons (or both) are affected, or how these deficits relate to symptoms. Participants with schizophrenia (Scz, n=108), their relatives (n=57), and controls (n=107) underwent three electroencephalography paradigms – resting, mismatch negativity, and 40 Hz auditory steady-state response – and resting functional magnetic resonance imaging. Dynamic causal modelling was used to quantify synaptic connectivity in cortical microcircuits. Across all four paradigms, characteristic Scz data features were best explained by models with greater self-inhibition (decreased synaptic gain), in pyramidal cells. Furthermore, disinhibition in auditory areas predicted abnormal auditory perception (and positive symptoms) in Scz, in three paradigms. Thus, psychotic symptoms of Scz may result from a downregulation of inhibitory interneurons that may compensate for diminished postsynaptic gain in pyramidal cells.
Predicting severity of Covid-19 using standard laboratory parameters
Authors: Buchmüller Thimo , Gröning Ingmar , Ihl Ralf 
Published: January 2021

AbstractBackgroundMore than 1.6 million people have already deceased due to a COVID-19 infection making it a major public health concern. A prediction of severe courses can enhance treatment quality and thus lower fatality and morbidity rates. The use of laboratory parameters has recently been established for a prediction. However, laboratory parameters have rarely been used in combination to predict severe outcomes.MethodWe used a retrospective case-control design to analyze risk factors derived from laboratory parameters. Patients treated for COVID-19 at an hospital in Krefeld, Germany, from March to May 2020 were included (n =42). Patients were classified into two categories based on their outcome (Mild course vs. treatment in intensive care unit). Laboratory parameters were compared across severity categories using non-parametric statistic. Identified laboratory parameters were used in a logistic regression model. The model was replicated using a) clinical standardized parameters b) aggregated factors derived from a factor analysis.ResultsPatients in intensive care unit showed elevated ALT, CRP and LDH levels, a higher leukocyte and neutrophile count, a higher neutrophile ratio and a lowered lymphocyte ratio. We were able to classify 95.1% of all cases correctly (96.6% of mild and 91.7% of severe cases, p<.001).ConclusionA number of routinely collected laboratory parameters is associated with a severe outcome of COVID-19. The combination of these parameters provides a powerful tool in predicting severity and can enhance treatment effectiveness.
Analysis of Intervention Effectiveness Using Early Outbreak Transmission Dynamics to Guide Future Pandemic Management and Decision-Making in Kuwait
Authors: Tyshenko Michael G. , Oraby Tamer , Longenecker Joseph , Vainio Harri , Gasana Janvier , Alali Walid Q. , AlSeaidan Mohammad , Elsaadany Susie , Al-Zoughool Mustafa 
Published: January 2021

AbstractSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a World Health Organization designated pandemic that can result in severe symptoms and death that disproportionately affects older patients or those with comorbidities. Kuwait reported its first imported cases of COVID-19 on February 24, 2020. Analysis of data from the first three months of community transmission of the COVID-19 outbreak in Kuwait can provide important guidance for decision-making when dealing with future SARS-CoV-2 epidemic wave management. The analysis of intervention scenarios can help to evaluate the possible impacts of various outbreak control measures going forward which aim to reduce the effective reproduction number during the initial outbreak wave. Herein we use a modified susceptible-exposed-asymptomatic-infectious-removed (SEAIR) transmission model to estimate the outbreak dynamics of SARS-CoV-2 transmission in Kuwait. We fit case data from the first 96 days in the model to estimate the basic reproduction number and used Google mobility data to refine community contact matrices. The SEAIR modelled scenarios allow for the analysis of various interventions to determine their effectiveness. The model can help inform future pandemic wave management, not only in Kuwait but for other countries as well.
Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner
Authors: Hwang Sun-Hee , Somatilaka Bandarigoda N. , White Kevin , Mukhopadhyay Saikat 
Published: January 2021

AbstractThe role of compartmentalized cAMP signaling in primary cilia is not well understood. The cilia-localized G-protein-coupled receptor—Gpr161 represses hedgehog pathway via cAMP signaling. Here, by generating knock-in mutant mouse at endogenousGpr161locus (mut1), we show that ciliary and extraciliary receptor pools repress hedgehog signaling in a tissue-specific manner. Gpr161mut1was competent in generating cAMP but did not transit through cilia. Compared to knockout,Gpr161mut1had delayed embryonic lethality, less upregulation of hedgehog targets and partially down-regulated Gli3-repressor. Ventral-most progenitor expansion in neural tube ofGpr161knockout occurred in a Gli2-activator-dependent manner but was not seen inGpr161mut1. Intermediate-level ventralization occurred from Gpr161 lack specifically in cilia but was restored by increased extraciliary mutant generating Gli3-repressor. Morphogenesis in limb buds and midface that require Gli-repressor manifested hedgehog hyperactivation phenotypes— polydactyly and midfacial widening—inGpr161mut1. Thus, ciliary and extraciliary cAMP signaling establishes tissue-specific Gli-repressor thresholds in dictating morpho-phenotypic outcomes.Impact statementSignaling by CiliaSignaling by cAMP specifically in cilia directs tissue-specific morphogenesis
Silencing and stimulating the medial amygdala impairs ejaculation but not sexual incentive motivation in male rats
Authors: Huijgens Patty T. , Heijkoop Roy , Snoeren Eelke M.S. 
Published: January 2021

AbstractThe medial amygdala (MeA) is a sexually dimorphic brain region that integrates sensory information and hormonal signaling, and is involved in the regulation of social behaviors. Lesion studies have shown a role for the MeA in copulation, most prominently in the promotion of ejaculation. The role of the MeA in sexual motivation, but also in temporal patterning of copulation, has not been extensively studied in rats. Here, we investigated the effect of chemogenetic inhibition and stimulation of the MeA on sexual incentive motivation and copulation in sexually experienced male rats. AAV5-CaMKIIa viral vectors coding for Gi, Gq, or no DREADDs (sham) were bilaterally infused into the MeA. Rats were assessed in the sexual incentive motivation test and copulation test upon systemic CNO or vehicle administration. We report that MeA stimulation and inhibition did not affect sexual incentive motivation. Moreover, both stimulation and inhibition of the MeA decreased the number of ejaculations in a 30 minute copulation test and increased ejaculation latency and the number of mounts and intromissions preceding ejaculation, while leaving the temporal pattern of copulation intact. These results indicate that the MeA may be involved in the processing of sensory feedback required to reach ejaculation threshold. The convergence of the behavioral effects of stimulating as well as inhibiting the MeA may reflect opposing behavioral control of specific neuronal populations within the MeA.
A class I hydrophobin inTrichoderma virensinfluences plant-microbe interactions through enhancement of enzyme activity and MAMP recognition
Authors: Taylor James T. , Krieger Inna , Crutcher Frankie K. , Jamieson Pierce , Horwitz Benjamin A. , Kolomiets Michael V. , Kenerley Charles M. 
Published: January 2021

AbstractThe filamentous fungus,Trichoderma virens, is a well-known mycoparasitic plant symbiont, valued for its biocontrol capabilities.T. virensinitiates a symbiotic relationship with a plant host through the colonization of its roots. To achieve colonization, the fungus must communicate with the host and evade its innate defenses. Hydrophobins fromTrichoderma spp.have previously been demonstrated to be involved in colonization of host roots. In this study, the class I hydrophobin, HFB9A fromT. virenswas characterized for a potential role in root colonization. Δhfb9a gene deletion mutants colonized less than the wild-type strain, were unable to induce systemic resistance againstColletotrichum graminicola, and showed a reduction in the activity of its cell wall degrading enzymes. The purified HFB9A protein was able to complement the enzyme activity of mutant culture filtrates as well as enhance the activity of commercially sourced cellulase. When exogenously applied to Arabidopsis plants, HFB9A protein induced phosphorylation of AtMAPK3/6, suggesting that it functions as a microbe-associated molecular pattern.
Allopatric divergence of cooperators confers cheating resistance and limits the effects of a defector mutation
Authors: Schaal Kaitlin A. , Yu Yuen-Tsu Nicco , Vasse Marie , Velicer Gregory J. 
Published: January 2021

Social defectors may meet diverse cooperators. Genotype-by-genotype interactions may constrain the ranges of cooperators upon which particular defectors can cheat, limiting cheater spread. The bacterium Myxococcus xanthus undergoes cooperative multicellular development, but some developmental defectors cheat on cooperators during this process. In this study, interactions between a cheater disrupted at the signaling genecsgAand allopatrically diversified cooperators reveal a very small cheating range. Expectedly, the cheater failed to cheat on all natural-isolate cooperators owing to non-cheater-specific antagonisms. Surprisingly, lab-evolved cooperators that diverged from their cheating-susceptible ancestor by fewer than 20 mutations and without experiencing cheating had already exited thecsgAmutant’s cheating range. Cooperators might also diversify in the potential for a mutation to reduce expression of cooperative trait or generate a cheating phenotype. A newcsgAmutation constructed in several highly diverged cooperators generated diverse sporulation phenotypes, ranging from a complete defect to no defect, indicating that genetic backgrounds can limit the set of genomes in which a mutation creates a defector. Our results suggest that natural populations feature geographic mosaics of cooperators that have diversified in their susceptibility to particular cheaters and in the phenotypes generated by any given cooperation-gene mutation.Significance statementSelection on cooperators exploited by obligate cheaters can induce evolution of resistance to cheating. Here we show that cooperators can also rapidly evolve immunity to cheating simply as a byproduct of evolutionary divergence in environments in which cooperation and cheating at the focal trait do not occur because the trait is not expressed. We also find that differences in the genomic context in which a cooperation-gene mutation arises can profoundly alter its phenotypic effect and determine whether the mutation generates a social defect at all - a pre-requisite for obligate cheating. These findings suggest that general divergence of social populations under a broad range of environmental conditions can restrict both the set of mutations that might generate social defectors in the first place and the host range of such defectors once they arise.