bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short-term plasticity persists in the absence of PKC phosphorylation of Munc18-1
Authors: Wang Chih-Chieh , Weyrer Christopher , Fioravante Diasynou , Kaeser Pascal S. , Regehr Wade G. 
Published: February 2021

AbstractPost tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knockin mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1 SA mice). Expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3 to CA1 synapse, and the granule cell parallel fiber to Purkinje cell (PF to PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1 SA mice. In Munc18-1 SA mice, 70% of PTP remained at CA3 to CA1 synapses, and the amplitude of PTP was not reduced at PF to PC synapses. These findings indicate that at both CA3 to CA1 and PF to PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1.Significance StatementA leading mechanism for a prevalent form of short-term plasticity, post-tetanic potentiation (PTP), involves protein kinase C phosphorylation of Munc18-1. This study tests this mechanism by creating a knock in mouse in which Munc18-1 is replaced by a mutated form of Munc18-1 that cannot be phosphorylated. The main finding is that most PTP at hippocampal CA3 to CA1 synapses, or at cerebellar granule cell to Purkinje cell synapses does not rely on PKC phosphorylation of Munc18-1. Thus, mechanisms independent of PKC phosphorylation of Munc18-1 are important mediators of PTP.
Sphingosine kinase 2 is essential for remyelination following cuprizone intoxication
Authors: Song Huitong , McEwen Holly P. , Duncan Thomas , Lee Jun Yup , Teo Jonathan D. , Don Anthony S. 
Published: February 2021

AbstractTherapeutics that promote oligodendrocyte survival and remyelination are needed to restore neurological function in demyelinating diseases. Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through five G-protein coupled receptors. S1P receptor agonists such as Fingolimod are valuable immunosuppressants used to treat multiple sclerosis, and promote oligodendrocyte survival. However, the role for endogenous S1P, synthesized by the enzyme sphingosine kinase 2 (SphK2), in oligodendrocyte survival and myelination has not been established. This study investigated the requirement for SphK2 in oligodendrocyte survival and remyelination using the cuprizone mouse model of acute demyelination, followed by spontaneous remyelination. Oligodendrocyte density did not differ between untreated wild- type (WT) and SphK2 knockout (SphK2-/-) mice. However, cuprizone treatment caused significantly greater loss of mature oligodendrocytes in SphK2-/-compared to WT mice. Following cuprizone withdrawal, spontaneous remyelination occurred in WT but not SphK2-/-mice, even though progenitor and mature oligodendrocyte density increased in both genotypes. Levels of cytotoxic sphingosine and ceramide were higher in the corpus callosum of SphK2-/-mice, and in contrast to WT mice, did not decline following cuprizone withdrawal in SphK2-/-mice. We also observed a significant reduction in myelin thickness with ageing in SphK2-/-compared to WT mice. These results provide the first evidence that SphK2, the dominant enzyme catalysing S1P synthesis in the adult brain, is essential for remyelination following a demyelinating insult and myelin maintenance with ageing. We propose that persistently high levels of sphingosine and ceramide, a direct consequence of SphK2 deficiency, may block remyelination.Table of Contents ImageMain PointsThe lipid kinase sphingosine kinase 2 (SphK2) is essential for remyelination following a demyelinating insult (cuprizone).SphK2 protects against cuprizone-mediated oligodendrocyte loss.SphK2 deficiency leads to thinner myelin with ageing.
SARS-CoV-2 antibody immunoassays in serial samples reveal earlier seroconversion in acutely ill COVID-19 patients developing ARDS
Authors: Buchholtz Marie-Luise , Arend Florian M. , Eichhorn Peter , Weigand Michael , Kleinhempel Alisa , Häusler Kurt , Bruegel Mathias , Holdt Lesca M. , Teupser Daniel 
Published: February 2021

AbstractObjectivesDuring the COVID-19 pandemic, SARS-CoV-2 antibody testing has been suggested for (1) screening populations for disease prevalence, (2) diagnostics, and (3) guiding therapeutic applications. Here, we conducted a detailed clinical evaluation of four Anti-SARS-CoV-2 immunoassays in samples from acutely ill COVID-19 patients and in two negative cohorts.Methods443 serum specimens from serial sampling of 29 COVID-19 patients were used to determine clinical sensitivities. Patients were stratified for the presence of acute respiratory distress syndrome (ARDS). Individual serum specimens from a pre-COVID-19 cohort of 238 healthy subjects and from a PCR-negative clinical cohort of 257 patients were used to determine clinical specificities. All samples were measured side-by-side with the Anti-SARS-CoV-2-ELISA (IgG), Anti-SARS-CoV-2-ELISA (IgA) and Anti-SARS-CoV-2-NCP-ELISA (IgG) (Euroimmun AG, Lübeck, Germany) and the Elecsys Anti-SARS-CoV-2 ECLIA (Roche Diagnostics International, Rotkreuz, Switzerland).ResultsMedian seroconversion occurred earlier in ARDS patients (8-9 days) than in non-ARDS patients (11-17 days), except for EUR N-IgG. Rates of positivity and mean signal ratios in the ARDS group were significantly higher than in the non-ARDS group. Sensitivities between the four tested immunoassays were equivalent. In the set of negative samples, the specificity of the Anti-SARS-CoV-2-ELISA (IgA) was lower (93.9 %) compared to all other assays (≥98.8 %) and the specificity of Anti-SARS-CoV-2-NCP-ELISA (IgG) was lower (98.8 %) than that of Elecsys Anti-SARS-CoV-2 (100 %).ConclusionsSerial sampling in COVID-19 patients revealed earlier seroconversion and higher signal ratios of SARS-CoV-2 antibodies as a potential risk marker for the development of ARDS, suggesting a utility for antibody testing in acutely diseased patients.
Nets-within-nets for modeling emergent patterns in ontogenetic processes
Authors: Bardini Roberta , Benso Alfredo , Politano Gianfranco , Di Carlo Stefano 
Published: February 2021

ABSTRACTOntogenesis is the development of an organism from its earliest stage to maturity, including homeostasis maintenance throughout adulthood despite environmental perturbations. Almost all cells of a multicellular organism share the same genomic information. Nevertheless, phenotypic diversity and complex supra-cellular architectures emerge at every level, starting from tissues and organs. This is possible thanks to a robust and dynamic interplay of regulative mechanisms.To study ontogenesis, it is necessary to consider different levels of regulation, both genetic and epigenetic. Each cell undergoes a specific path across a landscape of possible regulative states affecting both its structure and its functions during development. This paper proposes using the Nets-Within-Nets formalism, which combines Petri Nets’ simplicity with the capability to represent and simulate the interplay between different layers of regulation connected by non-trivial and context-dependent hierarchical relations.In particular, this work introduces a modeling strategy based on Nets-Within-Nets that can model several critical processes involved in ontogenesis. Moreover, it presents a case study focusing on the first phase of Vulval Precursor Cells specification inC. Elegans. The case study shows that the proposed model can simulate the emergent morphogenetic pattern corresponding to the observed developmental outcome of that phase, in both the physiological case and different mutations. The model presented in the results section is available online athttps://github.com/sysbio-polito/NWN_CElegans_VPC_model/
Region-specific, maladaptive, gray matter myelination is associated with differential susceptibility to stress-induced behavior in rats and humans
Authors: Long Kimberly L. P. , Chao Linda L. , Kazama Yurika , An Anjile , Hu Kelsey Y. , Peretz Lior , Muller Dyana C. Y. , Roan Vivian D. , Misra Rhea , Toth Claire E. , Breton Jocelyn M. , Casazza William , Mostafavi Sara , Huber Bertrand R. , Woodward Steven H. , Neylan Thomas C. , Kaufer Daniela 
Published: February 2021

AbstractIndividual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter myelin contributes to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin content in multiple brain areas. We found that oligodendrocyte cell density and myelin content were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and myelin. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with myelin in the amygdala and spatial processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species- independent relationship between region-specific, gray matter oligodendrocytes and myelin and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.
Coordination between nucleotide excision repair and specialized polymerase DnaE2 action enables DNA damage survival in non-replicating bacteria
Authors: Joseph Asha Mary , Daw Saheli , Sadhir Ismath , Badrinarayanan Anjana 
Published: February 2021

AbstractTranslesion synthesis (TLS) is a highly conserved mutagenic DNA lesion tolerance pathway, which employs specialized, low-fidelity DNA polymerases to synthesize across lesions. Current models suggest that activity of these polymerases is predominantly associated with ongoing replication, functioning either at or behind the replication fork. Here we provide evidence for DNA damage-dependent function of a specialized polymerase, DnaE2, in replication-independent conditions. We develop an assay to follow lesion repair in non-replicatingCaulobacterand observe that components of the replication machinery localize on DNA in response to damage. These localizations persist in the absence of DnaE2 or if catalytic activity of the polymerase is mutated. Single-stranded DNA gaps for SSB binding and low-fidelity polymerase-mediated synthesis are generated by nucleotide excision repair, as replisome components fail to localize in its absence. This mechanism of gap-filling facilitates cell cycle restoration when cells are released into replication-permissive conditions. Thus, such cross-talk (between activity of NER and specialized polymerases in subsequent gap-filling) helps preserve genome integrity and enhances survival in a replication-independent manner.
Dynamic association of IκBα to chromatin is regulated by acetylation and cleavage of histone H4
Authors: Marruecos Laura , Bertran Joan , Álvarez-Villanueva Daniel , Floor Martin , Mulero María Carmen , Vert Anna , Guillén Yolanda , Arce Sara , Batlle Laura , Villà-Freixa Jordi , Ghosh Gourisankar , Bigas Anna , Espinosa Lluís 
Published: February 2021

ABSTRACTIκBs exert a principal function as cytoplasmic inhibitors of the NF-kB transcription factors. Additional functions for IκB homologues have been described including association to chromatin and transcriptional regulatioin. Phosphorylated and SUMOylated IκBα (pS-IκBα) binds histones H2A and H4 in the stem and progenitor compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unstudied.We here show that serine 32-36 phosphorylation of IκBα favors its binding with nucleosomes and demonstrated that p-IκBα association to H4 is favored by acetylation at specific H4 lysine residues. N-terminal tail of H4 is lost during intestinal cell differentiation by proteolytic cleavage at residues 17-19 imposed ny trypsin or chymotrypsin, which interferes p-IκBα binding. Paradoxically, inhibition of trypsin and chymotrypsin activity in HT29 cells increased p-IκBα chromatin binding and impaired goblet cell differentiation, comparable to IκBα deletion. Together our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular base for the restricted nuclear distribution of p-IκBα at specific stem cell compartments.
In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia
Authors: Cole Basiel , Lambrechts Laurens , Gantner Pierre , Noppe Ytse , Bonine Noah , Witkowski Wojciech , Chen Lennie , Palmer Sarah , Mullins James I. , Chomont Nicolas , Pardons Marion , Vandekerckhove Linos 
Published: February 2021

AbstractClonal expansion of HIV-infected cells contributes to the long-term persistence of the HIV reservoir in ART-suppressed individuals. However, the contribution to plasma viremia from cell clones that harbor inducible proviruses is poorly understood. Here, we describe a single-cell approach to simultaneously sequence the TCR, integration sites and proviral genomes from translation-competent reservoir cells, called STIP-Seq. By applying this approach to blood samples from eight participants, we showed that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5’-end of the genome, often involving the major splice donor site. TCR and integration site sequencing revealed that antigen-responsive cells can harbor inducible proviruses integrated into cancer-related genes. Furthermore, we found several matches between proviruses retrieved with STIP-Seq and plasma viruses obtained during ART and upon treatment interruption, showing that STIP-Seq can capture clones that are responsible for low-level viremia or viral rebound.
A quantitative study of the Golgi retention of glycosyltransferases
Authors: Sun Xiuping , Chen Bing , Song Zhiwei , Lu Lei 
Published: February 2021

ABSTRACTHow Golgi glycosyltransferases and glycosidases (hereafter glycosyltransferases) localize to the Golgi is still unclear. Here, we first investigated the post-Golgi trafficking of glycosyltransferases. We found that glycosyltransferases can escape the Golgi to the plasma membrane, where they are subsequently endocytosed to the endolysosome. Post-Golgi glycosyltransferases are probably degraded by the ecto-domain shedding. We discovered that most glycosyltransferases are not retrieved from post-Golgi sites, indicating that retention but not retrieval should be the main mechanism for their Golgi localization. We proposed to use the Golgi residence time to study the Golgi retention of glycosyltransferases quantitatively and systematically. Various chimeras between ST6GAL1 and either transferrin receptor or tumor necrosis factor α quantitatively revealed the contributions of three regions of ST6GAL1, namely the N-terminal cytosolic tail, transmembrane domain and ecto-domain, to the Golgi retention. We found that each of the three regions is sufficient to produce a retention in an additive manner. The N-terminal cytosolic tail length negatively affects the Golgi retention of ST6GAL1, similar to what is known of the transmembrane domain. Therefore, long N-terminal cytosolic tail and transmembrane domain can be a Golgi export signal for transmembrane secretory cargos.
Quantitative susceptibility mapping of carotid arterial tissueex vivo: assessing sensitivity to vessel microstructural composition
Authors: Stone Alan J. , Tornifoglio Brooke , Johnston Robert D. , Shmueli Karin , Kerskens Christian , Lally Caitríona 
Published: February 2021

AbstractPurposeTo characterise microstructural contributions to the magnetic susceptibility of carotid arteries.MethodArterial vessels were scanned using high resolution quantitative susceptibility mapping (QSM) at 7T. Models of vessel degradation were generated usingex vivoporcine carotid arteries that were subjected to several different enzymatic digestion treatments that selectively removed microstructural components (smooth muscle cells, collagen and elastin). Magnetic susceptibilities measured in these tissue models were compared to those in untreated (native) porcine arteries. Magnetic susceptibility measured in native porcine carotid arteries was further compared to the susceptibility of cadaveric human carotid arteries to investigate their similarity.ResultsThe magnetic susceptibility of native porcine vessels was diamagnetic (𝒳native= −0.1820ppm), with higher susceptibilities in all models of vessel degradation (𝒳elastin degraded= −0.0163ppm; 𝒳collagen degraded= −0.1158ppm; 𝒳decellularised= −0.1379ppm; 𝒳fixed native= −0.2199ppm). Magnetic susceptibility was significantly higher incollagen degradedcompared tonativeporcine vessels (Tukey-Kramer, p<0.01) and betweenelastin degradedand all other models (includingnative, Tukey-Kramer, p<0.001). The susceptibility of fixed healthy human arterial tissue was diamagnetic and no significant difference was found between fixed human and fixed porcine arterial tissue susceptibilities (ANOVA, p>0.05).ConclusionsMagnetic susceptibility measured using QSM is sensitive to the microstructural composition of arterial vessels – most notably to collagen. The similarity of human and porcine arterial tissue susceptibility values provides a solid basis for translational studies. As vessel microstructure becomes disrupted during the onset and progression of carotid atherosclerosis, QSM has the potential to provide a sensitive and specific marker of vessel disease.
Synaptotagmin-like protein 2a regulates lumen formation via Weibel-Palade body apical secretion of angiopoietin-2 during angiogenesis
Authors: Francis Caitlin R. , Claflin Shea , Kushner Erich J. 
Published: February 2021

ABSTRACTObjectiveVascular lumen formation requires the redistribution of intracellular proteins to instruct apico-basal polarity, thereby enforcing maturation of both luminal and basal domains. In the absence of proper apical signaling, lumen formation can be distorted leading to lumen collapse and cessation of blood flow. Synaptotagmin-like protein-2a (Slp2a) has been implicated in apical membrane signaling; however, the role of Slp2a in vascular lumen formation has never been assessed.Approach and ResultsOur results demonstrate that Slp2a is required for vascular lumen formation. Using a 3- dimensional sprouting assay, sub-cellular imaging, and zebrafish blood vessel development we establish that Slp2a resides at the apical membrane acting as a tether for Rab27a that decorates Weibel-Palade bodies (WPBs). Unique to endothelial tissue, we show that Slp2a regulates exocytic activity of WPBs, thus regulating release of WPB contents into the luminal space during angiogenesis. Angiopoietin-2 is a Tie-2 receptor ligand that is selectively released from WPB secretory granules. We identify a critical role for angiopoietin-2 in regulating endothelial lumenization and show that in the absence of Slp2a, WPB contents cannot fuse with the apical membrane. This disrupts the release of angiopoietin-2 and blocks Tie-2 signaling necessary for proper lumen formation.ConclusionsOur results demonstrate a novel requirement of Slp2a for vascular lumen formation. Moreover, we show that Slp2a is required for the exocytic release of WPB secretory granule cargo during vascular lumen development, and thus is a core upstream component of the WPB secretory pathway. Furthermore, we provide evidence that WPB-housed angiopoietin-2 is required for vascular lumen formation.HIGHLIGHTSSynaptotagmin-like protein-2a (Slp2a) is required for vascular lumen formation via its interaction with Rab27a and Weibel Palade Body secretory granules.Slp2a is recruited to the apical membrane where it regulates secretion of Weibel Palade Body components into the luminal space.In the absence of Slp2a, Weibel Palade Body-housed angiopoietin-2 ligand cannot be exocytosed, this impedes activation of Tie-2 signaling required for lumen biogenesis.Knockout of Slp2a or Tie-2 in zebrafish blunts the formation of vascular lumens during angiogenic development.
Predictive coding is a consequence of energy efficiency in recurrent neural networks
Authors: Ali Abdullahi , Ahmad Nasir , Groot Elgar de , van Gerven Marcel A. J. , Kietzmann Tim C. 
Published: February 2021

AbstractPredictive coding represents a promising framework for understanding brain function. It postulates that the brain continuously inhibits predictable sensory input, ensuring a preferential processing of surprising elements. A central aspect of this view is its hierarchical connectivity, involving recurrent message passing between excitatory bottom-up signals and inhibitory top-down feedback. Here we use computational modelling to demonstrate that such architectural hard-wiring is not necessary. Rather, predictive coding is shown to emerge as a consequence of energy efficiency. When training recurrent neural networks to minimise their energy consumption while operating in predictive environments, the networks self-organise into prediction and error units with appropriate inhibitory and excitatory interconnections, and learn to inhibit predictable sensory input. Moving beyond the view of purely top-down driven predictions, we furthermore demonstrate, via virtual lesioning experiments, that networks perform predictions on two timescales: fast lateral predictions among sensory units, and slower prediction cycles that integrate evidence over time.
Cortical compensation for hearing loss, but not age, in neural tracking of the fundamental frequency of the voice
Authors: Canneyt Jana Van , Wouters Jan , Francart Tom 
Published: February 2021

AbstractAuditory processing is affected by advancing age and hearing loss, but the underlying mechanisms are still unclear. We investigated the effects of age and hearing loss on temporal processing of naturalistic stimuli in the auditory system. We analysed neural phase-locking to the fundamental frequency of the voice (f0) in 54 normal-hearing and 14 hearing-impaired adults between 17 and 82 years old. We found that both subcortical and cortical neural sources contributed to the responses. Results indicated that advancing age was related to smaller responses with less cortical response contributions, consistent with an age-related decrease in neural phase-locking ability. Conversely, hearing impaired subjects displayed larger responses compared to age-matched normal hearing controls. This was due to additional cortical response contributions which were stronger for participants with more severe hearing loss. This is consistent with the recruitment of additional cortical sources for auditory processing in persons with hearing impairment.