bluuebunny/crossref_metadata_2025_split huggingface dataset:
Switching Neuron Contributions to Second Network Activity
Authors: Fahoum Savanna-Rae H , Blitz Dawn M 
Published: October 2023

AbstractNetwork flexibility is important for adaptable behaviors. This includes neuronal switching, where neurons alter their network participation, including changing from single-to dual-network activity. Understanding the implications of neuronal switching requires determining how a switching neuron interacts with each of its networks. Here, we tested 1) whether “home” and second networks, operating via divergent rhythm generation mechanisms, regulate a switching neuron, and 2) if a switching neuron, recruited via modulation of intrinsic properties, contributes to rhythm or pattern generation in a new network. Small, well-characterized feeding-related networks (pyloric, ∼1 Hz; gastric mill, ∼0.1 Hz) and identified modulatory inputs make the isolated crab (Cancer borealis) stomatogastric nervous system (STNS) a useful model to study neuronal switching. In particular, the neuropeptide Gly1-SIFamide switches the lateral posterior gastric (LPG) neuron (2 copies) from pyloric-only to dual-frequency pyloric/gastric mill (fast/slow) activity via modulation of LPG intrinsic properties. Using current injections to manipulate neuronal activity, we found that gastric mill, but not pyloric, network neurons regulated the intrinsically generated LPG slow bursting. Conversely, selective elimination of LPG from both networks using photoinactivation revealed that LPG regulated gastric mill neuron firing frequencies but was not necessary for gastric mill rhythm generation or coordination. However, LPG alone was sufficient to produce a distinct pattern of network coordination. Thus, modulated intrinsic properties underlying dual-network participation may constrain which networks can regulate switching neuron activity. Further, recruitment via intrinsic properties may occur in modulatory states where it is important for the switching neuron to actively contribute to network output.New and NoteworthyWe used small, well-characterized networks to investigate interactions between rhythmic networks and neurons that switch their network participation. For a neuron switching into dual-network activity, only the second network regulated its activity in that network. Additionally, the switching neuron was sufficient but not necessary to coordinate second network neurons, and regulated their activity levels. Thus, regulation of switching neurons may be selective, and a switching neuron is not necessarily simply a follower in additional networks.
Discovery of a new activator of Slack potassium channels with robust efficacy in models of histamine-independent and chronic itch
Authors: Balzulat Annika , Zhu W. Felix , Flauaus Cathrin , Hernandez-Olmos Victor , Heering Jan , Sethumadhavan Sunesh , Dubiel Mariam , Frank Annika , Menge Amelie , Hebchen Maureen , Metzner Katharina , Lu Ruirui , Lukowski Robert , Ruth Peter , Knapp Stefan , Müller Susanne , Steinhilber Dieter , Hänelt Inga , Stark Holger , Proschak Ewgenij , Schmidtko Achim 
Published: October 2023

AbstractVarious disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. In this study, we hypothesized that pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch-sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack-activating antipsychotic drug, loxapine, we designed a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles that enabled us to validate Slack as a pharmacological targetin vivo. One of these new Slack activators, compound 6, exhibited negligible dopamine D2and D3receptor binding, unlike loxapine. We found that compound 6 displayed potent on-target antipruritic activity in multiple mouse models of acute histamine-independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.
Unravelling the origins of boldness: A common garden experiment with cave fish (Barbatula barbatula)
Authors: Jolles Jolle W. , Böhm Alexander , Brinker Alexander , Behrmann-Godel Jasminca 
Published: October 2023

AbstractMany animals show an aversion to bright, open spaces, with significant variability seen across species, populations, and individuals within populations. Although there is much interest in the underlying causes of this behaviour, few studies have been able to systematically isolate the role of heritable and environmental effects. Here we addressed this gap using a common garden experiment with cave fish. Specifically, we bred and cross-bred cave loaches (Barbatula barbatula) in the lab, raised the offspring in complete darkness or normal light conditions, and studied their light avoidance behaviour. Cave fish spent much more time in a light area and ventured further out, while surface fish spent considerable time on the edge between light and dark areas. Hybrids behaved most similarly to cave fish. Light treatment and eye size and quality only had a modest effect. Our results suggest light avoidance behaviour of cave fish has a heritable basis and is fundamentally linked to increased boldness rather than reduced vision, which is likely adaptive given the complete lack of macropredators in the cave environment. Our study provides novel experimental insights into the behavioural divergence of cave fish and contributes to our broader understanding of the evolution of boldness and behavioural adaptation.
Human brain representations of internally generated outcomes of approximate calculation revealed by ultra-high-field brain imaging
Authors: Czajko Sébastien , Vignaud Alexandre , Eger Evelyn 
Published: October 2023

AbstractMuch of human culture’s advanced technology owes its existence to the ability to mentally manipulate quantities. Neuroscience has described the brain regions overall recruited by numerical tasks and the neuronal codes representing individual quantities during perceptual tasks. Nevertheless, it remains unknown how quantity representations are combined or transformed during mental computations and how specific quantities are coded in the brain when generated as the result of internal computations rather than evoked by a stimulus. Here, we imaged the brains of adult human subjects at 7 Tesla during an approximate calculation task designed to disentangle in- and outputs of the computation from the operation itself. While physically presented sample numerosities were distinguished in activity patterns along the dorsal visual pathway and within frontal and occipito-temporal regions, a representation of the internally generated result was most prominently detected in higher order regions such as angular gyrus and lateral prefrontal cortex. Behavioral precision in the task was related to cross-decoding performance between sample and result representations in medial IPS regions. This suggests the transformation of sample into result may be carried out within dorsal stream sensory-motor integration regions, and resulting outputs maintained for task purposes in higher-level regions in a format possibly detached from sensory-evoked inputs.
TheRAD51paralogueHvXRCC2regulates meiosis and recombination in barley
Authors: Colas Isabelle , Macaulay Malcolm , Arrieta Mikel , Schreiber Miriam , Orr Jamie , Sandhu Amritpal , Augustine Anu , Targońska-Karasek Małgorzata , Armstrong Susan J , Waugh Robbie , Ramsay Luke 
Published: October 2023

AbstractUsing a positional candidate-gene approach we show that semi-steriledesynaptic8mutants are associated with deletions in or complete knockout of the barley homolog ofXRCC2(X-Ray Repair Cross Complementing 2). In barleyXRCC2mutants, the initial meiotic progression is normal, albeit with a small delay in initiation, with completion of synapsis. However, the absence ofHvXRCC2subsequently leads to a dramatic reduction in the number of crossovers, chromosome mis-segregation, and infertility, suggesting thatHvXRCC2plays a major role in recombination. This mutant phenotype is congruent with that reported in mammalian studies but contrasts with theXRCC2mutant in Arabidopsis which is fertile, exhibits normal chromosome pairing and correct chromosome segregation, and is associated with an increased rate of crossovers. This indicates that theXRCC2mutant phenotype in Arabidopsis is not representative of all plants and thatXRCC2is not a good candidate for the modulation of recombination in barley.HighlightThe mutants of the barley homolog ofXRCC2exhibit delays in replication leading to defective meiosis, altered RAD51 orthologue behaviour, and significant reduction in the number of crossovers as in canonical mammalianXRCC2mutants but unlike those in Arabidopsis.
The SAM Domain of EphA2 Inhibits Ligand-Independent Clustering and Activation
Authors: Shi Xiaojun , Lingerak Ryan , Shrestha Pravesh , Buck Matthias , Wang Bing-Cheng , Smith Adam W. 
Published: October 2023

AbstractEph receptors are the largest family of receptor tyrosine kinases (RTKs). They play a role in the pathogenesis of various diseases including cancer, atherosclerosis, fibrosis, infectious diseases, diseases of the central nervous system and age-related cataract. EphA2 has attracted much attention over the years owing to its dysregulation in many diseases. Previous studies have revealed the unique molecular organizations of Eph receptors, and particularly EphA2, into large clusters of receptor-ligand complexes. One unique feature of Eph receptors is a C-terminal sterile alpha motif (SAM) domain, which has been proposed to alter dimerization and kinase activity in EphA2. However, the precise role of the SAM domain in regulating the function and oligomerization state of EphA2 has not been reported. Here we apply a time-resolve fluorescence spectroscopy, PIE-FCCS, to characterize the oligomerization state of EphA2 in live cells and determine the role of the SAM domain. We deleted the SAM domain in the context of full length EphA2 and an intracellular domain (ICD) construct to assess the effect of the SAM domain on oligomerization state, kinase activity, and cellular behavior. Overall, we find that the SAM domain inhibits ligand-independent clustering and kinase activity in both full-length EphA2 and the isolated ICD construct at the cell membrane. These results are consistent with the autoinhibitory features of the C-terminal tail of EGFR and may help resolve the allosteric regulation of other RTKs.
Ly6G+Granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis
Authors: Sharma Priya , Sharma Raman Deep , Das Mrinmoy , Sarkar Binayak , Singh Lakshyaveer , Jain Neharika , Chaturvedi Shivam , Mehra Lalita , Rathee Aditya , Sharma Shilpa , Foo Shihui , Lee Andrea , kumar N Pavan , Das Prasenjit , Viswanathan Vijay , Kornfeld Hardy , Howland Shanshan W. , Babu Subash , Nandicoori Vinay , Singhal Amit , Kumar Dhiraj 
Published: October 2023

AbstractThe protective correlates ofMycobacterium tuberculosis(Mtb) infection-elicited host immune responses are incompletely understood. Here, we report pro-pathogenic crosstalk involving Ly6G+granulocytes (Ly6G+Gra), IL-17 and COX2. We show that in the lungs ofMtb-infected wildtype mice, either BCG-vaccinated or not, most intracellular bacilli are Ly6G+Gra-resident four weeks post-infection onwards. In the genetically susceptibleIFNγ−/−mice, excessive Ly6G+Gra infiltration correlates with severe bacteraemia. Neutralizing IL-17 (anti-IL17mAb) and COX2 inhibition by celecoxib reverse Ly6G+Gra infiltration, associated pathology and death inIFNγ−/−mice. Surprisingly, Ly6G+Gra also serves as the major source of IL-17 in the lungs ofMtb-infected WT orIFNγ−/−mice. The IL-17-COX2-Ly6G+Gra interplay also operates in WT mice. Inhibiting RORγt, the key transcription factor for IL-17 production or COX2, reduces the bacterial burden in Ly6G+Gra, leading to reduced bacterial burden and pathology in the lungs of WT mice. In theMtb-infected WT mice, COX2 inhibition abrogates IL-17 levels in the lung homogenates and significantly enhances BCG’s protective efficacy, mainly by targeting the Ly6G+Gra-residentMtbpool. Furthermore, in pulmonary TB patients, high neutrophil count and IL-17 correlated with adverse treatment outcomes. Together, our results suggest that IL-17 and PGE2 are the negative correlates of protection, and we propose targeting the pro-pathogenic IL-17-COX2-Ly6G+Gra axis for TB prevention and therapy.
Concordant dynamic changes of global network properties in the frontoparietal and limbic compartments: an EEG study
Authors: Lee Tien-Wen , Tramontano Gerald , Hinrichs Clay 
Published: October 2023

ABSTRACTIntroductionDespite its complexity, deciphering nodal interaction is imperative to understanding a neural network. Network interaction is an even more complicated topic that must be addressed. This study aimed to examine the relationship between the brain waves of two canonical brain structures, i.e., the frontoparietal and limbic compartments, during a resting state.MethodsElectroencephalography (EEG) of 51 subjects in eye-closed condition was analyzed, and the eLORETA method was applied to convert the signals from the scalp to the brain. By way of community detection, representative neural nodes and the associated mean activities were retrieved. Total and lagged coherences were computed to indicate functional connectivity between those neural nodes. Two global network properties were elucidated based on the connectivity measures, i.e., global efficiency and mean functional connectivity strength. The temporal correlation of the global network indices between the two studied networks was explored.ResultsIt was found that there was a significant trend of positive correlation across the four metrics (lagged vs. total coherence x global efficiency vs. average connectivity). In other words, when the neural interaction in the FP network was stronger, so did that in the limbic network, and vice versa. Notably, the above interaction was not spectrally specific and only existed at a finer temporal scale (under hundreds of milliseconds level).ConclusionThe concordant change in network properties indicates an intricate balance between FP and LM compartments. Possible mechanisms and implications for the findings are discussed.
Biomarker discovery in progressive supranuclear palsy from human cerebrospinal fluid using mass spectrometry-based proteomics
Authors: Jang Yura , Oh Sungtaek , Hall Anna J. , Zhang Zhen , Tropea Thomas F. , Chen-Plotkin Alice , Rosenthal Liana S. , Dawson Ted M. , Na Chan Hyun , Pantelyat Alexander Y. 
Published: October 2023

ABSTRACTProgressive supranuclear palsy (PSP) is a neurodegenerative disorder that is often misdiagnosed as Parkinson’s Disease (PD) because of shared symptoms. PSP is characterized by the accumulation of tau protein in specific brain regions, which results in loss of balance, gaze impairment, and dementia. Diagnosing PSP is often challenging, and there’s a significant demand for reliable biomarkers. However, existing biomarkers, including tau protein and neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF), show inconsistencies in distinguishing PSP from other neurodegenerative disorders. To overcome these limitations, we conducted a comprehensive proteome analysis for CSF samples from 40 PSP, 40 PD, and healthy controls (HC) using the tandem mass tag-based quantification method, identifying 3,653 unique proteins. Our statistical analysis identified 190, 152, and 247 differentially expressed proteins when comparing PSP vs. HC, PSP vs. PD, and PSP against both PD and HC, respectively. Gene set enrichment analysis and interactome analysis conducted with the differentially expressed proteins in PSP CSF indicated that most of them were implicated in cell adhesion, cholesterol metabolism, and glycan biosynthesis. Cell-type enrichment analysis revealed that neuronally-derived proteins were predominant among the differentially expressed proteins. Potential biomarker classification performance showed that ATP6AP2 (reduced in PSP) had the highest AUC (0.922), followed by NEFM, EFEMP2, LAMP2, CHST12, FAT2, B4GALT1, LCAT, CBLN3, FSTL5, ATP6AP1, and GGH. This is the first large-scale mass spectrometry-based proteome analysis to discover CSF PSP biomarkers differentiating from both controls and PD, thereby laying a foundation for further development and validation.
Variants in theDDX6-CXCR5autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland
Authors: Wiley Mandi M. , Khatri Bhuwan , Joachims Michelle L. , Tessneer Kandice L. , Stolarczyk Anna M. , Rasmussen Astrid , Anaya Juan-Manuel , Aqrawi Lara A. , Bae Sang-Cheol , Baecklund Eva , Björk Albin , Brun Johan G. , Bucher Sara Magnusson , Dand Nick , Eloranta Maija-Leena , Engelke Fiona , Forsblad-d’Elia Helena , Fugmann Cecilia , Glenn Stuart B. , Gong Chen , Gottenberg Jacques-Eric , Hammenfors Daniel , Imgenberg-Kreuz Juliana , Jensen Janicke Liaaen , Johnsen Svein Joar Auglænd , Jonsson Malin V. , Kelly Jennifer A. , Khanam Sharmily , Kim Kwangwoo , Kvarnström Marika , Mandl Thomas , Martín Javier , Morris David L. , Nocturne Gaetane , Norheim Katrine Brække , Olsson Peter , Palm Øyvind , Pers Jacques-Olivier , Rhodus Nelson L. , Sjöwall Christopher , Skarstein Kathrine , Taylor Kimberly E. , Tombleson Phil , Thorlacius Gudny Ella , Venuturupalli Swamy , Vital Edward M. , Wallace Daniel J , Grundahl Kiely M. , Radfar Lida , Brennan Michael T. , James Judith A. , Scofield R. Hal , Gaffney Patrick M. , Criswell Lindsey A. , Jonsson Roland , Appel Silke , Eriksson Per , Bowman Simon J. , Omdal Roald , Rönnblom Lars , Warner Blake M. , Rischmueller Maureen , Witte Torsten , Farris A. Darise , Mariette Xavier , Shiboski Caroline H. ,   Sjögren’s International Collaborative Clinical Alliance (SICCA), Wahren-Herlenius Marie , Alarcón-Riquelme Marta E. ,   PRECISESADS Clinical Consortium, Ng Wan-Fai ,   UK Primary Sjögren’s Syndrome Registry, Sivils Kathy L. , Guthridge Joel M. , Adrianto Indra , Vyse Timothy J. , Tsao Betty P. , Nordmark Gunnel , Lessard Christopher J. 
Published: October 2023

ABSTRACTFine mapping and bioinformatic analysis of theDDX6-CXCR5genetic risk association in Sjögren’s Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects onDDX6andCXCR5expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, includinglnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression ofDDX6,CXCR5, andlnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.
Deep-seain situand laboratory proteomics provide insights into the sulfur metabolism of a novel deep-sea bacterium,Pseudodesulfovibrio serpenssp. nov.
Authors: Wang Chong , Zheng Rikuan , Sun Chaomin 
Published: October 2023

ABSTRACTSulfate-reducing bacteria (SRB) are ubiquitously distributed across various biospheres and play key roles in global sulfur cycles. However, few deep-sea SRB have been cultivated and studiedin situ, limiting our understanding of the true metabolism of SRB in the deep biosphere. Here, we firstly clarified the high abundance of SRB in deep-sea cold seep sediments and successfully isolated a sulfate-reducing bacterium (strain zrk46). Our genomic, physiological and phylogenetic analyses indicate that strain zrk46 is a novel species, which we propose asPseudodesulfovibrio serpens. Based on the combined results from growth assays and proteomic analyses, we found that supplementation with sulfate (SO42-), thiosulfate (S2O32-), or sulfite (SO32-) promoted the growth of strain zrk46 by facilitating energy production through the dissimilatory sulfate reduction with the auxiliary functions of heterodisulfide reductases, ferredoxins, and nitrate reduction associated proteins, which were coupled with the oxidation of environmental organic matter in both laboratory and deep-seain situconditions. Moreover, metatranscriptomic results confirmed the dissimilatory sulfate reduction of deep-sea SRB in deep-sea environment, which might be coupled to the methane oxidation of anaerobic methanotrophic archaea (ANME-2) through direct interspecies electron transfer via cytochromes.IMPORTANCEThe deep-sea cold seep sediments were ideal habitats for uncovering diverse metabolisms of SRB. Unfortunately, the paucity of SRB isolates has limited further insights into their physiological and metabolic features as well as ecological roles. In the present study, we demonstrated the high abundance of SRB in the deep-sea cold seep sediments and isolated a sulfate-reducing bacterium. Our results demonstrate that the existence of dissimilatory sulfate reduction of strain zrk46 in both laboratory and deep-seain situenvironments, accompanied by the auxiliary effect of heterodisulfide reductases, ferredoxins, and nitrate reduction associated proteins. Our findings also unravel that the sulfate reduction of deep-sea SRB inin situenvironment might be coupled to the methane oxidation of ANME-2. Overall, these findings expand our understanding of deep-sea SRB, while highlighting their importance for deep-sea elemental cycles.
Systematic analysis of transcription factor combinatorial binding uncovers TEAD1 as an antagonist of tissue-specific transcription factors in human organogenesis
Authors: Garcia-Mora Araceli , Mallen Joshua , Zarrineh Peyman , Hanley Neil , Gerrard Dave , Bobola Nicoletta 
Published: October 2023

ABSTRACTGene expression is largely controlled by transcription factors (TFs), which bind to enhancers in combination with other TFs in a mechanism known as combinatorial binding. While combinatorial binding is well established, a comprehensive view of tissue-specific TF combinations at active enhancers during human embryonic development is still lacking. Using a two-step pipeline to detect co-occurring TF motifs in developmental enhancers across 11 human embryonic tissues, we found that motifs recognized by ubiquitous TF families, including TEAD, TALE, ETS, and STAT, are enriched near tissue-specific sequence signatures in developmental enhancers across multiple tissues. In human heart enhancers, TEAD and GATA motifs frequently co-occur, and in the developing mouse heart TEAD1 and GATA4 co-occupy a set of genomic regions, which are also preferentially bound by CHD4, a component of the NuRD complex involved in transcriptional repression. Consistently, TEAD1 attenuates enhancer activation in vitro, with this repressive effect dependent on tissue-specific activators. Overall, our findings reveal universal patterns of TF connectivity within organ-specific transcriptional networks and highlight a broad, previously unrecognized role for TEAD in coordinating organ growth and differentiation across multiple tissues.