bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes
Authors: Lam Mable , Takeo Koji , Almeida Rafael G. , Cooper Madeline H. , Wu Kathryn , Iyer Manasi , Kantarci Husniye , Zuchero J. Bradley 
Published: July 2022

AbstractMyelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is unknown. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease.
TPH2 knockout male rats are aggressive, show less anxiety, and exhibit an altered oxytocin system
Authors: Meng Xianzong , Grandjean Joanes , Sbrini Giulia , Schipper Pieter , Hofwijks Nita , Calabrese Francesca , Homberg Judith 
Published: July 2022

ABSTRACTThe central serotoninergic system is critical for stress responsivity and social behavior, and its dysregulations has been centrally implicated in virtually all neuropsychiatric disorders. Genetic serotonin depletion animal models could provide a tool to elucidate the causes and mechanisms of diseases and to develop new treatment approaches. Previously mice lacking tryptophan hydroxylase 2 (Tph2) have been developed, showing altered behaviors and neurotransmission. However, the effect of congenital serotonin deficiency on emotional and social behavior in rats is still largely unknown, as are the underlying mechanisms. In this study, we used Tph2 knockout (Tph2-/-) male rat model to study how the lack of serotonin in the rat brain affects anxiety-like and social behaviors. Since oxytocin is centrally implicated in these behaviors, we furthermore explored whether effects of Tph2 knockout on behavior would relate to changes in the oxytocin system. We show that Tph2-/- rats display reduced anxiety-like behavior and a high level of aggression in social interactions. In addition, oxytocin receptor expression was increased in the infralimbic and prelimbic cortex, paraventricular nucleus, dorsal raphe nucleus and some subregions of hippocampus, which was paralleled by increased levels of oxytocin in the medial frontal cortex, paraventricular nucleus, but not the dorsal raphe nucleus, central amygdala and hippocampus. In conclusion, our study demonstrated reduced anxiety but exaggerated aggression in Tph2-/- male rats and reveals for the first time a potential involvement of altered oxytocin system function.SIGNIFICANCE STATEMENTWe explored the changes in behavior and oxytocin system functioning in the tryptophan hydroxylase 2 (Tph2) knockout rat model, lacking serotonin in the brain. This rat model contributes to our understanding of the role of serotonin in psychiatric transdiagnostic features and underlying mechanisms. We found that Tph2 knockout male rats are aggressive, less anxious, and exhibit an altered oxytocin system. The observed changes in oxytocin signaling may lead to a new target for the treatment of diseases caused by genetic serotonin deficiency.
Enhanced brain structure-function tethering in transmodal cortex revealed by high-frequency eigenmodes
Authors: Yang Yaqian , Zheng Zhiming , Liu Longzhao , Zheng Hongwei , Zhen Yi , Zheng Yi , Wang Xin , Tang Shaoting 
Published: July 2022

AbstractThe brain’s structural connectome supports signal propagation between neuronal elements, shaping diverse coactivation patterns that can be captured as functional connectivity. While the link between structure and function remains an ongoing challenge, the prevailing hypothesis is that the structure-function relationship may itself be gradually decoupled along a macroscale functional gradient spanning unimodal to transmodal regions. However, this hypothesis is strongly constrained by the underlying models which may neglect requisite signaling mechanisms. Here, we transform the structural connectome into a set of orthogonal eigenmodes governing frequency-specific diffusion patterns and show that regional structure-function relationships vary markedly under different signaling mechanisms. Specifically, low-frequency eigenmodes, which are considered sufficient to capture the essence of the functional network, contribute little to functional connectivity reconstruction in transmodal regions, resulting in structurefunction decoupling along the unimodal-transmodal gradient. In contrast, high-frequency eigenmodes, which are usually on the periphery of attention due to their association with noisy and random dynamical patterns, contribute significantly to functional connectivity prediction in transmodal regions, inducing gradually convergent structure-function relationships from unimodal to transmodal regions. Although the information in high-frequency eigenmodes is weak and scattered, it effectively enhances the structure-function correspondence by 35% in unimodal regions and 56% in transmodal regions. Altogether, our findings suggest that the structure-function divergence in transmodal areas may not be an intrinsic property of brain organization, but can be narrowed through multiplexed and regionally specialized signaling mechanisms.
Cellular contributions to ictal population signals
Authors: Lau Lauren A. , Zhao Zhuoyang , Gomperts Stephen N. , Staley Kevin J. , Lillis Kyle P. 
Published: July 2022

AbstractObjectiveThe amplitude of ictal activity is a defining feature of epileptic seizures, but the determinants of this amplitude have not been identified. Clinically, ictal amplitudes are measured electrographically (using e.g. EEG, ECoG, and depth electrodes), but these methods do not enable the assessment of the activity of individual neurons. To identify the cellular determinants of the ictal signal, we measured single cell and population electrical activity and neuronal calcium levels via optical imaging of the genetically encoded calcium indicator (GECI) GCaMP.MethodsSpontaneous seizure activity was assessed in an awake, behaving mouse model of focal cortical injury and in organotypic hippocampal slice cultures (OHSC), an in vitro preparation from which recurrent seizures can be readily captured. Single cell calcium signals were linked to a range of electrical activities by performing simultaneous GECI-based calcium imaging and whole-cell patch-clamp recordings in spontaneously seizing OHSCs. Neuronal resolution calcium imaging was then performed during spontaneous seizures in vivo and in vitro to quantify the cellular contributions to the population-level calcium signal.ResultsPopulation signal may increase from three potential sources: 1) increased synchrony, i.e. more co-active neurons, 2) altered active state, from bursts of action potentials and/or paroxysmal depolarizing shifts in membrane potential, and 3) altered subthreshold state, which includes all lower levels of activity. The largest contributor to the signal recorded at seizure onset was increased subthreshold activity, consistent with either barrages of excitatory postsynaptic potentials or sustained membrane depolarization. The relative contribution of synchrony increased as seizures progressed, but cell intrinsic alterations in both the subthreshold and active states remained the largest driver of the ictal signal.SignificanceWe introduce here a novel method for the quantification of the relative contributions of inter-versus intra-cellular changes to provide a critical link between single neuron activity and population measures of seizure activity.Key PointsNeuronal calcium as measured by GCaMP reports a range of membrane depolarizations, from EPSPs to action potential firing and paroxysmal depolarizing shiftsThe mean population calcium signal is highly correlated with the electrographic local field potentialIncreased calcium signal during seizure onset is largely driven by increased subthreshold calcium within individual neuronsRecruitment of newly active neurons is a minor contributor to the increasing population-level signal during the transition to frank seizure
Virus Infection Causes Dysbiosis to Promote Type 1 Diabetes Onset
Authors: Morse Zachary J. , Simister Rachel L. , Crowe Sean A. , Horwitz Marc S. , Osborne Lisa C. 
Published: July 2022

AbstractAutoimmune disorders like type 1 diabetes (T1D) are complex diseases caused by numerous factors including both genetic variance and environmental influences. Two such exogenous factors, intestinal microbial composition and enterovirus infection, have been independently associated with T1D onset in both humans and animal models. Since environmental factors rarely work in isolation, we examined the cross-talk between the microbiome and Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice. We demonstrate that CVB4-infection induced restructuring of the intestinal microbiome prior to T1D onset that was associated with thinning of the mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased detection of circulating and intestinal commensal-reactive antibodies. Notably, the CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, thus implying a mutual “diabetogenic” microbiome. Furthermore, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice was sufficient to enhance T1D susceptibility in naïve NOD recipients. These findings support a model whereby CVB infection disrupts the microbiome and intestinal homeostasis in a way that promotes activation of autoreactive immune cells and T1D.
Nitrate-dependent salt tolerance mediated by OsNLP4-OsMADS27 module
Authors: Alfatih Alamin , Zhang Jing , Song Ying , Jan Sami Ullah , Zhang Zi-Sheng , Xia Jing-Qiu , Zhang Zheng-Yi , Nazish Tahmina , Wu Jie , Zhao Ping-Xia , Xiang Cheng-Bin 
Published: July 2022

AbstractSalt stress is a major constraint of plant growth and yield. Nitrogen (N) fertilizers are known to alleviate salt stress. However, the underlying molecular mechanisms remain unclear. Here we show that OsNLP4-OsMADS27 module controls nitrate-dependent salt tolerance in rice. The expression ofOsMADS27is specifically induced by nitrate. TheOsMADS27knockout mutants are more sensitive to salt stress than the wild type, whereas theOsMADS27overexpression lines are more tolerant. Transcriptomic analyses revealed that OsMADS27 controls the expression of a number of known stress-responsive genes as well as those involved in ion homeostasis and antioxidation. We demonstrated that OsMADS27 directly binds to the promoter ofOsHKT1.1andOsSPL7to regulate their expression. Notably,OsMADS27-mediated salt tolerance is nitrate-dependent and positively correlated with nitrate concentration. We further showed that OsNLP4, a nitrate-responsive key regulator in N metabolism and N use efficiency, positively regulates the expression ofOsMADS27by directly binding to the nitrate-responsivecis-element in its promoter, thereby transmitting the nitrate signal toOsMADS27and conferring its nitrate dependence. Our results reveal the role of nitrate-responsive OsNLP4-OsMADS27 module and its downstream target genes in salt tolerance, filling the gap in the molecular mechanism of nitrate-dependent salt tolerance of rice. Moreover,OsMADS27overexpression increased grain yield under salt stress in presence of sufficient nitrate, indicating thatOsMADS27is a promising candidate for the improvement of salt tolerance in rice.
Proteomic profile of nuclei containing p62-positive inclusions in neuronal intranuclear inclusion disease
Authors: Kurihara Masanori , Mano Tatsuo , Eto Fumihiro , Yao Ikuko , Sato Kenichiro , Ohtomo Gaku , Bannai Taro , Shibata Shota , Ishiura Hiroyuki , Ikemura Masako , Matsubara Tomoyasu , Morishima Maho , Saito Yuko , Murayama Shigeo , Toda Tatsushi , Setou Mitsutoshi , Iwata Atsushi 
Published: July 2022

AbstractNeuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Intranuclear inclusions are the pathological hallmark of NIID. Previously, immunohistochemistry has revealed that intranuclear inclusions are ubiquitin-, p62-, and SUMO-1-positive, suggesting the possible alteration of the ubiquitin-proteasomal protein degradation system in the nuclei with inclusions. However, the molecular mechanisms within these nuclei remain unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in NIID with CGG repeat expansion in NOTCH2NLC to discover the proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins in the autopsy brain samples from three NIID patients was confirmed via immunofluorescence. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A3, hnRNP A2/B1, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than those without; however, they were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. These data can form the basis for understanding the pathophysiology of NIID.
Discovery of a monomeric green fluorescent protein sensor for chloride by structure-guided bioinformatics
Authors: Peng Weicheng , Maydew Caden , Kam Hiu , Lynd Jacob , Tutol Jasmine N. , Phelps Shelby M. , Abeyrathna Sameera , Meloni Gabriele , Dodani Sheel C. 
Published: July 2022

AbstractChloride is an essential anion for all forms of life. Beyond electrolyte balance, an increasing body of evidence points to new roles for chloride in normal physiology and disease. Over the last two decades, this understanding has been advanced by chloride-sensitive fluorescent proteins for imaging applications in living cells. To our surprise, these sensors have been primarily engineered from the green fluorescent protein (GFP) found in the jellyfishAequorea victoria. However, the GFP family has a rich sequence space that could already encode for new sensors with desired properties, thereby minimizing protein engineering efforts and accelerating biological applications. To efficiently sample this space, we present and validate a stepwise bioinformatics strategy focused first on the chloride binding pocket and second on a monomeric oligomerization state. Using this, we identified GFPxm163 from GFPxm found in the jellyfishAequorea macrodactyla. In vitrocharacterization shows that the binding of chloride as well as bromide, iodide, and nitrate rapidly tunes the ground state chromophore equilibrium from the phenolate to the phenol state generating a pH-dependent, turn-off fluorescence response. Furthermore, live-cell fluorescence microscopy reveals that GFPxm163 provides a reversible, yet indirect readout of chloride transport via iodide exchange. With this demonstration, we anticipate that the paring of bioinformatics with protein engineering methods will provide an efficient methodology to discover and design new chloride-sensitive fluorescent proteins for cellular applications.Abstract Figure
Micropatterned Organoids Enable Modeling of the Earliest Stages of Human Cardiac Vascularization
Authors: Abilez Oscar J. , Yang Huaxiao , Tian Lei , Wilson Kitchener D. , Lyall Evan H. , Shen Mengcheng , Bhoi Rahulkumar , Zhuge Yan , Jia Fangjun , Wo Hung Ta , Zhou Gao , Guan Yuan , Aldana Bryan , Obal Detlef , Peltz Gary , Zarins Christopher K. , Wu Joseph C. 
Published: July 2022

AbstractAlthough model organisms have provided insight into the earliest stages of cardiac vascularization, we know very little about this process in humans. Here we show that spatially micropatterned human pluripotent stem cells (hPSCs) enablein vitromodeling of this process, corresponding to the first three weeks ofin vivohuman development. Using four hPSC fluorescent reporter lines, we create cardiac vascular organoids (cVOs) by identifying conditions that simultaneously give rise to spatially organized and branched vascular networks within endocardial, myocardial, and epicardial cells. Using single-cell transcriptomics, we show that the cellular composition of cVOs resembles that of a 6.5 post-conception week (PCW) human heart. We find that NOTCH and BMP pathways are upregulated in cVOs, and their inhibition disrupts vascularization. Finally, using the same vascular-inducing factors to create cVOs, we produce hepatic vascular organoids (hVOs). This suggests there is a conserved developmental program for creating vasculature within different organ systems.Graphic Abstract
Development of Polymer/DNA Polyplexes System for Nucleic Acid Delivery to the Multicellular OrganismC. elegans
Authors: Yenisert Ferhan , Bayram Nazende Nur , Köseoğlu Beyza Nur , Topuzoğulları Murat , Isoglu Sevil Dincer , Kaplan Oktay I. 
Published: July 2022

AbstractGene therapy studies have been of great importance in the elimination of genetic diseases, and the capability of the CRISPR/Cas9 genome editing technique to correct genetic defects has shown great promise. As DNA-based Cas9 nuclease delivery is preferable because of its low cost and higher stability, effective vector-based CRISPR/Cas9 administration is urgently needed. Here, we used the multicellular organismCaenorhabditis elegansto optimize the polymer-mediated DNA delivery system to generate mutants with CRISPR/Cas9. Toward this end, the cationically quaternized polymer of POEGMA-b-P4VP (POEGMA-b-QP4VP) as a carrier of CRISPR/Cas9 components was first synthesized, followed by the formation of plasmid DNA-polymer complex called polyplexes.1H NMR, Zeta-Sizer, Scanning Electron Microscopy (SEM) analysis, and gel retardation experiments confirmed the polyplexes formation, including pRF4 (Roller) and sgRNAdpy-10, which were then incubated withC. elegans. The polymer-mediated delivery system facilitated the generation of transgenic Roller animals and heritable Dumpy mutants with CRISPR/Cas9. Our study for the first time demonstrated optimized administration of CRISPR/Cas 9 components toC. elegans.
Comprehensive collection and prediction of ABC transmembrane protein structures in the AI era of structural biology
Authors: Tordai Hedvig , Suhajda Erzsébet , Sillitoe Ian , Nair Sreenath , Váradi Mihály , Hegedűs Tamás 
Published: July 2022

AbstractThe number of unique transmembrane (TM) protein structures doubled in the last four years that can be attributed to the revolution of cryo-electron microscopy. In addition, AlphaFold2 (AF2) also provided a large number of predicted structures with high quality. However, if a specific protein family is the subject of a study, collecting the structures of the family members is highly challenging in spite of existing general and protein domain-specific databases. Here, we demonstrate this and assess the applicability and usability of automatic collection and presentation of protein structures via the ABC protein superfamily. Our pipeline identifies and classifies transmembrane ABC protein structures using PFAM search and also aims to determine their conformational states based on special geometric measures, conftors. Since the AlphaFold database contains structure predictions only for single polypeptide chains, we performed AF2-Multimer predictions for human ABC half transporters functioning as dimers. Our AF2 predictions warn of possibly ambiguous interpretation of some biochemical data regarding interaction partners and call for further experiments and experimental structure determination. We made our predicted ABC protein structures available through a web application, and we joined the 3D-Beacons Network to reach the broader scientific community through platforms such as PDBe-KB.
Comparison of different models in predicting habitat suitability of rare species in Uzbekistan: 8 rare Tulipa species case-study
Authors: Rustamov Khondamir 
Published: July 2022

AbstractSpecies distribution models (SDMs) have become an essential tool in conservational biology, biogeography and ecology. But there is no consequence in what SDM method is the most efficient in predicting suitable habitat distribution of rare species. To explore this issue, we chose 8 rareTulipaspecies in Uzbekistan as case study to test 8 common Machine Learning (GLM, GBM, MARS, CTA, SRE, FDA, RF, MaxEnt) and Deep Neural Network (DNN) SDM models, using three different methods of pseudo-absence data generation (random sampling, random sampling with exclusion buffer, random sampling with environmental profiling). To compare the effectiveness of each model 3 common metrics (Area under ROC (AUC), True skill statistics (TSS) and Cohen’s Kappa (K)) were used. We have found that RF and GBM combined with RSEP strategy are superior to other modeling methods.