bluuebunny/crossref_metadata_2025_split huggingface dataset:
Control ofClostridiodes difficilevirulence and physiology by the flagellin homeostasis checkpoint FliC-FliW-CsrA in the absence of motility
Authors: Zhu Duolong , Wozniak Katherine J. , Midani Firas , Wang Shaohui , Sun Xingmin , Britton Robert A. 
Published: November 2022

ABSTRACTMutations affectingClostridioides difficileflagellin (FliC) have been shown to be hypervirulent in animal models and display increased toxin production and alterations in central metabolism. The regulation of flagellin levels in bacteria is governed by a tripartite regulatory network involvingfliC,fliW, andcsrA, which creates a feedback system to regulate flagella production. Through genomic analysis ofC. difficileclade 5 strains (non-motile), we identified they have jettisoned many of the genes required for flagellum biosynthesis yet retain the major flagellin genefliCand regulatory genefliW. We therefore investigated the roles offliC,fliW, andcsrAin the clade 5 ribotype 078 strainC. difficile1015, which lacks flagella and is non-motile. Analysis of mutations infliC,fliW, andcsrA(and all combinations) onC. difficilepathogenesis indicated that FliW plays a central role inC. difficilevirulence as animals infected with strains carrying a deletion offliWshowed decreased survival and increased disease severity. Thesein vivofindings were supported byin vitrostudies showing that mutations impacting the activity of FliW showed increased toxin production. We further identified that FliW can interact with the toxin positive regulator TcdR, indicating that modulation of toxin production via FliW occurs by sequestering TcdR from activating toxin transcription. Furthermore, disruption of thefliC-fliW-csrAnetwork results in significant changes in carbon source utilization and sporulation. This work highlights that key proteins involved in flagellar biosynthesis retain their regulatory roles inC. difficilepathogenesis and physiology independent of their functions in motility.IMPORTANCEC. difficileis a leading cause of nosocomial antibiotic-associated diarrhea in developed countries with many known virulence factors. In several pathogens, motility and virulence are intimately linked by regulatory networks that allow coordination of these processes in pathogenesis and physiology. Regulation ofC. difficletoxin production by FliC has been demonstratedin vitroandin vivoand has been proposed to link motility and virulence. Here we show that clinically important, non-motileC. difficilestrains have conserved FliC and regulatory partners FliW and CsrA, despite lacking the rest of the machinery to produce functional flagella. Our work highlights a novel role for flagellin outside of its role in motility and FliW in the pathogenesis and physiology ofC. difficile.
scmTE: multivariate transfer entropy builds interpretable compact gene regulatory networks by reducing false predictions
Authors: Weng Guangzheng , Kim Junil , Natarajan Kedar Nath , Won Kyoung-Jae 
Published: November 2022

AbstractGene regulatory network inference from single-cell RNA sequencing (scRNAseq) datasets has an incredible potential to discover new regulatory rules. However, current computational inference methods often suffer from excessive predictions as existing strategies fail to remove indirect or false predictions. Here, we report a new algorithm single-cell multivariate Transfer Entropy, ‘scmTE’, that generates interpretable regulatory networks with reduced indirect and false predictions. By utilizing multivariate transfer entropy, scmTE accounts for gene-to-gene interdependence when quantifying regulatory relationships. Benchmarking against other methods using synthetic data manifested that scmTE is the unique algorithm that did not produce a hair-ball structure (due to too many predictions) and recapitulated known ground-truth relationships with high accuracy.In silicoknockdown experiments shows that scmTE assigns higher scores for specific interactions important for differentiation processes. We apply scmTE to T-cell differentiation, myelopoiesis and pancreatic development and identified known and novel regulatory interactions. scmTE provides a robust approach to infer interpretable networks by effectively removing unwanted indirect relationships.
Functional differentiation of Sec13 paralogs in the euglenozoan protists
Authors: Faktorová Drahomíra , Záhonová Kristína , Benz Corinna , Dacks Joel B. , Field Mark C. , Lukeš Julius 
Published: November 2022

AbstractThe β-propeller protein Sec13 plays roles in at least three distinct processes by virtue of being a component of the COPII endoplasmic reticulum export vesicle coat, the nuclear pore complex (NPC) and the Seh1-associated (SEA)/GATOR nutrient-sensing complex, suggesting that regulatory mechanisms coordinating these cellular activities may operateviaSec13. The NPC, COPII and SEA/GATOR are all ancient features of eukaryotic cells. In the vast majority of eukaryotes, a single Sec13 gene is present, but here we report that the Euglenozoa, a lineage encompassing the diplonemid, kinetoplastid and euglenid protists contain two Sec13 paralogs. Furthermore, based on protein interactions and localization studies we show that Sec13 functions in diplonemids are divided between the Sec13a and Sec13b paralogs. Specifically, Sec13a interacts with COPII and the NPC, but Sec13b interacts with Sec16 and components of the SEA/GATOR complex. We infer that euglenozoan Sec13a is responsible for NPC functions and canonical anterograde transport activities while Sec13b acts within nutrient and autophagy-related pathways, indicating a fundamentally distinct organization of coatomer complexes in the euglenozoan flagellates.
Membrane-remodeling protein ESCRT-III homologs incarnate the evolution and morphogenesis of multicellular magnetotactic bacteria
Authors: Zhang Wenyan , Chen Jianwei , Dai Jie , Zhu Shiwei , Guenno Hugo Le , Kosta Artemis , Pan Hongmiao , Qian Xin-Xin , Santini Claire-Lise , Menguy Nicolas , Li Xuegong , Chen Yiran , Liu Jia , Cui Kaixuan , Zhao Yicong , Liu Guilin , Durand Eric , Zhang Wei-Jia , Roussel Alain , Xiao Tian , Wu Long-Fei 
Published: November 2022

AbstractEndosomal sorting complex required transport (ESCRT) III proteins are essential for membrane remodeling and repair across all domains of life. Eukaryotic ESCRT-III and the cyanobacterial homologs PspA and Vipp1/Imm30 remodel membrane into vesicles, rings, filaments and tubular rods structures. Here our microscopy analysis showed that multicellular bacteria, referred to as magnetoglobules, possess multiple compartments including magnetosome organelles, polyphosphate granules, vesicles, rings, tubular rods, filaments and MVB-like structures. Therefore, membrane remodeling protein PspA might be required for the formation of these compartments, and contribute to the morphogenesis and evolution of multicellularity. To assess these hypotheses, we sequenced nine genomes of magnetoglobules and found a significant genome expansion compared to unicellular magnetotactic bacteria. Moreover, PspA was ubiquitous in magnetoglobules and formed a distinct clade on the tree of eubacterial and archaeal ESCRT-III. The phylogenetic feature suggested the evolution of magnetoglobules from a unicellular ancestor of deltaproteobacterium. Hetero-expression of ellipsoidal magnetoglobulepspA2gene alone inEscherichia coliresulted in intracellular membrane aggregation. GFP fusion labeling revealed polar location of PspA2 in rod-shaped unicells and regular interval location in filamentous cells. Cryo-electron tomography analysis showed filament bundle, membrane sacculus, vesicles and MVB-like structure in the cells expressing PspA2. Moreover, electron-dense area with a similar distribution as GFP-PspA2 foci in filamentous cells changed the inward orientation of the septum, which might interfere with the cell division. Collectively, these results show the membrane remodeling function of magnetoglobule PspA proteins, which may contribute to morphogenesis and the evolution of multicellularity of magnetotactic bacteria.
Potassium regulates axon-oligodendrocyte signaling and metabolic coupling in white matter
Authors: Looser Zoe J. , Ravotto Luca , Jung Ramona B. , Werner Hauke B. , Ruhwedel Torben , Möbius Wiebke , Bergles Dwight E. , Barros L. Felipe , Nave Klaus-Armin , Weber Bruno , Saab Aiman S. 
Published: November 2022

AbstractThe integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs), which is essential for brain function. However, the mechanisms by which OLs detect axonal spiking and rapidly control axon-OL metabolic coupling are largely unknown. Here, we combine optic nerve electrophysiology and two-photon imaging to study activity-dependent calcium (Ca2+) dynamics in OLs and metabolite fluxes in myelinated axons. Both high-frequency axonal firing and extracellular potassium (K+) elevations trigger a fast Ca2+response in OLs that is facilitated by barium-sensitive, inwardly rectifying K+channels. Using OL-specific Kir4.1 knockout mice (Kir4.1 cKO) we now demonstrate that, in addition to being crucial for K+clearance, oligodendroglial Kir4.1 regulates axonal energy metabolism and long-term axonal integrity. Before the manifestation of axonal damage, we observed reduced glucose transporter GLUT1 and monocarboxylate transporter MCT1 expression in myelin of young Kir4.1 cKO mice, suggesting early deficits in metabolite supply to axons. Strikingly, we found lower resting lactate levels and activity-induced lactate surges in optic nerve axons of young Kir4.1 cKO mice. Moreover, both axonal glucose uptake and consumption were hampered in the absence of oligodendroglial Kir4.1, uncovering a new role of OLs in regulating axonal glucose metabolism. Our findings reveal a novel model of axon-OL signaling and metabolic coupling in which OLs detect high-frequency axonal activity through K+signaling, which is critical in adjusting the axon-OL metabolic unit and in preserving long-term axonal health.
Sensory tuning in neuronal movement commands
Authors: Baumann Matthias P. , Bogadhi Amarender R. , Denninger Anna F. , Hafed Ziad M. 
Published: November 2022

AbstractMovement control is critical for successful interaction with our environment. However, movement does not occur in complete isolation of sensation, and this is particularly true of eye movements. Here we show that the neuronal eye movement commands emitted by the superior colliculus, a structure classically associated with oculomotor control, encompass a robust visual sensory representation of eye movement targets. Thus, similar saccades towards different images are associated with different saccade-related “motor” bursts. Such sensory tuning in superior colliculus saccade motor commands appeared for all image manipulations that we tested, from simple visual features to real-life object images, and it was also strongest in the most motor neurons in the deeper collicular layers. Visual-feature discrimination performance in the motor commands was also stronger than in visual responses. Comparing superior colliculus motor command feature discrimination performance to that in the primary visual cortex during steady gaze fixation revealed that collicular motor bursts possess a reliable peri-saccadic sensory representation of the peripheral saccade target’s visual appearance, exactly when retinal input is most uncertain. Consistent with this, we found that peri-saccadic perception is altered as a function of saccade target visual features. Therefore, superior colliculus neuronal movement commands likely serve a fundamentally sensory function.
Combined promoter-capture Hi-C and Hi-C analysis reveals a fine-tuned regulation of 3D chromatin architecture in colorectal cancer
Authors: Saw Ajay Kumar , Madhok Ayush , Bhattacharya Anupam , Nandi Soumyadeep , Galande Sanjeev 
Published: November 2022

ABSTRACTHi-C is a widely used method for profiling chromosomal interactions in the 3-dimensional context. Due to limitations on the depth of sequencing, the resolution of most Hi-C datasets is often insufficient for scoring fine-scale interactions. We therefore used promoter-capture Hi-C (PCHi-C) data for mapping these subtle interactions. From multiple colorectal cancer (CRC) studies, we combined PCHi-C with Hi-C datasets to understand the dynamics of chromosomal interactions from cis regulatory elements to topologically associated domain (TAD)-level, enabling detection of fine-scale interactions of disease-associated loci within TADs. Our integrated analyses of PCHi-C and Hi-C datasets from CRC cell lines along with histone modification landscape and transcriptome signatures highlight significant genomic structural instability and their association with tumor-suppressive transcriptional programs. Such analyses also yielded nine dysregulated genes. Transcript profiling revealed a dramatic increase in their expression in CRC cell lines as compared to NT2D1 human embryonic carcinoma cells, supporting the predictions of our bioinformatics analysis. We further report increased occupancy of activation associated histone modifications H3K27ac and H3K4me3 at the promoter regions of the targets analyzed. Our study provides deeper insights into the dynamic 3D genome organization in CRC and identification of affected genes which may serve as potential biomarkers for CRC.GRAPHICAL ABSTRACT
Valence-dependent synaptic plasticity drives approach and avoidance behavior in social context
Authors: Espinosa Pedro , Girard Benoit , Lucchini Mattia , Campanelli Federica , Tiriticco Valentina , Mohrhauer Lucy , Bellone Camilla 
Published: November 2022

AbstractThe nature of social interactions determines engagement or avoidance with conspecifics. Here, we explore the circuit mechanisms that guide approach or avoidance behavior in mice based on the valence of previous social interactions. We identify a novel circuit connecting D1 receptor expressing neurons of the anterior insular cortex (AIC) to D1R expressing neurons of the nucleus accumbens (NAc). These cells become active during social interactions in a valence-dependent manner. Lower frequency patterns encoded appetitive interactions, while aversive interactions led to higher activation. These activity patterns elicited distinct forms of synaptic plasticity in the accumbal target neurons, which were causal for subsequent approach or avoidance behavior. Our results unravel the synaptic mechanisms instructing behavior after the social interaction of opposite valence.
NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice
Authors: Zhang Ruolin , Mao Weibing , Niu Lumeng , Bao Wendai , wang Yiqi , Yang Zhihao , Zhu Yasha , Song Haikun , Chen Jincao , Li Guangqiang , Cai Meng , Yuan Zilong , Dong Jiawen , Zhang Min , Xiong Nanxiang , Wei Jun , Dong Zhiqiang 
Published: November 2022

AbstractTransplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation is limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells (iPSCs) together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiationin vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarct, neuronal death and glial scarring, and promoted the motor function recovery. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.
Compressive sensing of neuronal connectivity maps from subsampled, cell-targeted optogenetic stimulation of a network model
Authors: Navarro Phillip , Oweiss Karim 
Published: November 2022

AbstractMapping functional connectivity between neurons is an essential step towards probing the neural computations mediating behavior. The ability to consistently and robustly determine synaptic connectivity maps in large populations of interconnected neurons is a significant challenge in terms of yield, accuracy and experimental time. Here we developed a compressive sensing approach to reconstruct synaptic connectivity maps based on random two photon (2p) cell-targeted optogenetic stimulation and membrane voltage readout of many putative postsynaptic neurons. Using a biophysical network model of interconnected populations of excitatory and inhibitory neurons, we found that the mapping can be achieved with far fewer measurements than the standard pairwise sequential approach. We characterized the recall and precision probabilities as a function of network observability, sparsity, number of neurons stimulated per trial, off-target stimulation, synaptic reliability, propagation latency and network topology. We found that that network sparsity and synaptic reliability were primary determinants of the performance. In particular, in a network with 10% probability of neuronal connectivity, functional connections were recovered with >85% recall and >80% precision in half the trials that would be required for single cell stimulation. Our results suggest a rapid and efficient method to reconstruct functional connectivity of brain networks where sparsity is predominantly present.
Dysfunctional feedback processing in methamphetamine abuser; evidence from neurophysiological and computational analysis
Authors: Ghaderi Sadegh , Amanirad Jamal , Hemami Mohammad , Khosrowabadi Reza 
Published: November 2022

AbstractMethamphetamine use disorder associated with a dysfunctional neural feedback (reward-punishment) processing system and is considered a public health risk. Although several behavioral, computational, and electrocortical studies have explored feedback processing in other groups of individuals, the precise mechanisms of feedback processing dysfunction in methamphetamine use dependent (MUD) individuals remain unclear. Furthermore, our recent knowledge about the underlying feedback-related connectivity patterns and intertwining latent components of behavior with electrocortical signals in MUDs remained quite poor. The present study intended to fill these gaps by exploring the behavioral and electrocortical responses of abstained MUDs during a feedback-based learning paradigm. As mathematical models revealed, MUDs have less sensitivity to distinguishing optimal options (less sensitivity to options value) and learned less from negative feedback, compared with healthy controls. The MUDs also presented smaller medial-frontal theta (5–8 Hz) oscillations in response to negative feedback (300-550 ms post feedback) while other measures responsible for learning including, feedback-related negativity (FRN), parietal-P300, and a flux originated from medial frontal to lateral prefrontal remained intact for them. Further, in contrast to healthy controls, the observed association between feedback sensitivity and medial-frontal theta activity is eliminated in MUDs. We suggested that these results in MUDs may be due to the adverse effect of methamphetamine on the cortico-striatal dopamine circuit, reflected in anterior cingulate cortex (ACC) activity as the best candidate region responsible for efficient behavior adjustment. This study unveils the underlying neural mechanism of feedback processing in individuals with methamphetamine use history and could offer individual therapeutic approaches.
Synaptic Connectivity of Sensorimotor Circuits for Vocal Imitation in the Songbird
Authors: Trusel Massimo , Zhao Ziran , Alam Danyal H. , Marks Ethan S. , Ikeda Maaya Z. , Roberts Todd F. 
Published: November 2022

AbstractSensorimotor computations for learning and behavior rely on precise patterns of synaptic connectivity. Yet, we typically lack the synaptic wiring diagrams for long-range connections between sensory and motor circuits in the brain. Here we provide the synaptic wiring diagram for sensorimotor circuits involved in learning and production of zebra finch song, a natural and ethologically relevant behavior. We examined the functional synaptic connectivity from the 4 main sensory afferent pathways onto the 3 known classes of projection neurons of the song premotor cortical region HVC. Recordings from hundreds of identified projection neurons reveal rules for monosynaptic connectivity and the existence of polysynaptic ensembles of excitatory and inhibitory neuronal populations in HVC. Circuit tracing further identifies novel connections between HVC’s presynaptic partners. Our results indicate a modular organization of ensemble-like networks for integrating long-range input with local circuits, providing important context for information flow and computations for learned vocal behavior.
Stepwise modifications of transcriptional hubs link pioneer factor activity to a burst of transcription
Authors: Cho Chun-Yi , O’Farrell Patrick H. 
Published: November 2022

ABSTRACTEukaryotic transcription begins with the binding of transcription factors (TFs), which promotes the subsequent recruitment of coactivators and pre-initiation complexes. It is commonly assumed that these factors eventually co-reside in a higher-order structure, allowing distantly bound TFs to activate transcription at core promoters. Here we performed live imaging of endogenously tagged proteins, including the pioneer TF Zelda, the coactivator dBrd4, and RNA polymerase II (RNAPII), in earlyDrosophilaembryos. We show that these factors are sequentially and transiently recruited to discrete clusters during activation of non-histone genes. We present evidence that Zelda acts with the acetyltransferase dCBP to nucleate dBrd4 hubs, which then trigger pre-transcriptional clustering of RNAPII; continuous transcriptional elongation then disperses clusters of dBrd4 and RNAPII. Our results suggest that activation of transcription by eukaryotic TFs involves a succession of distinct biochemical complexes that culminate in a self-limiting burst of transcription.
Correction of age-associated defects in dendritic cell functions enables CD4+T cells to eradicate tumors in the elderly
Authors: Zhivaki Dania , Boriello Francesco , Kennedy Stephanie N. , Evavold Charles L. , Bahleda Kristin M. , Chapman Kate L. , Zanoni Ivan , Kagan Jonathan C. 
Published: November 2022

AbstractDefective host defenses later in life are associated with changes in immune system activity. The means to correct immune defects to ensure immunity in the elderly are undefined. In this study, we found that CD8+T cells, which are necessary for anti-tumor immunity in young mice, are not required to eradicate the same cancers later in life. Rather, CD4+T cells drive anti-tumor immunity in elderly mice. The generation of anti-tumor CD4+T cells requires multiple dendritic cell (DC) activities that are elicited by immune agonists known as hyperactivators, but not by adjuvants that model those used clinically. DC hyperactivators correct age-associated defects in DC migration and T cell co-stimulation while enabling NLRP3 inflammasome activities within living cells. These combined activities enable DCs to induce TH1-skewed T cells that persist into old age and eliminate implantable tumors. These results raise the possibility of correcting age-associated immune defects through DC manipulation.