bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Role of Neuroplastin in Pancreatic β Cells: Regulating Insulin Secretion and Promoting Islet Inflammation
Authors: Kitamura Rie Asada , Hummel Devynn , Urano Fumihiko 
Published: September 2023

AbstractMesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident secretory protein that reduces inflammation and promotes proliferation in pancreatic β cells. Numerous studies have highlighted the potential of MANF as a therapeutic agent for diabetes mellitus (DM), making it essential to understand the mechanisms underlying MANF’s functions. In our previous search for a molecule that mediates MANF signaling, we identified Neuroplastin (NPTN) as a binding partner of MANF that localizes on the cell surface. However, the roles of NPTN in pancreatic β cells remain unclear. In this study, we generated β cell-specificNptnknockout (KO) mice and conducted metabolic characterization. NPTN deficiency improved glucose tolerance by increasing insulin secretion and β cell mass in the pancreas. Moreover, proliferation and mitochondrial numbers in β cells increased inNptnKO islets. These phenotypes resulted from elevated cytosolic Ca2+levels and subsequent activation of downstream molecules. Simultaneously, we demonstrated that NPTN induces the expression of proinflammatory cytokines via the TRAF6-NF-κB axis in β cells. Additionally, NPTN deficiency conferred resistance to STZ-induced diabetic phenotypes. Finally, exogenous MANF treatment in islets or β cells led to similar phenotypes as those observed in NPTN-deficient models. These results indicate that NPTN plays important roles in the regulation of insulin secretion, proliferation, and mitochondrial quantity, as well as pro-inflammatory responses, which are antagonized by MANF treatment. Thus, targeting the MANF-NPTN interaction may lead to a novel treatment for improving β cell functions in diabetes mellitus.Significance statementMesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident small secretory protein that has the potential as therapeutic agent for various diseases related to inflammation and ER stress, such as Type 1 diabetes mellitus. Our work shed light on the roles of a binding partner protein of MANF, Neuroplastin (NPTN), in pancreatic β cells. We demonstrated NPTN regulates Ca2+dynamics as well as inflammation in pancreatic β cells. NPTN deficiency caused improved insulin secretion as well as the resistance to Type 1 diabetic phenotypes. We also found out that MANF treatment leads to similar phenotypes observed in NPTN deficient models through antagonizing NPTN’s functions. Overall, our results provide a new insight into treatment for improving β cell functions in diabetes mellitus.
Nuclear Lipid Droplets Exit to the Cytoplasm: A Novel Mechanism of non-nuclear pore-dependent material exchange
Authors: Jin Yi , Huang Jin , Zhao Zichen , Tan Yanjie , Wu Jian , Ren Zhuqing 
Published: September 2023

AbstractIn cellular biology, the extrusion of large molecular complexes from the nucleus has consistently represented a considerable challenge. In this investigation, we reveal a hitherto unexplored mechanism facilitating the efflux of nuclear lipid droplets (nLDs) from the nucleus directly into the cytoplasm, a process integral to comprehending cellular processes and nuclear dynamics. Through high-throughput sequencing, immunoprecipitation, and immunofluorescence experimentation, we demonstrated that the type I nucleoplasmic reticulum engages with nLDs, enabling the dynamic protein Rab8a’s transfer to the nLDs and fostering their translocation to the nuclear membrane. Phosphorylation of LMNA/C at the S392 site, adjacent to the nLD-nuclear membrane contact site, induces local depolymerization of lamins, creating an aperture that enables gradual nuclear exit of nLDs. Following this, nLDs, carrying DNA fragments, are released into the cytoplasm through budding and subsequently undergo autophagy-mediated degradation. Furthermore, we demonstrate that RhoA-PKC signaling enhances nLD movement and LMNA/C phosphorylation, while its inhibition impedes nuclear nLD efflux. Our groundbreaking investigation illuminates non-nuclear pore-dependent mechanisms of material exchange and offers fresh perspectives on nuclear metabolic pathways.In BriefIn this study, Jin et al. elucidate a novel mechanism for the expulsion of nuclear lipid droplets (nLDs) from the nucleus. They demonstrate that the activation of RhoA within the nucleus recruits Rab8a to the surface of nLDs. Concurrently, PKC phosphorylation triggers the phosphorylation of LMNA/C at the S392 site, leading to a localized depolymerization of lamins. This creates an aperture that allows for the gradual exit of nLDs from the nucleus. The efflux process of nLDs involves three sequential steps: rupture of the nuclear fibril layer, fusion of nLDs with the inner nuclear membrane (INM), and subsequent fusion with the outer nuclear membrane (ONM). This enables nLDs to enter the cytoplasm, shedding light on a previously unknown process of large molecular entity expulsion from the nucleus.
Molecular model of a bacterial flagellar motorin situreveals a “parts-list” of protein adaptations to increase torque
Authors: Drobnič Tina , Cohen Eli J. , Calcraft Tom , Alzheimer Mona , Froschauer Kathrin , Svensson Sarah , Hoffmann William H. , Singh Nanki , Garg Sriram G. , Henderson Louie , Umrekar Trishant R. , Nans Andrea , Ribardo Deborah , Pedaci Francesco , Nord Ashley L. , Hochberg Georg K. A. , Hendrixson David R. , Sharma Cynthia M. , Rosenthal Peter B. , Beeby Morgan 
Published: September 2023

AbstractOne hurdle to understanding how molecular machines work, and how they evolve, is our inability to see their structuresin situ. Here we describe a minicell system that enablesin situcryogenic electron microscopy imaging and single particle analysis to investigate the structure of an iconic molecular machine, the bacterial flagellar motor, which spins a helical propeller for propulsion. We determine the structure of the high-torqueCampylobacter jejunimotorin situ,including the subnanometre-resolution structure of the periplasmic scaffold, an adaptation essential to high torque. Our structure enables identification of new proteins, and interpretation with molecular models highlights origins of new components, reveals modifications of the conserved motor core, and explain how these structures both template a wider ring of motor proteins, and buttress the motor during swimming reversals. We also acquire insights into universal principles of flagellar torque generation. This approach is broadly applicable to other membrane-residing bacterial molecular machines complexes.
Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation
Authors: Malik Samaresh , Biswas Joyanta , Sarkar Purandar , Nag Subhadeep , Gain Chandrima , Roy Shatadru Ghosh , Bhattacharya Bireswar , Ghosh Dipanjan , Saha Abhik 
Published: September 2023

AbstractEpstein-Barr virus (EBV) contributes to ∼1% of all human cancers including several B-cell neoplasms. A characteristic feature of EBV life cycle is its ability to transform metabolically quiescent B-lymphocytes into hyperproliferating B-cell blasts with the establishment of viral latency, while intermittent lytic cycle induction is necessary for the production of progeny virus. Our RNA-Seq analyses of both latently infected naïve B-lymphocytes and transformed B-lymphocytes upon lytic cycle replication indicate a contrasting expression pattern of a membrane-associated carbonic anhydrase isoform CA9, an essential component for maintaining cell acid-base homeostasis. We show that while CA9 expression is transcriptionally activated during latent infection model, lytic cycle replication restrains its expression. Pharmacological inhibition of CA-activity using specific inhibitors retards EBV induced B-cell transformation, inhibits B-cells outgrowth and colony formation ability of transformed B-lymphocytes through lowering the intracellular pH, induction of cell apoptosis and facilitating degradation of CA9 transcripts. Reanalyses of ChIP-Seq data along with utilization of EBNA2 knockout virus and sh-RNA mediated knockdown of CA9 expression we further demonstrate that EBNA2 mediated CA9 transcriptional activation is essential for EBV latently infected B-cell survival. In contrast, during lytic cycle reactivation CA9 expression is transcriptionally suppressed by the key EBV lytic cycle transactivator, BZLF1 through its transactivation domain. Overall, our study highlights the dynamic alterations of CA9 expression and its activity in regulating pH homeostasis act as one of the major drivers for EBV induced B-cell transformation and subsequent B-cell lymphomagenesis.
Poke And Delayed Drink Intertemporal Choice Task (POKE-ADDICT): an open-source behavioral apparatus for intertemporal choice testing in rodents
Authors: Moro Andrea Stefano , Saccenti Daniele , Seccia Alessia , Ferro A Mattia , Malgaroli Antonio , Lamanna Jacopo 
Published: September 2023

AbstractAdvancements in neuroscience research present opportunities and challenges, requiring substantial resources and funding. To address this, we describe here “Poke And Delayed Drink Intertemporal Choice Task (POKE-ADDICT)”, an open-source, versatile, and cost-effective apparatus for intertemporal choice testing in rodents. This allows quantification of delay discounting (DD), a cross-species phenomenon observed in decision making which provides valuable insights into higher-order cognitive functioning. In DD, the subjective value of a delayed reward is reduced as a function of the delay for its receipt. Using our apparatus, we implemented an effective intertemporal choice paradigm for the quantification of DD based on an adjusting delayed amount (ADA) algorithm using mango juice as a reward. Our paradigm requires limited training and can be directly translated to human subjects using monetary rewards. Our apparatus comprises a few 3D-printed parts and inexpensive electrical components, including a Raspberry Pi control unit. Furthermore, it is compatible with severalin vivoprocedures and the use of nose pokes instead of levers allows for faster task learning. Beside the main application described here, the apparatus can be further extended to implement other behavioral tests and protocols, including standard operant conditioning. In conclusion, we describe a versatile and cost-effective design based on Raspberry Pi that can support research in animal behavior, decision making and, more specifically, delay discounting.
Unveiling the ecology, taxonomy and metabolic capabilities of MBA03, a potential key player in anaerobic digestion
Authors: Puchol-Royo Roser , Pascual Javier , Ortega-Legarreta Asier , Otto Pascal , Tideman Jeroen , de Vries Sjoerd-Jan , Abendroth Christian , Tanner Kristie , Porcar Manuel , Latorre-Perez Adriel 
Published: September 2023

AbstractBiogas, a mix of CO2, CH4and small proportions of other gases, is a biofuel obtained by anaerobic digestion (AD). Biogas production is often considered a black box process, as the role and dynamics of some of the microorganisms involved remain undisclosed. Previous metataxonomic studies in the frame of the MICRO4BIOGAS project (www.micro4biogas.eu) revealed that MBA03, an uncharacterised and uncultured bacterial taxon, was very prevalent and abundant in industrial full-scale AD plants. Surprisingly, no culturable specimen or genome of this taxon has ever been reported, so its role in AD has remained unclear. In the present work, thirty samples derived from anaerobic digesters were sequenced, allowing the reconstruction of 108 metagenome-assembled genomes (MAGs) potentially belonging to MBA03. According to phylogenetic analyses and genomic similarity indices, MBA03 constitutes a new bacterial order, proposed asDarwinibacterialesord. nov., which includesDarwinibacter acetoxidansgen. nov., sp. nov. of the familyDarwinibacteriaceaefam. nov., along withWallacebacter crypticagen. nov., sp. nov. of theWallacebacteriaceaefam. nov. Ecotaxonomic studies determined that AD processes are the main ecological niche ofDarwinibacteriales. Moreover, metabolic predictions identifiedDarwinibacteraceaemembers as putative syntrophic acetate oxidising bacteria (SAOB), as they encode for the reversed Wood-Ljungdahl (W-L) pathway coupled to the glycine cleavage system. This suggests thatDarwinibacteraceaemembers work in collaboration with hydrogenotrophic archaea to produce methane in industrial biogas plants. Overall, our findings presentDarwinibacterialesas a potential key player in anaerobic digestion and pave the way towards the complete characterisation of this newly described bacterial taxa.
Automated workflow for BioID improves reproducibility and identification of protein-protein interactions
Authors: Cirri Emilio , Knaudt Hannah , Fraia Domenico Di , Pömpner Nadine , Rahnis Norman , Heinze Ivonne , Ori Alessandro , Dau Therese 
Published: September 2023

AbstractProximity dependent biotinylation is an important method to study protein-protein interactions in cells, for which an expanding number of applications has been proposed. The laborious and time consuming sample processing has limited project sizes so far. Here, we introduce an automated workflow on a liquid handler to process up to 96 samples at a time. The automation does not only allow higher sample numbers to be processed in parallel, but also improves reproducibility and lowers the minimal sample input. Furthermore, we combined automated sample processing with shorter liquid chromatography gradients and data-independent acquisition to increase analysis throughput and enable reproducible protein quantitation across a large number of samples. We successfully applied this workflow to optimise the detection of proteasome substrates by proximity-dependent labelling.
On Global Brain Reconfiguration after Local Manipulations
Authors: Rabuffo Giovanni , Lokossou Houefa-Armelle , Li Zengmin , Ziaee-Mehr Abolfazl , Hashemi Meysam , Quilichini Pascale P , Ghestem Antoine , Arab Ouafae , Esclapez Monique , Verma Parul , Raj Ashish , Gozzi Alessandro , Sorrentino Pierpaolo , Chuang Kai-Hsiang , Perles-Barbacaru Teodora-Adriana , Viola Angèele , Jirsa Viktor K. , Bernard Christophe 
Published: September 2023

AbstractUnderstanding how localized brain interventions translate into whole-brain dynamics is crucial for deciphering neural function and tailoring therapeutic strategies. Combining mouse experimental datasets of focal interventions (thalamic lesion and chemogenetic silencing of cortical hubs), we demonstrate both local and global effects. Using whole-brain simulations of experimental data, we not only confirm the distributed nature of local manipulations but also offer mechanistic insights into these processes. Our simulations predict specific alterations in firing rates and spectral characteristics across specific brain networks, leading to structured changes in functional connectivity patterns. Some of these predictions have been empirically validated. Notably, the affected brain subnetworks—and their resultant ‘signatures’ of change—are contingent on the original intervention site, suggesting a method to accurately localize the source of alteration. Our results provide a general framework for interpreting localized intervention effects, offering insights that could refine clinical interventions for focal brain disorders by enabling targeted circuit-level neuromodulation strategies.
Unsupervised identification of internal perceptual states influencing psychomotor performance
Authors: Vardal Ozan , Karapanagiotidis Theodoros , Stafford Tom , Drachen Anders , Wade Alex R. 
Published: September 2023

AbstractWhen humans perform repetitive tasks over long periods, their performance is not constant. People may drift in and out of states that might be loosely categorised as engagement, disengagement or ‘flow’ and these will be reflected in multiple aspects of their performance (for example, reaction time, accuracy, criteria shifts and potentially longer-term strategy) but until recently it has been challenging to relate these behavioural states to the underlying neural mechanisms that generate them. Here, we took Magnetoencephalograpy recordings of participants performing an engaging task that required rapid, strategic behavioural responses. In this way we acquired both high density neural data and contemporaneous, dense behavioural data. Specifically, participants played a laboratory version of Tetris which collects detailed recordings of player input and game-state throughout performance. We asked whether it was possible to infer the presence of distinct behavioural states from the behavioural data and, if so, whether these states would have distinct neural correlates. We used hidden Markov modelling to segment the behavioural time series into states with unique behavioural signatures, finding that we could identify three distinct and robust behavioural states. We then computed occipital alpha power across each state. These within-participant differences in alpha power were statistically significant, suggesting that individuals shift between behaviourally and neurally distinct states during complex performance, and that visuo-spatial attention change across these states.
Cohesin still drives homologous recombination repair of DNA double-strand breaks in late mitosis
Authors: Ayra-Plasencia Jessel , Symington Lorraine , Machín Félix 
Published: September 2023

AbstractThe cohesin complex maintains sister chromatid cohesion from S phase to anaphase onset. Cohesin also plays roles in chromosome structure and DNA repair. At anaphase onset, the cohesin subunit Scc1 is cleaved to allow segregation in an orderly manner, although some residual cohesin subunits remain to maintain chromosome structure. Efficient DNA double-strand break (DSB) repair by homologous recombination (HR) with the sister chromatid also depends on cohesin. Here, we have tested whether residual cohesin is important during DSB repair in anaphase/telophase (late mitosis). Using the well-established MAT switching system, we first show that HR is molecularly functional in late mitosis, and then show that cohesin is required for its efficiency. During DSBs in late mitosis, the segregated sister loci get closer and have episodes of coalescence, which may favour repair by HR. Here, we also show that these cytological phenotypes also depend on cohesin. Finally, full-length Scc1 returns after DSBs in late mitosis, suggesting thatde novowidespread cohesin complexes can support these retrograde behaviours.
Assessing cortical excitability with electroencephalography: a pilot study with EEG-iTBS
Authors: Pellegrino Giovanni , Schuler Anna-Lisa , Cai Zhengchen , Marinazzo Daniele , Tecchio Franca , Ricci Lorenzo , Tombini Mario , di Lazzaro Vincenzo , Assenza Giovanni 
Published: September 2023

AbstractCortical excitability measures neural reactivity to stimuli, usually delivered via Transcranial Magnetic Stimulation (TMS). Excitation/inhibition balance (E/I) is the ongoing equilibrium between excitatory and inhibitory activity of neural circuits. According to some studies, E/I could be estimated in-vivo and non-invasively through the modeling of electroencephalography (EEG) signals. Several measures have been proposed (phase consistency in the gamma band, sample entropy, exponent of the power spectral density 1/f curve, E/I index extracted from detrend fluctuation analysis, and alpha power). It remains to be investigated to what extent they scale with excitability and how they relate to each other. Intermittent theta burst stimulation (iTBS) of the primary motor cortex (M1) is a non-invasive neuromodulation technique allowing controlled and focal enhancement of cortical excitability and E/I of the stimulated hemisphere. M1 excitability and several E/I estimates extracted from resting state EEG recordings were assessed before and after iTBS in a cohort of healthy subjects. Enhancement of M1 excitability, as measured through motor-evoked potentials (MEPs), and phase consistency of the cortex in high gamma band correlated with each other. Other measures of E/I showed some expected results, but no correlation with TMS excitability measures or consistency with each other. EEG E/I estimates offer an intriguing opportunity to map cortical excitability non-invasively, with high spatio-temporal resolution and with a stimulus independent approach. While different EEG E/I estimates may reflect the activity of diverse excitatory-inhibitory circuits, spatial phase synchrony in the gamma band is the measure that best captures excitability changes in the primary motor cortex.
Sequential deregulation of histone marks, chromatin accessibility and gene expression in response to PROTAC-induced degradation of ASH2L
Authors: Barsoum Mirna , Sayadi-Boroujeni Roksaneh , Stenzel Alexander T. , Bussmann Philip , Lüscher-Firzlaff Juliane , Lüscher Bernhard 
Published: September 2023

AbstractThe trithorax protein ASH2L is essential for organismal and tissue development. As a subunit of COMPASS/KMT2 complexes, ASH2L is necessary for methylation of histone H3 lysine 4 (H3K4). Mono- and trimethylation at this site mark active enhancers and promoters, respectively, although the molecular relevance of H3K4 methylation is only partially understood. Due to the importance of ASH2L in all 6 COMPASS-like complexes and its long half-life, it has been difficult to define direct consequences. To overcome this limitation, we employed a PROTAC system, which allows the rapid degradation of ASH2L and addressing direct effects. Loss of ASH2L resulted in rapid inhibition of proliferation of mouse embryo fibroblasts. Shortly after ASH2L degradation, H3K4me3 decreased with its half-life revealing considerable variability between promoters. Subsequently, H3K4me1 increased at promoters and decreased at some enhancers. H3K27ac and H3K27me3, histone marks closely linked to H3K4 methylation, were affected with considerable delay. In parallel, chromatin compaction increased at promoters. Of note, nascent gene transcription was not affected early but overall RNA expression was deregulated late after ASH2L loss. Together, these findings suggest that downstream effects are ordered but relatively slow, despite the rapid loss of ASH2L and inactivation of KMT2 complexes. It appears that the systems that control gene transcription are well buffered and strong effects are only beginning to unfold after considerable delay.
Mapping the developmental potential of mouse inner ear organoids at single-cell resolution
Authors: Waldhaus Joerg , Jiang Linghua , Liu Liqian , Liu Jie , Duncan Robert Keith 
Published: September 2023

SummaryInner ear organoids recapitulate development and are intended to generate cell types of the otic lineage for applications such as basic science research and cell replacement strategies. Here, we use single-cell sequencing to study the cellular heterogeneity of late-stage mouse inner ear organoid sensory epithelia, which we validated by comparison with data sets of the mouse cochlea and vestibular epithelia. We resolved supporting cell sub-types, cochlear like hair cells, and vestibular Type I and Type II like hair cells. While cochlear like hair cells aligned best with an outer hair cell trajectory, vestibular like hair cells followed developmental trajectories similar toin vivoprograms branching into Type II and then Type I extrastriolar hair cells. These results highlight the transcriptional accuracy of the organoid developmental program but will also inform future strategies to improve synaptic connectivity and regional specification.