bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ultradian rhythms of CRHPVNneuron activity, behaviour and stress hormone secretion
Authors: Zheng Shaojie , Focke Caroline M. B. , Young Calvin K. , Tripp Isaac , Ganeshan Dharshini , Power Emmet M. , Schwenke Daryl O. , Herbison Allan E. , Kim Joon S. , Iremonger Karl J. 
Published: July 2024

AbstractThe stress axis is always active, even in the absence of any threat. This manifests as hourly pulses of corticosteroid stress hormone secretion over the day. Corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN) control both the neuroendocrine stress axis as well as stress-associated behaviours. However, it is currently unclear how the resting activity of these neurons is coordinated with both spontaneous behaviour and ultradian pulses of corticosteroid secretion. To investigate this, we performed fiber photometry recordings of CRHPVNneuron activity inCrh-Ires-Cremice and a newly generated line ofCrh-Ires-Crerats. In both mice and rats, CRHPVNneurons displayed an ultradian rhythm of activity with reoccurring upstates of activity approximately once per hour over the 24-hour day. Upstates in activity were coordinated with increases in animal activity/arousal. Chemogenetic activation of CRHPVNneurons was also sufficient to induce behavioural arousal. In rats, increases in CRH neural activity preceded some pulses of corticosteroid secretion but not others. Thus, while CRHPVNneurons display an ultradian rhythm of activity over the 24-hour day that is coordinated with behavioural arousal, the relationship between CRHPVNactivity and pulses of corticosteroid secretion is not one-to-one.Significance StatementUltradian rhythms are present in many biological systems, however, the underlying neural mechanisms responsible for generating these rhythms is unclear. Corticotropin-releasing hormone (CRH) neurons control corticosteroid levels in the body as well as arousal and behaviour. Here we show that CRH neurons exhibit a pronounced ultradian rhythm in neural activity over the 24-hour day. CRH neural activity was highly correlated with, and predictive of, behavioral arousal. However, CRH neural activity was not as well correlated with pulses of corticosteroid secretion. Together, these data revel the patterns of CRH neuron activity over the 24-hour day and their relationship with behaviour and stress hormone secretion.
Mixed recurrent connectivity architecture in primate prefrontal cortex
Authors: Sigalas Evangelos , Libedinsky Camilo 
Published: July 2024

AbstractThe functional properties of a network depend on its connectivity, which includes the strength of its inputs and the strength of the connections between its units, or recurrent connectivity. Because we lack a detailed description of the recurrent connectivity in the lateral prefrontal cortex of primates, we developed an indirect method to estimate it. This method leverages the elevated noise correlation of mutually-connected units. To estimate the connectivity of prefrontal regions, we trained recurrent neural network models with varying percentages of bump attractor architecture and noise levels to match the noise correlation properties observed in two specific prefrontal regions: the dorsolateral prefrontal cortex and the frontal eye field. We found that models initialized with approximately 20% and 7.5% bump attractor architecture closely matched the noise correlation properties of the frontal eye field and dorsolateral prefrontal cortex, respectively. These findings suggest that the different percentages of bump attractor architecture may reflect distinct functional roles of these brain regions. Specifically, lower percentages of bump attractor units, associated with higher-dimensional representations, likely support more abstract neural representations in more anterior regions.
Reversible ubiquitination of integrated domain controls paired NLR immune receptor complex homeostasis
Authors: Chen Zhiyi , Huang Jianhua , Li Jianyu , Menke Frank L.H. , Jones Jonathan D.G. , Guo Hailong 
Published: July 2024

AbstractPlant intracellular NLR immune receptors can function individually or in pairs to detect pathogen effectors and activate immune responses. NLR homeostasis has to be tightly regulated to ensure proper defense without triggering autoimmunity. However, in contrast to singleton NLRs, the mechanisms controlling the paired NLRs complex homeostasis are less understood. The paired Arabidopsis RRS1/RPS4 immune receptor complex confers disease resistance through effector recognition mediated by the integrated WRKY domain of RRS1. Here, through proximity labelling, we reveal a ubiquitination-deubiquitination cycle that controls the homeostasis of the RRS1/RPS4 complex. E3 ligase RARE directly binds and ubiquitinates RRS1’s WRKY domain to promote its proteasomal degradation, thereby destabilizing RPS4 indirectly and compromising the stability and function of the RRS1/RPS4 complex. Conversely, the deubiquitinating enzymes UBP12/UBP13 deubiquitinate RRS1’s WRKY domain, counteracting RARE’s effects. Interestingly, the abundance of WRKY transcription factors WRKY70 and WRKY41 is also regulated by RARE and UBP12/UBP13. Phylogenetic analysis suggests this regulation likely transferred from WRKY70/WRKY41 to RRS1 upon WRKY domain integration. Our findings improve our understanding of homeostatic regulation of paired NLR complex and uncover a new paradigm whereby domain integration can co-opt preexisting post-translational modification to regulate novel protein functions.
Large transient assemblies of Apaf1 constitute the apoptosome in cells
Authors: Borgeaud Alicia C. , Ganeva Iva , Klein Calvin , Stooss Amandine , Ross-Kaschitza Daniela , Wu Liyang , Riley Joel S. , Tait Stephen W.G. , Lemmin Thomas , Kaufmann Thomas , Kukulski Wanda 
Published: July 2024

AbstractUpon cell death signals, the apoptotic protease-activating factor Apaf1 and cytochrome c interact to form the apoptosome complex. The apoptosome is crucial for mitochondrial apoptosis, as it activates caspases that dismantle the cell. However, the assembly mechanism and appearance of the apoptosomein vivoremain unclear. We show that upon onset of apoptosis, Apaf1 molecules accumulate into multiple foci per cell. Disassembly of the foci is linked to survival of the cell. Structurally, Apaf1 foci resemble organelle-sized, cloud-like assemblies. Foci form upon specific molecular interactions with cytochrome c and depending on procaspase-9. We propose that Apaf1 foci correspond to the apoptosome in cells. Transientness and ultrastructure of Apaf1 foci suggest that the dynamic spatiotemporal organisation of apoptosome components regulates progression of apoptosis.
Unsilenced inhibitory cortical ensemble gates remote memory retrieval
Authors: Wang Shaoli , Sheng Tao , Su Feng , Yang He , Cao Rui , Wang Qiao , Fang Wei-Qun , Zhang Chen , Lu Wei 
Published: July 2024

AbstractAcquired information can be consolidated to remote memory for storage but persists in a dormant state until its retrieval. However, it remains unknown how dormant memory is reactivated. Using a combination of simultaneous two-photon calcium imaging and holographic optogenetics in the anterior cingulate cortex (ACC) in vivo, we discover a subset of GABAergic neurons that are specifically associated with dormant memory retrieval. These interneurons display persistent activity and inter-neuronal synchronization at the remote memory stage. In the absence of natural contextual cues, directly activating these interneurons reliably recalls cortical ensembles relevant to remote memory retrieval with context specificity. Conversely, targeted volumetric inactivation of these interneurons suppresses context-induced memory retrieval. Our results reveal an unexpected role of unsilenced inhibitory cortical ensembles in causally gating the retrievability of dormant remote memory.
Contributions of source populations, habitat suitability and trait overlap to benthic invertebrate community assembly in restored urban streams
Authors: Gillmann Svenja M. , Schuwirth Nele , Lorenz Armin W. , Hering Daniel 
Published: July 2024

AbstractCommunity development in restored streams is often slow or even absent, but reasons remain obscure. Inadequate restoration measures, catchment-scale pressures, community closure and colonization barriers all may prevent or slow down recovery processes. For initial colonization, dispersal processes are supposed to be most important, which are referred to as dispersal filter. Environmental conditions of a restored reach determine if a dispersing species can successfully establish (environmental filter). Lastly, while available niches at those reaches fill up, biotic interactions, such as competition, become more important (biotic filter). To investigate the importance of these different filters, we compared benthic invertebrate communities of 20 sites in the Boye catchment (Western Germany), a former open sewer system. The sites were grouped, based on the years since restoration, into ‘unimpacted’ (never restored), ‘recently restored’ (< 4 years) and ‘mature restored’ (> 10 years) sites. Data collected at 28 additional sites in the catchment informed us on distances to potential source populations. Habitat suitability describes the fit between environmental conditions (abiotic site data) and species preferences and was used to assess the role of environmental filtering. We evaluated the role of the biotic filter based on trait overlap, referring to possible interspecific competition.Communities collected at recently restored sites differed from those of mature restored and unimpacted sites. Taxa present at recently restored and mature sites had closer source populations than those of unimpacted sites. Taxa at mature and unimpacted sites had a better fit to the present habitats than those of recently restored sites. The trait overlap did not differ between co-occurring and not co-occurring taxa at any of the site groups. Our findings show that communities of mature restored sites that have been restored more than 10 years ago, resembled those of unimpacted sites. Dispersal was most important in early years of recovery. Taxa occurrences at sites with nearby source populations and low habitat suitability are likely the result of high rates of dispersal from upstream sources (mass effects). These can be caused by hatching events or environmental disturbances. Habitat suitability played a larger role for communities at mature and unimpacted sites which indicates that optimal communities shape over time. We did not find indications that competition played a role for community assembly. Hence, dispersal and habitat suitability were most relevant for species’ occurrences. Competition could be more important on micro scales and the results may differ if species abundances are taken into account.Graphical Abstract
Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease
Authors: Yang Jian-Ping , Toughiri Rachel , Gounder Anshu P. , Scheibe Dan , Petrus Matt , Fink Sarah J. , Vallee Sebastien , Kenniston Jon , Papaioannou Nikolaos , Langston Steve , Gavva Narender R. , Horman Shane R. 
Published: July 2024

AbstractInduction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other β-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenousHBG1gene locus, which codes for γ-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics of sickle cell disease and other β-hemoglobinopathies.Key PointsEstablished a robust HbF luciferase reporter cell line to monitor endogenous γ-globin expression for a chemogenomic screen of compounds for the treatment of sickle cell disease.Lead hit compounds were mechanistically confirmed for their ability to decrease expression of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1.Visual Abstract
Connexin 43 drives glioblastoma cancer stem cell phenotypes through a WNK lysine-deficient protein kinase 1-c-MYC signaling axis
Authors: Mulkearns-Hubert Erin E. , Hajdari Nicole , Hong Ellen S. , Jacobs Ashley P. , Kay Kristen E. , Wang Sabrina Z. , Silver Daniel J. , Hubert Christopher G. , Lathia Justin D. 
Published: July 2024

SummaryThe coordination of cellular processes such as growth and survival relies on communication between cells through gap junctions. Gap junction intercellular communication is driven by connexin proteins, which also mediate protein-protein interactions and communication with the extracellular space via hemichannels. Despite their essential roles, connexin function in cancer is context dependent, with connexin 43 (Cx43) reported to both promote and suppress tumor growth in glioblastoma, the most common primary malignant brain tumor. Here, we detect expression of Cx43 in glioblastoma patient-derived cancer stem cells and demonstrate that Cx43 is essential for their survival and self-renewal. Mechanistically, depletion of Cx43 reduces c-MYC expression through reduced levels of the upstream mediator WNK lysine-deficient protein kinase 1 (WNK1). Depletion of WNK1 phenocopies Cx43 knockdown and reduces MYC expression and tumor growth. Together, these results define a novel signaling axis downstream of Cx43 that promotes tumor growth and cancer stem cell phenotypes in glioblastoma.
Microglia Morphological Response to Mesenchymal Stromal Cell Extracellular Vesicles Demonstrates EV Therapeutic Potential for Modulating Neuroinflammation
Authors: Daga Kanupriya R. , Larey Andrew M. , Morfin Maria G. , Chen Kailin , Bitarafan Sara , Carpenter Jana M. , Hynds Hannah M. , Hines Kelly M. , Wood Levi B. , Marklein Ross A. 
Published: July 2024

ABSTRACTBackgroundMesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.g. morphology and secretion. However, these changes in response to MSC-EVs are not well understood. Additionally, no disease-relevant screening tools to assess MSC-EV bioactivity exist, which has further impeded clinical translation. Here, we developed a quantitative, high throughput morphological profiling approach to assess the response of microglia to neuroinflammation-relevant signals and whether this morphological response can be used to indicate the bioactivity of MSC-EVs.ResultsUsing an immortalized human microglia cell-line, we observed increased size (perimeter, major axis length) and complexity (form factor) upon stimulation with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Upon treatment with MSC-EVs, the overall morphological score (determined using principal component analysis) shifted towards the unstimulated morphology, indicating that MSC-EVs are bioactive and modulate microglia. The morphological effects of MSC-EVs in TNF-γ/IFN-α stimulated cells were concomitant with reduced secretion of 14 chemokines/cytokines (e.g. CXCL6, CXCL9) and increased secretion of 12 chemokines/cytokines (e.g. CXCL8, CXCL10). Proteomic analysis of cell lysates revealed significant increases in 192 proteins (e.g. HIBADH, MEAK7, LAMC1) and decreases in 257 proteins (e.g. PTEN, TOM1, MFF) with MSC-EV treatment. Of note, many of these proteins are involved in regulation of cell morphology and migration. Gene Set Variation Analysis revealed upregulation of pathways associated with immune response, such as regulation of cytokine production, immune cell infiltration (e.g. T cells, NK cells) and morphological changes (e.g. Semaphorin, RHO/Rac signaling). Additionally, changes in microglia mitochondrial morphology were measured suggesting that MSC-EV modulate mitochondrial metabolism.ConclusionThis study comprehensively demonstrates the effects of MSC-EVs on human microglial morphology, cytokine secretion, cellular proteome, and mitochondrial content. Our high-throughput, rapid, low-cost morphological approach enables screening of MSC-EV batches and manufacturing conditions to enhance EV function and mitigate EV functional heterogeneity in a disease relevant manner. This approach is highly generalizable and can be further adapted and refined based on selection of the disease-relevant signal, target cell, and therapeutic product.
Mobile Integrons Encode Phage Defense Systems
Authors: Kieffer Nicolas , Hipólito Alberto , Ortiz-Miravalles Laura , Blanco Paula , Delobelle Thomas , Vizuete Patricia , Ojeda Francisco Manuel , Jové Thomas , Jurenas Dukas , García-Quintanilla Meritxell , Carvalho André , Domingo-Calap Pilar , Escudero José Antonio 
Published: July 2024

AbstractIntegrons are bacterial genetic elements that capture, stockpile and modulate the expression of genes encoded in integron cassettes. Mobile Integrons (MI) are borne on plasmids, acting as a vehicle for hundreds of antimicrobial resistance genes among key pathogens. These elements also carrygenecassettes ofunknown function (gcus) whose role and adaptive value remains unexplored. Here we show thatgcus encode phage resistance systems, many of which are novel.Bacteriophageresistanceintegroncassettes (BRiCs) can be combined and mixed with resistance cassettes to produce multiphage or drug/phage-resistance. The fitness costs of BRiCs are variable, dependent on the genetic context, and can be modulated by changing the order of cassettes in the array. Hence, MIs act as highly mobile, low-cost defense islands.Abstract FigureSummary FigureNovel phage defense systems identified in Mobile Integrons.We confronted genes of unknown function from mobile integrons against a panel of phage. We characterized 13 Bacteriophage Resistance integron Cassettes (BRiCs) and confirmed their function inKlebsiella pneumoniaeandPseudomonas aeruginosa. Combined with other cassettes, BRiCs produce multi-phage/antibiotic resistance. Additionally, their cost can be reduced in an array.
Sexual and Reproductive Health Needs of Women with Severe Mental Illness in Low- and Middle-Income Countries: A Scoping Review
Authors: Sisodia Shilpa , Hammond Zara , Leonardi-Bee Jo , Hanlon Charlotte , Asher Laura 
Published: July 2024

AbstractBackgroundThis scoping review aimed to understand the extent and type of evidence in relation to sexual and reproductive health needs of women with severe mental illness (SMI) in low-and middle-income countries (LMIC) and to summarise those needs.MethodsInclusion criteria were 1) focus on sexual and reproductive health needs 2) women or girls with SMI, professionals, caregivers of women with SMI and community members 3) study set in a LMIC 4) peer reviewed literature (no restriction on study date or design). Studies were identified from comprehensive searches of Medline, EMBASE, CINAHL and PsycINFO (to July 2023).ResultsThe review included 100 papers. Most studies were cross-sectional and set in hospital outpatient departments. We identified studies in only 19 of 140 LMIC countries and only 15 studies were set-in low-income countries. Included studies often had multiple focus areas which were grouped into themes of HIV (prevalence, risk behaviour and knowledge), other sexually transmitted infections (STIs), sexual function, contraception use and family planning, sexual violence, fertility, pregnancy and postpartum.Included studies indicated women with SMI have worse outcomes and worse sexual and reproductive health compared to both women without SMI and men with SMI. Women with SMI were shown to have higher rates of HIV and low levels of contraception knowledge and use, with little advice offered by professionals.ConclusionsThis review highlights the need for a greater diversity of study methodology, robustness of ethical and consensual reporting when researching vulnerable populations and for further research on interventions and models of care aimed at addressing stigma, discrimination and improving the sexual and reproductive health of women with SMI. Future research should better represent the breadth of LMIC, investigate cultural adaptability of interventions and consider sexual health needs across the life course.
PT
-symmetry-enabled stable modes in a multicore fiber
Authors: Gratcheva Tamara , Joglekar Yogesh N. , Gopalakrishnan Jay 
Published: July 2024

Open systems with balanced gain and loss, described by parity-time (PT-symmetric) Hamiltonians have been deeply explored over the past decade. Most explorations are limited to finite discrete models (in real or reciprocal spaces) or continuum problems in one dimension. As a result, these models do not leverage the complexity and variability of two-dimensional continuum problems on a compact support. Here, we investigate eigenvalues of the Schrödinger equation on a disk with zero boundary condition, in the presence of constant, PT-symmetric, gain-loss potential that is confined to two mirror-symmetric disks. We find a rich variety of exceptional points, re-entrant PT-symmetric phases, and a nonmonotonic dependence of the PT-symmetry breaking threshold on the system parameters. By comparing results of two model variations, we show that this simple model of a multicore fiber supports propagating modes in the presence of gain and loss.

Published by the American Physical Society
2024