bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth in early infancy drives optimal brain functional connectivity which predicts cognitive flexibility in later childhood
Authors: Bulgarelli Chiara , Blasi Anna , McCann Samantha , Milosavljevic Bosiljka , Ghillia Giulia , Mbye Ebrima , Touray Ebou , Fadera Tijan , Acolatse Lena , Moore Sophie E. , Lloyd-Fox Sarah , Elwell Clare E. , Eggebrecht Adam T. ,   the BRIGHT Study Team
Published: January 2024

AbstractFunctional brain network organization, measured by functional connectivity (FC), reflects key neurodevelopmental processes for healthy development. Early exposure to adversity, e.g. undernutrition, affects neurodevelopment, observable via disrupted FC, and leads to poorer outcomes from preschool age onward. We assessed longitudinally the impact of early growth trajectories on developmental FC in a rural Gambian population from age 5 to 24 months. To investigate how these early trajectories relate to later childhood outcomes, we assessed cognitive flexibility at 3-5 years. We observed that early physical growth before the fifth month of life drove optimal developmental trajectories of FC that in turn predicted cognitive flexibility at pre-school age. In contrast to previously studied developmental populations, this Gambian sample exhibited long-range interhemispheric FC that decreased with age. Our results highlight the measurable effects that poor growth in early infancy has on brain development and the subsequent impact on pre-school age cognitive development, underscoring the need for early life interventions throughout global settings of adversity.
Editing of endogenous tubulins reveals varying effects of tubulin posttranslational modifications on axonal growth and regeneration
Authors: Lu Yu-Ming , Yan Shan , Ti Shih-Chieh , Zheng Chaogu 
Published: January 2024

AbstractTubulin posttranslational modifications (PTMs) modulate the dynamic properties of microtubules and their interactions with other proteins. However, the effects of tubulin PTMs were often revealed indirectly through the deletion of modifying enzymes or the overexpression of tubulin mutants. In this study, we directly edited the endogenous tubulin loci to install PTM-mimicking or -disabling mutations and studied their effects on microtubule stability, neurite outgrowth, axonal regeneration, cargo transport, and sensory functions in the touch receptor neurons ofCaenorhabditis elegans. We found that the status of β-tubulin S172 phosphorylation and K252 acetylation strongly affected microtubule dynamics, neurite growth, and regeneration, whereas α-tubulin K40 acetylation had little influence. Polyglutamylation and detyrosination in the tubulin C-terminal tail had more subtle effects on microtubule stability likely by modulating the interaction with kinesin-13. Overall, our study systematically assessed and compared several tubulin PTMs for their impacts on neuronal differentiation and regeneration and established anin vivoplatform to test the function of tubulin PTMs in neurons.
Translational repression ofNox4mRNA via the EI24-RTRAF interaction is crucial for hydrogen peroxide homeostasis and insulin synthesis
Authors: Pei Xintong , Wang Zhe , He Wenting , Li Shunqin , Lan Yongguang , Yuan Lin , Xu Pingyong 
Published: January 2024

AbstractAs a double-edged sword, the content of reactive oxygen species (ROS) is precisely controlled. Disordered actions of ROS contribute to deleterious effects, such as cancer and metabolic dysregulation associated with aging and obesity. Although it is well established that cells have developed evolutionarily conserved programs to sense and adapt to redox fluctuations, it remains unclear how to control the expression of key ROS-producing enzymes to regulate continued ROS production at healthy levels for cells such as neurons and pancreatic beta cells. These cells have weaker antioxidant defense systems but strong secretion ability. Here, we found that the endoplasmic reticulum membrane-localized protein, EI24, controls the translation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), which constitutively produces hydrogen peroxide (H2O2), by recruiting an RNA transcription, translation, and transport factor (RTRAF) to the 3’-UTRs ofNox4. Depletion of EI24 causes RTRAF to relocate into the nucleus, releasing the brake onNox4mRNA translation, and thus, the uncontrolled translation ofNox4leads to a substantial generation of intracellular H2O2. This suppresses the translation of V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), inhibits its binding to theIns2gene promoter, and ultimately hinders insulin transcription. Treatment with a specific NOX4 inhibitor or the antioxidant N-acetyl-cysteine (NAC) restoredMafAtranslation and downstream insulin synthesis while alleviating the diabetic symptoms in pancreatic beta-cell specificEi24-KO mice. In summary, our study revealed a molecular mechanism that controls the expression of NOX4, a key enzyme responsible for continuous ROS generation. This mechanism ensures low levels of H2O2and normal biological functions under physiological conditions.
Dominant negative mutations in yeast Hsp90 reveal triage decision mechanism targeting client proteins for degradation
Authors: Flynn Julia M. , Joyce Margot E. , Bolon Daniel N. A. 
Published: January 2024

AbstractMost of the fundamental processes of cells are mediated by proteins. However, the biologically-relevant mechanism of most proteins are poorly understood. Dominant negative mutations have provided a valuable tool for investigating protein mechanisms but can be difficult to isolate because of their toxic effects. We used a mutational scanning approach to identify dominant negative mutations in yeast Hsp90. Hsp90 is a chaperone that forms dynamic complexes with many co-chaperones and client proteins. In vitro analyses have elucidated some key biochemical states and structures of Hsp90, co-chaperones, and clients; however, the biological mechanism of Hsp90 remains unclear. For example, high throughput studies have found that many E3 ubiquitin ligases bind to Hsp90, but it is unclear if these are primarily clients or acting to tag other clients for degradation. We introduced a library of all point mutations in the ATPase domain of Hsp90 into yeast and noticed that 176 were more than 10-fold depleted at the earliest point that we could analyze. There were two hot spot regions of the depleted mutations that were located at the hinges of a loop that closes over ATP. We quantified the dominant negative growth effects of mutations in the hinge regions using a library of mutations driven by an inducible promoter. We analyzed individual dominant negative mutations in detail and found that addition of the E33A mutation that prevents ATP hydrolysis by Hsp90 abrogated the dominant negative phenotype. Pull-down experiments did not reveal any stable binding partners, indicating that the dominant effects were mediated by dynamic complexes. DN Hsp90 decreased the expression level of two model Hsp90 clients, glucocorticoid receptor (GR) and v-src kinase. Using MG132, we found that GR was rapidly destabilized in a proteasome-dependent fashion. These findings provide evidence that the binding of E3 ligases to Hsp90 may serve a quality control function fundamental to eukaryotes.
Long range projections of oxytocin neurons in the marmoset brain
Authors: Lefevre Arthur , Meza Jazlynn , Miller Cory T. 
Published: January 2024

AbstractThe neurohormone oxytocin (OT) has become a major target for the development of novel therapeutic strategies to treat psychiatric disorders such as autism spectrum disorder because of its integral role in governing many facets of mammalian social behavior. Whereas extensive work in rodents has produced much of our knowledge of OT, we lack basic information about its neurobiology in primates making it difficult to interpret the limited effects that OT manipulations have had in human patients. In fact, previous studies have revealed only limited OT fibers in primate brains. Here, we investigated the OT connectome in marmoset using immunohistochemistry, and mapped OT fibers throughout the brains of adult male and female marmoset monkeys. We found extensive OT projections reaching limbic and cortical areas that are involved in the regulation of social behaviors, such as the amygdala, the medial prefrontal cortex and the basal ganglia. The pattern of OT fibers observed in marmosets is notably similar to the OT connectomes described in rodents. Our findings here contrast with previous results by demonstrating a broad distribution of OT throughout the marmoset brain. Given the prevalence of this neurohormone in the primate brain, methods developed in rodents to manipulate endogenous OT are likely to be applicable in marmosets.
An opponent striatal circuit for distributional reinforcement learning
Authors: Lowet Adam S. , Zheng Qiao , Meng Melissa , Matias Sara , Drugowitsch Jan , Uchida Naoshige 
Published: January 2024

AbstractMachine learning research has achieved large performance gains on a wide range of tasks by expanding the learning target from mean rewards to entire probability distributions of rewards — an approach known as distributional reinforcement learning (RL)1. The mesolimbic dopamine system is thought to underlie RL in the mammalian brain by updating a representation of mean value in the striatum2,3, but little is known about whether, where, and how neurons in this circuit encode information about higher-order moments of reward distributions4. To fill this gap, we used high-density probes (Neuropixels) to acutely record striatal activity from well-trained, water-restricted mice performing a classical conditioning task in which reward mean, reward variance, and stimulus identity were independently manipulated. In contrast to traditional RL accounts, we found robust evidence for abstract encoding of variance in the striatum. Remarkably, chronic ablation of dopamine inputs disorganized these distributional representations in the striatum without interfering with mean value coding. Two-photon calcium imaging and optogenetics revealed that the two major classes of striatal medium spiny neurons — D1 and D2 MSNs — contributed to this code by preferentially encoding the right and left tails of the reward distribution, respectively. We synthesize these findings into a new model of the striatum and mesolimbic dopamine that harnesses the opponency between D1 and D2 MSNs5–15to reap the computational benefits of distributional RL.
Single-cell RNA-seq analysis profiling characterizes differences in cell composition and physiology between normal tissue, treatment naive, and cisplatin-treated ovarian cancer
Authors: Guo Fang , Yang Zhi , Sehouli Jalid , Kaufmann Andreas M. 
Published: January 2024

AbstractBackgroundIntense efforts have focused on identifying heterogeneity of the cellular composition in ovarian cancer. However, tissue composition and physiological conditions of cancer cells in cisplatin-sensitive ovarian cancer remains largely unknown. Moreover, comparisons of different cellular states in normal tissue, in treatment naive ovarian cancer, and in cisplatin-treated tissue after adjuvant therapy of cisplatin-sensitive ovarian cancer at the single-cell level might offer clues for ovarian cancer treatment and prevention of cisplatin-resistance formation.MethodsSingle-cell transcriptome sequencing of a cisplatin-treated ovarian cancer was performed. Data sets of non-tumorous ovarian tissues and treatment-naive ovarian cancer were downloaded from the European Genome-phenome Archive (accession number EGAS00001004987). Quality control, batch effect correction, integration, and clustering analysis of the integrated single-cell transcriptome data was done. Cell subsets were annotated based on surface marker phenotypes. Finally, the proportions of subclusters, the immune cell population, and the potential biological processes among different cellular states were compared.ResultsSixteen distinct cell subsets were identified from the integrated single-cell transcriptome sequencing data of a pool of all tissues. The composition of the three different tissue types was characterized. The proportion of fibroblasts in cisplatin-treated ovarian tumor was remarkably lower than in treatment-naive ovarian tumor (1.33% vs. 13.53%, p < 0.05). Moreover, each subject’s sample had differing relative proportions of the identified cell types. In primary untreated ovarian cancer, the prevalent immune cells were B cells and myeloid-related immunosuppressive M2 macrophages. However, there were less B cells and myeloid-related immunosuppressive M2 macrophages after cisplatin-treatment, while significantly more T cells were found. The physiological cellular state in primary untreated ovarian tumors was associated with dysfunctional gene expression and modulation of cellular homeostasis, while cells from cisplatin-treated tumor showed more activation of immune and inflammatory genes as compared to healthy ovarian tissue.ConclusionOur molecular gene expression analysis allowed for the separation and identification of differences in normal ovarian tissues, treatment-naive, and cisplatin-sensitive ovarian cancer cell populations at single-cell resolution. We identified different cell type composition and discriminative marker expression concerning specific cell subsets and identified differences among their physiological cell states. This knowledge may open new possibilities for elucidating important pathogenetic features and therapeutic strategies for treating ovarian cancer.
Inhibiting YAP1 reduced abdominal aortic aneurysm formation by suppressing adventitial fibroblast phenotype transformation and migration
Authors: Xie Cuiping , Hu Yanting , Yin Zhehui , Xie Cuiping 
Published: January 2024

AbstractBACKGROUNDThe adventitial fibroblast (AF) is the most abundant cell in the vascular adventitia, a few studies had confirmed that AF contributed to abdominal aortic aneurysm (AAA) development; YAP1 involved in several vascular diseases by promoting AF transformed to myofibroblast, the role of YAP1 in AAA is not clear yet. This study aims to determine whether YAP1 play a role in AAA process by regulating AF function.METHODSElastase-induced and Cacl2-induced mice AAA model were used in this study, we applied YAP1 inhibitor-Verteporfinin vivoto explore the role of YAP1 in AAA information;in vitro, Verteporfin and YAP1-siRNA were used to intervened TGF-β1 induced fibroblasts phenotype transformation and migration model.RESULTSAt first, we use immunohistochemistry (IHC) and western blotting (WB) to compare the expression of YAP1 in aneurysm tissues of AAA patients with normal adjacent vascular tissues, we found that the expression of YAP1 in AAA tissues was significantly increased, and YAP1 mainly increased in adventitia. YAP1 also upregulated in elastase-induced and Cacl2-induced mice AAA model. Then, we diminished YAP1 function with YAP1 inhibitor-Verteporfin in above mice AAA model, AAA incident rate was remarkably declined, and the collagen deposition in the adventitia was alleviated obviously. Afterwards, we studied the effect of YAP1 on the function of AF, we found that the process of AF transforming to myofibroblast and migration were almost completely eliminated after inhibiting YAP1 expression.CONCLUSIONSThis study demonstrated that YAP1 may play a key role in AAA development, inhibiting YAP1 significantly reduced AAA formation through suppressed the process of AF transformed to myofibroblast and migration.
SYNTERUPTOR: mining genomic islands for non-classical specialised metabolite gene clusters
Authors: Haas Drago , Barba Matthieu , Vicente Cláudia M. , Nezbedová Šarká , Garénaux Amélie , Bury-Moné Stéphanie , Lorenzi Jean-Noël , Hôtel Laurence , Laureti Luisa , Thibessard Annabelle , Goff Géraldine Le , Ouazzani Jamal , Leblond Pierre , Aigle Bertrand , Pernodet Jean-Luc , Lespinet Olivier , Lautru Sylvie 
Published: January 2024

ABSTRACTMicrobial specialised metabolite biosynthetic gene clusters (SMBGCs) are a formidable source of natural products of pharmaceutical interest. With the multiplication of genomic data available, very efficient bioinformatic tools for automatic SMBGC detection have been developed. Nevertheless, most of these tools identify SMBGCs based on sequence similarity with enzymes typically involved in specialised metabolism and thus may miss SMBGCs coding for under characterised enzymes. Here we present SYNTERUPTOR (https://bioi2.i2bc.paris-saclay.fr/synteruptor), a program that identifies genomic islands, known to be enriched in SMBGCs, in the genomes of closely related species. With this tool, we identified a SMBGC in the genome ofStreptomyces ambofaciensATCC23877, undetected by earlier versions of antiSMASH, and experimentally demonstrated that it directs the biosynthesis of two metabolites, one of which was identified as sphydrofuran. SYNTERUPTOR is also a valuable resource for the delineation of individual SMBGCs within antiSMASH regions that may encompass multiple clusters, and for refining the boundaries of these SMBGCs.
Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity
Authors: Santollani Luciano , Zhang Yiming J. , Maiorino Laura , Palmeri Joseph R. , Stinson Jordan A. , Duhamel Lauren R. , Qureshi Kashif , Suggs Jack R. , Porth Owen T. , Pinney William , Msari Riyam Al , Dane Wittrup K. , Irvine Darrell J. 
Published: January 2024

AbstractCytokine therapies are potent immunotherapy agents but exhibit severe dose-limiting toxicities. One strategy to overcome this involves engineering cytokines for intratumoral retention following local delivery. Here, we develop a localized cytokine therapy that elicits profound anti-tumor immunity by engineered targeting to the ubiquitous leukocyte receptor CD45. We designed CD45-targeted immunocytokines (αCD45-Cyt) that, upon injection, decorated the surface of leukocytes in the tumor and tumor-draining lymph node (TDLN) without systemic exposure. αCD45-Cyt therapy eradicated both directly treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models. Mechanistically, αCD45-Cyt triggered prolonged pSTAT signaling and reprogrammed tumor-specific CD8+T cells in the TDLN to exhibit an anti-viral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.
Environmental biofilms versus POCIS: efficiency to highlight environmental presence of pharmaceuticals and their effect on biofilm microbiome
Authors: Chonova Teofana , Bouchez Agnès , Mondamert Leslie , Aubertheau Elodie , Labanowski Jérôme 
Published: January 2024

AbstractPharmaceutical compounds (PhC) are an important environmental issue, because of their high variety, potentially toxic byproducts and bioactivity at low concentrations. PhC concentrations in WWTP effluents often exhibit large and rapid variations that are difficult to record. Passive samplers are helpful to incorporate spot pollution events and register PhC occurrence at low concentrations.In this work, we aim at (i) studying PhC accumulation in polar organic chemical integrative samplers (POCIS) and environmental biofilms exposed to urban (U) and hospital (H) treated effluents and (ii) evaluating the capacity of POCIS to predict changes in biofilm microbiome over a defined time period. Moreover, we (iii) determine the enrichment of PhC in the recipient river to evaluate levels of environmental contamination and potential effects on microbial biofilms. Biofilms and POCIS were installed in treated effluents and in the recipient river to measure the accumulation of PhC. In parallel, microbial biofilm communities were studied using DNA metabarcoding. The duration of each deployment was one month and the experiment was repeated six times. The performance of POCIS and biofilms to quantify PhC was depending on the compound. POCIS appeared well adapted to reveal contamination trends similar to these in the water column and to identify key PhC drivers of microbial changes. POCIS have the potential to predict pharmaceutical effects on biofilm community structure.
Enzymatic modulation of the pulmonary glycocalyx alters susceptibility toStreptococcus pneumoniae
Authors: Goekeri Cengiz , Linke Kerstin A.K. , Hoffmann Karen , Lopez-Rodriguez Elena , Gluhovic Vladimir , Voß Anne , Kunder Sandra , Zappe Andreas , Timm Sara , Nettesheim Alina , Schickinger Sebastian M.K. , Zobel Christian M. , Pagel Kevin , Gruber Achim D. , Ochs Matthias , Witzenrath Martin , Nouailles Geraldine 
Published: January 2024

ABSTRACTThe pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the precise role of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice withStreptococcus pneumoniaein the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma levels of pro-inflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage and pulmonary inflammation in mice infected withStreptococcus pneumoniae. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier. Notably, enzymatic pre-treatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococcal-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in controlling pneumococcal virulence, pulmonary inflammation, and epithelial barrier function.