bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anhedonic behaviour in a TLR7-driven neuroinflammation mouse model is associated with impaired thalamostriatal signalling and immune cell ingress into the brain
Authors: Sharma Deepika , Andrianova Lilya , McGonigal Rhona , Gardner-Stephen Kirstyn , al Fadhel Hassan , Barrie Jennifer A , Hohne Richard , Saathoff Megan , Karabalci Yaprak , Bourgognon Julie-Myrtille , Cole John J , Craig Michael T , Cavanagh Jonathan T 
Published: June 2024

AbstractDepression is a heterogenous condition driven by multiple aetiologies, which make its pathophysiology challenging to map. Stratifying depression by underlying biological causes may allow for more effective, targeted treatments. Immune-mediated inflammation is present in around 20% of individuals with depression and provides a potential mechanistic pathway for some key symptoms such as reward / hedonic impairment. Here we used a non-invasive model of neuroinflammation, topical application of Aldara (a TLR7/8 agonist) for 3 days in mice, to explore relationships between the intracerebral immune response, neural circuitry and behaviours closely linked to depression: motivation, reward and anxiety.Mice that were treated with Aldara exhibited anhedonia-like behaviour and impairments in intrinsic motivational behaviours (measured through assays such as sucrose preference and nest-building tests) relative to untreated controls, but displayed little anxiety-like behaviour. Aldara-driven neuroinflammation was associated with evidence of immune cell (including lymphoid and myeloid cells) ingression into the brain, and both microglia and astrocytes showed evidence of activation. Within 4 to 6 hours of Aldara treatment, neurons in midline thalamus showed strongly increased Fos immunoreactivity relative to controls. Optogenetic activation of midline thalamic projections onto ventral striatum medium spiny neurons (MSNs) revealed that Aldara treatment substantially reduced the magnitude of the evoked thalamic AMPA receptor-mediated EPSC, but with no change to the AMPA/NMDA ratio nor change in the frequency of amplitude of spontaneous EPSP. Finally, whole brain transcriptome overrepresentation analysis revealed that Aldara treatment led to significant upregulation of genes associated with immune response and downregulation of genes associated with glutamate metabolism and synaptic transmission.Altogether, our data suggest potential, testable mechanisms through which neuroinflammation can drive anhedonic-like behaviour through activation of resident neural cells, infiltrating activated immune cells and functional changes in thalamostriatal circuitry consistent with increased extrasynaptic glutamate.
Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation
Authors: Heinbockel Hendrik , Leicht Gregor , Wagner Anthony D. , Schwabe Lars 
Published: June 2024

AbstractWhen retrieved, seemingly stable memories can become sensitive to significant events, such as acute stress. The mechanisms underlying these memory dynamics remain poorly understood. Here we show that noradrenergic stimulation after memory retrieval impairs subsequent remembering, depending on hippocampal and cortical signals emerging during retrieval. In a three-day study, we measured brain activity using fMRI during initial encoding, 24h-delayed memory cueing followed by pharmacological elevations of glucocorticoid or noradrenergic activity, and final recall. While post-retrieval glucocorticoids did not affect subsequent memory, the impairing effect of noradrenergic arousal on final recall depended on hippocampal reactivation and category-level reinstatement in ventral temporal cortex during memory cueing. These effects did not require a reactivation of the original memory trace and did not interact with offline reinstatement during rest. Our findings demonstrate that, depending on the retrieval-related neural reactivation of memories, noradrenergic arousal after retrieval can alter the future accessibility of consolidated memories.
A small RNA derived from the 5’ end of the IS200tnpAtranscript regulates multiple virulence regulons inSalmonellaTyphimurium
Authors: Trussler Ryan S. , Scherba Naomi-Jean Q. , Ellis Michael J. , Förstner Konrad U. , Albert Matthew , Westermann Alexander J. , Haniford David B. 
Published: June 2024

AbstractThe insertion sequence IS200 is widely distributed in Eubacteria. Despite its wide-ranging occurrence, IS200 does not appear to be mobile and as such is considered an ancestral component of bacterial genomes. Previous work inSalmonella entericarevealed that the IS200tnpAtranscript is processed to form a small highly structured RNA (5’tnpA) that participates in the post-transcriptional control ofinvFexpression, encoding a key transcription factor in this enteropathogen’s invasion regulon. To further examine the scope of5’tnpAtranscript integration intoSalmonellagene expression networks, we performed comparative RNA-seq revealing the differential expression of over 200 genes in aSalmonellaSL13445’tnpAdisruption strain. This includes the genes for the master regulators of both invasion and flagellar regulons (HilD and FlhDC, respectively), plus genes involved in cysteine biosynthesis (cysteine regulon) and an operon (phsABC) encoding a thiosulfate reductase complex. These expression changes were accompanied by an 80-fold increase inSalmonellainvasion of HeLa cells. Likewise, aphsABCdisruption strain was associated with an increased invasion specifically under anaerobic growth conditions. Based on these findings, we propose that early induction of invasion and motility regulons in the absence of5’tnpAcauses a metabolic stress resulting in cysteine limitation and activation of CysB, which turns down expression of thephsABCoperon to increase the flux of thiosulfate in the media towards cysteine production. Taken together, this study provides a powerful new example of bacterial transposon domestication that is based not on the production of a regulatory protein, but of a transposon-derived small RNA.
Inhibition of SF3B1 affects recruitment of P-TEFb to chromatin through multiple mechanisms
Authors: Ansa Gilbert , Murphy Shona , Tellier Michael 
Published: June 2024

ABSTRACTProcessing of nascent pre-mRNAs is tightly coupled to transcription by RNA polymerase II (RNAPII) through reversible phosphorylation of the polymerase and associated factors by transcriptional kinases. P-TEFb, comprising cyclin-dependent kinase (CDK)9 and cyclin T1, is a key transcription elongation kinase, which also regulates co-transcriptional splicing and mRNA cleavage and polyadenylation. Chemical inhibition of SF3B1, a component of the splicing factor U2 snRNP, decreases P-TEFb recruitment to chromatin and mirrors the effect of P-TEFb inhibition on transcription. However, the mechanism of this effect of SF3B1 inhibitors was unclear. Here we show that SF3B1 inhibition causes rapid nuclear export of P-TEFb and loss of SF3B1 phosphorylation. SF3B1 is in complex with P-TEFb on chromatin with the elongation/splicing factor HTATSF1 and the splicing factor SNW1. SF3B1 inhibition causes the nuclear export of SNW1, but not of HTATSF1. The chromatin association of AFF4, an interaction partner of P-TEFb, is also affected by SF3B1 inhibition. Surprisingly, SF3B1 inhibition promotes degradation of SRSF2, a splicing factor known to help recruit P-TEFb to chromatin. Our results indicate that SF3B1 inhibition affects P-TEFb recruitment to genes via multiple pathways. Together, these interactions ensure efficient coupling of transcription and splicing.
Beyond Histones: Unveiling the Functional Roles of Protein Acetylation in Prokaryotes and Eukaryotes
Authors: Sousa Bonifácio Bruno , Barbosa Leite Ariely , de Castro Nascimento Sousa Ana Caroline , Rodrigues Maran Suellen , Severo Gomes Antoniel Augusto , Vasconcelos Elton J. R. , Silvio Moretti Nilmar 
Published: June 2024

ABSTRACTLysine acetylation plays a crucial role in cellular processes and is found across various evolutionary organisms. Recent advancements in proteomic techniques revealed the presence of acetylation in thousands of non-histone proteins. Here, we conducted extensive meta-analysis of 48 acetylomes spanning diverse organisms, including archaea, bacteria, fungi, protozoa, worms, plants, insects, crustacea, fish, and mammals. Our analyzes revealed a predominance of a single acetylation site in a protein detected in all studied organisms, and proteins heavily acetylated, with >5-10 acetylated-sites, were represented by Hsp70, histone or transcription GTP-biding domain. Moreover, using gene enrichment approaches we found that ATP metabolic processes, glycolysis, aminoacyl-tRNA synthetase pathways and oxidative stress response are among the most acetylated cellular processes. Finally, to better explore the regulatory function of acetylation in glycolysis and oxidative stress we used aldolase and superoxide dismutase A (SODA) enzymes as model. For aldolase, we found that K147 acetylation, responsible to regulate human enzyme, conserved in all phylogenic clade, suggesting that this acetylation might play the same role in other species; while for SODA, we identified many lysine residues in different species present in the tunnel region, which was demonstrated for human andTrypanosoma cruzi,as negative regulator, also suggesting a conserved regulatory mechanism. In conclusion, this study provides insights into the conservation and functional significance of lysine acetylation in different organisms emphasizing its roles in cellular processes, metabolic pathways, and molecular regulation, shedding light in the extensive function of non-histone lysine acetylation.
A KIF1C-CNBP motor-adaptor complex for trafficking mRNAs to cell protrusions
Authors: Moissoglu Konstadinos , Wang Tianhong , Gasparski Alexander N. , Stueland Michael , Paine Elliott L. , Jenkins Lisa , Mili Stavroula 
Published: June 2024

SummarymRNA localization to subcellular compartments is a widely used mechanism that functionally contributes to numerous processes. mRNA targeting can be achieved upon recognition of RNA cargo by molecular motors. However, our molecular understanding of how this is accomplished is limited, especially in higher organisms. We focus on a pathway that targets mRNAs to peripheral protrusions of mammalian cells and is important for cell migration. Trafficking occurs through active transport on microtubules, mediated by the KIF1C kinesin. Here, we identify the RNA-binding protein CNBP, as a factor required for mRNA localization to protrusions. CNBP binds directly to GA-rich sequences in the 3’UTR of protrusion targeted mRNAs. CNBP also interacts with KIF1C and is required for KIF1C recruitment to mRNAs and for their trafficking on microtubules to the periphery. This work provides a molecular mechanism for KIF1C recruitment to mRNA cargo and reveals a motor-adaptor complex for mRNA transport to cell protrusions.
Dynamic Human Gut Microbiome and Immune Shifts During an Immersive Psychosocial Therapeutic Program
Authors: Zhou Xin , Ganz Ariel B. , Rayner Andre , Cheng Tess Yan , Oba Haley , Rolnik Benjamin , Lancaster Samuel , Lu Xinrui , Li Yizhou , Johnson Jethro S. , Hoyd Rebecca , Spakowicz Daniel J. , Slavich George M. , Snyder Michael P. 
Published: June 2024

ABSTRACTBackgroundDepression is a leading cause of disability worldwide yet its underlying factors, particularly microbial associations, are poorly understood.MethodsWe examined the longitudinal interplay between the microbiome and immune system in the context of depression during an immersive psychosocial intervention. 142 multi-omics samples were collected from 52 well-characterized participants before, during, and three months after a nine-day inquiry-based stress reduction program.ResultsWe found that depression was associated with both an increased presence of putatively pathogenic bacteria and reduced microbial beta-diversity. Following the intervention, we observed reductions in neuroinflammatory cytokines and improvements in several mental health indicators. Interestingly, participants with aPrevotella-dominant microbiome showed milder symptoms when depressed, along with a more resilient microbiome and more favorable inflammatory cytokine profile, including reduced levels of CXCL-1.ConclusionsOur findings reveal a protective link between the Prevotella-dominant microbiome and depression, associated with a less inflammatory environment and moderated symptoms. These insights, coupled with observed improvements in neuroinflammatory markers and mental health from the intervention, highlight potential avenues for microbiome-targeted therapies in depression management.
Luminescence-based complementation assay to assess target engagement and cell permeability of glycolate oxidase (HAO1) inhibitors
Authors: Mackinnon Sabrina R. , Zarganes-Tzitzikas Tryfon , Adams Cassandra J. , Brennan Paul E. , Yue Wyatt W. 
Published: June 2024

AbstractGlycolate oxidase (HAO1) catalyses the synthesis of glyoxylate, a common metabolic intermediate that causes renal failure if accumulated. HAO1 inhibition is an emerging treatment for primary hyperoxaluria, a rare disorder of glyoxylate metabolism. Here we report the first cell-based measurement of inhibitor uptake and engagement with HAO1, by adapting the cellular thermal shift assay (CETSA) based on Nano luciferase complementation and luminescence readout. By profiling the interaction between HAO1 and four well-characterised inhibitors in intact and lysed HEK293T cells, we showed that our CETSA method differentiates between low-permeability/high-engagement and high-permeability/low-engagement ligands and is able to rank HAO1 inhibitors in line with both recombinant protein methods and previously reported indirect cellular assays. Our methodology addresses the unmet need for a robust, sensitive, and scalable cellular assay to guide HAO1 inhibitor development and, in broader terms, can be rapidly adapted for other targets to simultaneously monitor compound affinity and cellular permeability.
White matter hyperintensity spatial patterns: risk factors and clinical correlates
Authors: Beyer Frauke , Tsuchida Ami , Soumaré Aicha , Reddy Rajula Hema Sekhar , Mishra Aniket , Crivello Fabrice , Loeffler Markus , Tzourio Christophe , Amouyel Philippe , Villringer Arno , Scholz Markus , Jacqmin-Gadda Hélène , Joliot Marc , Witte A. Veronica , Dufouil Carole , Debette Stéphanie 
Published: June 2024

AbstractINTRODUCTIONWhite matter hyperintensities (WMH), a major cerebral small vessel disease marker, may arise from different pathologies depending on their location. We explored clinical and genetic correlates of agnostically derived spatial WMH patterns in two longitudinal population-based cohorts (3C-Dijon, LIFE-Adult).METHODSWe derived seven WMH spatial patterns using Bullseye segmentation in 2,736 individuals aged 65+ and explored their associations with vascular and genetic risk factors, cognitive performance, dementia and stroke incidence.RESULTSWMH in the fronto-parietal and anterior periventricular region were associated with blood pressure traits, WMH genetic risk score (GRS), baseline and decline in general cognitive performance, incident all-cause dementia and ischemic stroke. Juxtacortical-deep occipital WMH were not associated with vascular risk factors and WMH GRS, but with incident all-cause dementia and intracerebral hemorrhage.CONCLUSIONAccounting for WMH spatial distribution is key to decipher mechanisms underlying cerebral small vessel disease subtypes, an essential step towards personalized therapeutic approaches.HighlightsWe studied spatial patterns of white matter hyperintensities in 2736 participantsBlood pressure was associated with fronto-parietal and anterior periventricular WMHAnterior periventricular WMH predicted dementia and stroke riskJuxtacortical-deep occipital WMH burden was not associated with blood pressure or WMH genetic riskJuxtacortical-deep occipital WMH predicted dementia and intracerebral hemorrhage.Research in contextSystematic Review: We performed a literature search using PubMed and Google Scholar. Most literature focuses on risk factors and outcomes for total WMH volume. Existing approaches to study WMH spatial patterns are heterogenous and often performed in single cohorts only.Interpretation: Across two independent cohorts of older community-dwelling individuals, we show that WMH in the anterior periventricular and juxtacortical-deep occipital WMH show differential associations with risk factors and clinical outcomes. Anterior periventricular WMH were associated with blood pressure (BP) traits, WMH genetic risk, cognitive performance, dementia and incident stroke. Juxtacortical-deep occipital WMH did not relate to BP or WMH genetic risk and were predictive of dementia and intracerebral hemorrhage. These findings are important for characterizing small vessel disease subtypes and developing targeted prevention and therapeutic strategies.Future Directions: Additional research is warranted to validate these findings and relate them to underlying vascular pathologies.
Association of preserved ratio impaired spirometry with mortality and airflow obstruction in the silicotics: a longitudinal cohort study
Authors: Yang Shuyuan , Tse Lap Ah 
Published: June 2024

AbstractRationalePreserved ratio impaired spirometry (PRISm), defined as an impaired forced expiratory volume in one second (FEV1) with a preserved ratio of FEV1to forced vital capacity (FVC), is associated with increased risk of airflow obstruction (AFO) and mortality in the general population. However, evidence is limited among the individuals with silicosis, an old occupational disease with an ongoing outbreak in some developed countries.ObjectivesTo investigate the association of PRISm with the risk of mortality and incident AFO in a cohort of workers with silicosis.MethodsA total of 4315 workers aged 18-80 years and diagnosed with silicosis at the Pneumoconiosis Clinic, Tuberculosis and Chest Service during 1981-2019 were enrolled in this study and followed up for a median of 12.3 years till 31 December 2019. Spirometry was included in the diagnostic examination of silicosis and follow-up reassessments. Lung function categories of participants were classified as normal spirometry (FEV1/FVC ≥ 0.7, FEV1≥ 80% predicted), PRISm (FEV1/FVC ≥ 0.7, FEV1< 80% predicted), and AFO (FEV1/FVC < 0.7). The hazard ratio (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusting for age, body mass index, tuberculosis history, smoking, and radiographic characteristics.Measurements and Main ResultsDuring the follow-up period, a total of 2399 (55.6%) subjects died, 1359 of whom died from respiratory-related diseases, and 780 subjects developed AFO. Subjects with PRISm had significantly increased multivariable-adjusted risk of all-cause death (adjusted HR=1.63, 95% CI 1.44-1.85) and respiratory-related mortality (adjusted HR=1.74, 95% CI 1.48-2.05) as compared with the those with normal spirometry. Besides, there was a higher risk of developing AFO in subjects with PRISm than in those with normal spirometry (adjusted HR=1.46, 95% CI 1.22-1.75). No significant interaction was observed between PRISm and smoking status in the risk of all-cause mortality and incident AFO.ConclusionsPRISm is significantly associated with increased all-cause and respiratory-related mortality and a greater risk of progression to AFO among the individuals with silicosis.
An Inherently Interpretable AI model improves Screening Speed and Accuracy for Early Diabetic Retinopathy
Authors: Djoumessi Kerol , Huang Ziwei , Kühlewein Laura , Rickmann Annekatrin , Simon Natalia , Koch Lisa M. , Berens Philipp 
Published: June 2024

AbstractBackgroundDiabetic retinopathy (DR) is a frequent concomitant disease of diabetes, affecting millions worldwide. Screening for this disease based on fundus images has been one of the first successful use cases for modern artificial intelligence in medicine. Current state-of-the-art systems typically use black-box models to make referral decisions, requiring post-hoc methods for AI-human interaction.MethodsIn this retrospective reader study, we evaluated an inherently interpretable deep learning model, which explicitly models the local evidence of DR as part of its network architecture, for early DR screening. We trained the network on 34,350 high-quality fundus images from a publicly available dataset and validated its state-of-the-art performance on a large range of ten external datasets. We obtained detailed lesion annotations from ophthalmologists on 65 images to study if the class evidence maps highlight clinically relevant information. Finally, we tested the clinical usefulness of our model in a reader study, where we compared screening for DR without AI support to screening with AI support with and without AI explanations.ResultsThe inherently interpretable deep learning model obtained an accuracy of .906 [.900-.913] (95%-confidence interval) and an AUC of .904 [.894 – .913] on the internal test set and similar performance on external datasets. High evidence regions directly extracted from the model contained clinically relevant lesions such as microaneurysms or hemorrhages with a high precision of .960 [.941 - .976]. Decision support by the model highlighting high-evidence regions in the image improved screening accuracy for difficult decisions and improved screening speed.InterpretationInherently interpretable deep learning models can reach state-of-the-art performance and support screening for early DR by improving human-AI collaboration.FundingThis work was supported by the Hertie Foundation, the German Science Foundation (BE5601/8-1 and the Excellence Cluster 2064 “Machine Learning — New Perspectives for Science”, project number 390727645), the Carl Zeiss Foundation (“Certification and Foundations of Safe Machine Learning Systems in Healthcare”) and International Max Planck Research School for Intelligent Systems.
Inter-cellular mRNA Transfer Alters Human Pluripotent Stem Cell State
Authors: Yoneyama Yosuke , Zhang Ran-Ran , Kimura Masaki , Cai Yuqi , Adam Mike , Parameswaran Sreeja , Masaki Hideki , Mizuno Naoaki , Bhadury Joydeep , Maezawa So , Ochiai Hiroshi , Nakauchi Hiromitsu , Potter S. Steven , Weirauch Matthew T. , Takebe Takanori 
Published: June 2024

ABSTRACTInter-cellular transmission of mRNA is being explored in mammalian species using immortal cell lines (1–3). Here, we uncover an inter-cellular mRNA transfer phenomenon that allows for the adaptation and reprogramming of human primed pluripotent stem cells (hPSCs). This process is induced by the direct cell contact-mediated coculture with mouse embryonic stem cells (mESCs) under the condition impermissible for human primed PSC culture. Mouse-derived mRNA contents are transmitted into adapted hPSCs only in the coculture. Transfer-specific mRNA analysis show the enrichment for divergent biological pathways involving transcription/translational machinery and stress-coping mechanisms, wherein such transfer is diminished when direct cell contacts are lost. After 5 days of mESC culture, surface marker analysis, and global gene profiling confirmed that mRNA transfer-prone hPSC efficiently gains a naïve-like state. Furthermore, transfer-specific knockdown experiments targeting mouse-specific transcription factor-coding mRNAs in hPSC show that mouse-derivedTfcp2l1,Tfap2c,andKlf4are indispensable for human naïve-like conversion. Thus, inter-species mRNA transfer triggers cellular reprogramming in mammalian cells. Our results support that episodic mRNA transfer can occur in cell cooperative and competitive processes(4), which provides a fresh perspective on understanding the roles of mRNA mobility for intra- and inter-species cellular communications.