bluuebunny/crossref_metadata_2025_split huggingface dataset:
MPXV Infects Human PBMCs in a Type I Interferon-Sensitive Manner
Authors: Bosquillon de Jarcy Laure , Postmus Dylan , Jansen Jenny , Melchert Julia , Hoffmann Donata , Corman Victor M. , Goffinet Christine 
Published: September 2024

AbstractMPOX virus (MPXV), formerly known as monkeypox virus, led to a rapidly evolving pandemic starting May 2022, with over 90,000 cases reported beyond the African continent. This pandemic outbreak was driven by the MPXV variant Clade IIb. In addition, Clade I viruses circulating in the Democratic Republic of Congo (DRC) are drawing increased attention as cases constantly rise and Clade Ib, first identified in 2023, is now co-circulating with Clade Ia and seems to exhibit enhanced human-to-human transmissibility. While most infected individuals display a self-limiting disease with singular pox-like lesions, some endure systemic viral spread leading to whole-body rash with risks for necrosis, organ loss, and death. Intra-host dissemination and cellular tropism of MPXV are largely unexplored in humans. To establish a potential susceptibility of circulating immune cells to MPXV, we exposed human PBMCs from healthy donorsex vivoto a currently circulating MPXV clade IIb virus isolate in absence and presence of IFN-α2a. qPCR of DNA extracted from cell lysates, but less from supernatants, revealed increasing MPXV DNA quantities that peaked at five to six days post-exposure, suggesting susceptibility of PBMCs to infection. IFN-α2a pretreatment markedly reduced the quantity of MPXV DNA, suggesting that infection is sensitive to type I IFNs. Plaque assays from supernatants showed that infection gave rise tode novoproduction of infectious MPXV. In virus-inclusive scRNA-sequencing, monocytes, cycling NK cells and regulatory CD4+T-cells scored positive for viral RNA, suggesting that these are the MPXV-susceptible cell types within the human PBMC population. Analysis of differentially expressed genes displayed a pronounced downregulation of expression pathways driving innate immunity in MPXV-infected cells, a well-established feature of poxviral infection. Pretreatment of PBMCs with current antivirals Cidofovir and Tecovirimat resulted in reduced amounts of viral antigen production and of released infectivity, suggesting suitability of the human PBMC infection model as a platform for evaluation of current and future antivirals and justifying trials to investigate Cidofovir and Tecovirimat as drugs reducing intra-patient viral spread. Together, our data suggest that human PBMCs are productively infected by MPXV which is accompanied by significant modulation of the cellular milieu. Our results have the potential to illuminate aspects of intra-host propagation of MPXV that may involve a lymphohematogenous route for replication and/or intra-host dissemination.
The Primate Major Histocompatibility Complex: An Illustrative Example of Gene Family Evolution
Authors: Fortier Alyssa Lyn , Pritchard Jonathan K. 
Published: September 2024

AbstractGene families are groups of evolutionarily-related genes. One large gene family that has experienced rapid evolution is the Major Histocompatibility Complex (MHC), whose proteins serve critical roles in innate and adaptive immunity. Across the ∼60 million year history of the primates, some MHC genes have turned over completely, some have changed function, some have converged in function, and others have remained essentially unchanged. Past work has typically focused on identifying MHC alleles within particular species or comparing gene content, but more work is needed to understand the overall evolution of the gene family across species. Thus, despite the immunologic importance of the MHC and its peculiar evolutionary history, we lack a complete picture of MHC evolution in the primates. We readdress this question using sequences from dozens of MHC genes and pseudogenes spanning the entire primate order, building a comprehensive set of gene and allele trees with modern methods. Overall, we find that the Class I gene subfamily is evolving much more quickly than the Class II gene subfamily, with the exception of the Class II MHC-DRB genes. We also pay special attention to the often-ignored pseudogenes, which we use to reconstruct different events in the evolution of the Class I region. We find that despite the shared function of the MHC across species, different species employ different genes, haplotypes, and patterns of variation to achieve a successful immune response. Our trees and extensive literature review represent the most comprehensive look into MHC evolution to date.
Precision-dependent modulation of social attention
Authors: Gao Wenhui , Zhu Changbo , Si Bailu , Zhou Liqin , Zhou Ke 
Published: September 2024

AbstractSocial attention, guided by cues like gaze direction, is crucial for effective social interactions. However, how dynamic environmental context modulates this process remains unclear. Integrating a hierarchical Bayesian model with fMRI, this study investigated how individuals adjusted attention based on the predictions about cue validity (CV). Thirty-three participants performed a modified Posner location-cueing task with varying CV. Behaviorally, individuals’ allocation of social attention was finely tuned to the precision (inverse variance) of CV predictions, with the predictions being updated by precision-weighted prediction errors (PEs) about the occurrence of target locations. Neuroimaging results revealed that the interaction between allocation of social attention and CV influenced activity in regions involved in spatial attention and/or social perception, such as the temporoparietal junction (TPJ), frontal eye field (FEF), superior temporal sulcus (STS), and inferior parietal sulcus (IPS). Precision-weighted PEs about target locations specifically modulated activity in the TPJ, STS, and primary visual cortex (V1), underscoring their roles in refining attentional predictions. Dynamic causal modeling (DCM) further demonstrated that enhanced absolute precision-weighted PEs about target locations strengthened the effective connectivity from V1 and STS to TPJ, emphasizing their roles in conveying residual error signals from low-level sensory areas to high-level critical attention areas. These findings elucidated how the precision of contextual predictions dynamically modulated social attention, offering insights into the computational and neurocognitive mechanisms of context-dependent social attention.
Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network
Authors: Boutelle Anthony M. , Mabene Aicha R. , Yao David , Xu Haiqing , Wang Mengxiong , Tang Yuning J. , Lopez Steven S. , Sinha Sauradeep , Demeter Janos , Cheng Ran , Benard Brooks A. , Valente Liz J. , Drainas Alexandros P. , Fischer Martin , Majeti Ravindra , Petrov Dmitri A. , Jackson Peter K. , Yang Fan , Winslow Monte M. , Bassik Michael C. , Attardi Laura D. 
Published: September 2024

AbstractTP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible geneZmat3as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltrasomatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorialin vivoCRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We establishedZmat3as a core component of p53-mediated tumor suppression and identifiedCdkn1aas the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combinedZmat3-Cdkn1ainactivation dramatically enhanced cell proliferation and migration compared to controls, akin top53inactivation. Together, our findings placeZMAT3andCDKN1Aas hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.
Reversible excision of thewzylocus inSalmonellaTyphimurium may aid recovery following phage predation
Authors: Charity Oliver JD , Thilliez Gaetan , Al-Khanaq Haider , Acton Luke , Kolenda Rafał , Bawn Matt , Petrovska Liljana , Kingsley Robert A 
Published: September 2024

AbstractBacteriophage (phage) are promising novel antimicrobials but a key challenge to their effective implementation is the rapid emergence of phage resistance. An improved understanding of phage-host interactions is therefore needed. The Anderson phage typing scheme differentiates closely related strains ofSalmonella entericaserovar Typhimurium (S. Typhimurium) based on sensitivity to a panel of phage preparations. Switches in phage type are indicative of changes in phage sensitivity and inform on the dynamics of phage interaction with their host bacteria. We investigated the molecular basis of switches between the relatively phage sensitiveS. Typhimurium DT8 and phage resistant DT30 strains that are present in the same phylogenetic clade. DT30 strains emerged from DT8 strains predominantly by deletion of a genomic region affecting thewzylocus encoding an O-antigen polymerase. The deletion site was flanked by two perfect direct repeats designated attL and attR. During broth culture in the presence of a typing phage that used O-antigen as primary receptor the Δwzygenotype increased in frequency compared with culture in the absence of phage and removal of attL prevented deletion of thewzylocus. Co-culture ofS. Typhimurium DT8 with a strain lackingwzyresulted in reversion of the latter to wild type. We propose a model in which reversible deletion of thewzylocus enables recovery ofS. Typhimurium DT8 following predation by phage that use O-antigen as their primary receptor. This was consistent with ancestral state reconstruction of DT8 and DT30 phylogeny that supported a model of reversible transition from DT8 to DT30 in natural populations.ImportanceS. Typhimurium is a major pathogen of livestock that adversely affects productivity and animal welfare and poses a risk of foodborne disease in the human population. Antibiotics are used to controlSalmonellainfections in livestock that contributes to the antimicrobial resistance global emergency. Viruses of bacteria (phage) are one alternative to antibiotics to controlSalmonellain the food chain but their successful implementation as antimicrobials is restricted by the rapid emergence of resistance to phage. A better understanding of the outcome of phage-bacteria interactions is needed to optimise the design and implementation of phage-based antimicrobials. This study identifies a genetic mechanism that confers resistance to phage that use O-antigen as a receptor on the surface ofSalmonella. The mechanism is likely to impart a fitness cost on the bacterium but importantly the mechanism has the potential to be revert to a fully fit state once phage predation ceases. A model for how the mechanism may contribute to survival and recovery following phage predation is proposed.
A rubrerythrin locus ofClostridioides difficileefficiently detoxifies reactive oxygen species
Authors: Knop Robert , Keweloh Simon , Dittmann Silvia , Zühlke Daniela , Sievers Susanne 
Published: September 2024

AbstractAs an intestinal human pathogen,Clostridioides difficileis the main cause of antibiotic-associated diarrhoea. Endospores of this gram-positive bacterium enter the intestinal tract via faecal-oral transmission, germinate into vegetative and toxin-producing cells and can trigger aClostridioides difficileinfection. The microaerophilic conditions (0.1 to 0.4 % O2) of the large intestine represent a challenge for the strictly anaerobic organism, which protects itself by a variety of oxidative stress proteins. Four of these are encoded in an operon that is assumed to be involved in the detoxification of H2O2and O2●-. This operon encodes a rubrerythrin (rbr), its own transcriptional repressor PerR (perR), a desulfoferrodoxin (rbo) and a putative glutamate dehydrogenase (CD630_08280) with an N-terminal rubredoxin domain, which is only expressed under high oxidative stress conditions.In this study, the enzyme activity of Rbr, Rbo and CD630_08280 was testedin-vitro. Recombinant proteins were overexpressed inC. difficileand purified anaerobically by affinity chromatography.A H2O2reduction potential was demonstrated for Rbr, Rbo and glutamate dehydrogenase. Rbr and glutamate dehydrogenase proved to synergistically detoxify H2O2very efficiently. Furthermore, Rbo was verified as a O2●-reductase and its activity compared to the superoxide dismutase ofE. coli.The investigated gene locus codes for an oxidative stress operon whose members are able to completely neutralize O2●-and H2O2to water and could thus be vital forC. difficileto establish an infection in the host.
Limbic System White Matter in Children and Adolescents with ADHD: A Longitudinal Diffusion MRI Analysis
Authors: Connaughton Michael , Leemans Alexander , Silk Timothy J. , Anderson Vicki , O’Hanlon Erik , Whelan Robert , McGrath Jane 
Published: September 2024

AbstractAttention-deficit/hyperactivity disorder (ADHD) is increasingly recognized as a disorder linked to atypical white matter development across large-scale brain networks. However, current research predominantly focuses on cortical networks, leaving the developmental trajectories of many subcortical networks, including the limbic system, largely unexplored. The limbic system is crucial for emotion and cognition, making it a key area of interest in ADHD research. This study employed multi-shell high angular resolution diffusion magnetic resonance imaging to map the development of limbic system white matter in individuals with ADHD (n = 72) and controls (n = 97) across three time points between ages 9 and 14. Diffusion kurtosis imaging and graph theory metrics were used to characterize limbic system white matter, alongside assessments of emotional regulation and ADHD symptom severity. Compared to controls, individuals with ADHD exhibited significantly lower microstructural organization, particularly in kurtosis anisotropy, within the bilateral cingulum bundle from childhood to adolescence. Brain-behavior analyses further revealed that higher ADHD symptom severity was associated with a lower number of limbic system white matter connections, notably decreased routing efficiency and network density. These findings offer novel insights into the role of disrupted limbic system white matter in ADHD pathophysiology, broadening our understanding of the disorder’s neural mechanisms and opening promising avenues for future exploration of subcortical brain networks.
Enhancing lysosome function via mTOR/TFEB activation reduces lipofuscin-like granules in early Age-related Macular Degeneration
Authors: Falcão Ana S , Lopes-da-Silva Mafalda , Antas Pedro , Escrevente Cristina , Pedro Margarida , Coelho Rita , Ferreira Inês S , Santos Inês P , Ciossek Thomas , Nicklin Paul , Tenreiro Sandra , Seabra Miguel C 
Published: September 2024

ABSTRACTAge-related macular degeneration (AMD) is the most common blinding disease in the western world and is currently incurable. Although the exact causes of AMD are not clear, the primary origin of pathology appears to be in the retinal pigment epithelium (RPE). RPE is responsible for the daily digestion of photoreceptor outer segments (POS), which imposes a heavy continuous burden on the lysosomal network. POS feeding assayin vitrosuggested that the accumulation of autofluorescence granules (AFG), similar to lipofuscinin vivo,derives from lysosomal dysfunction. Here we show that synchronous phagocytosis of POS leads to early transient mTOR activation followed by inhibition in late phagosome maturation. One of its substrates, the transcription factor EB (TFEB) increases during phagosome maturation albeit mostly in its inactive phosphorylated form. We questioned whether induction of the mTOR/TFEB axis could improve digestion of POS and hence reduce AFG load. Treatment of POS-fed cells with rapamycin, an mTORC1 inhibitor after the appearance of AFG results in 30% reduction of AFG load. This effect is dependent on active lysosomal enzymes and induction of active dephosphorylated TFEB with consequent activation of GADD34 and lysosomal biogenesis. As a proof of concept, we show that overexpressing a constitutively active form of unphosphorylated TFEB dramatically reduces POS-dependent AFG accumulation. Overall, this study suggests that viral or pharmacological approaches activating the mTOR/TFEB axis in the RPE could be beneficial as cell-protective treatment of early/intermediate cases of AMD, acting to delay progression of the disease.
Representational shifts from feedforward to feedback rhythms index phenomenological integration in naturalistic vision
Authors: Chen Lixiang , Cichy Radoslaw Martin , Kaiser Daniel 
Published: September 2024

AbstractHow does the brain integrate complex and dynamic visual inputs into phenomenologically seamless percepts? Previous results demonstrate that when visual inputs are organized coherently across space and time, they are more strongly encoded in feedback-related alpha rhythms, and less strongly in feedforward-related gamma rhythms. Here, we tested whether this representational shift from feedforward to feedback rhythms is linked to the phenomenological experience of coherence. In an EEG study, we manipulated the degree of spatiotemporal coherence by presenting two segments from the same video across visual hemifields, either synchronously or asynchronously (with a delay between segments). We asked participants whether they perceived the stimulus as coherent or incoherent. When stimuli were presented at the perceptual threshold (i.e., when the same stimulus was judged as coherent 50% of times), perception co-varied with stimulus coding across alpha and gamma rhythms: When stimuli were perceived as coherent, they were represented in alpha activity; when stimuli were perceived as incoherent, they were represented in gamma activity. Whether the same visual input is perceived as coherent or incoherent thus depends on representational shifts between feedback-related alpha and feedforward-related gamma rhythms.
Seipin Regulates Caveolin-1 Trafficking and Organelle Crosstalk
Authors: Carpentier Maxime , Omrane Mohyeddine , Shaaban Rola , Träger Jennica , El Khallouki Naima , Zouiouich Mehdi , Palard Marie , Harayama Takeshi , Vigouroux Corinne , Le Lay Soazig , Giordano Francesca , Prieur Xavier , Thiam Abdou Rachid 
Published: September 2024

AbstractCaveolin-1 (CAV1), the main structural component of caveolae, is essential in various biological processes, including mechanotransduction, lipid metabolism, and endocytosis1–4. Deregulation of CAV1 dynamics is linked to various pathologies, including cellular senescence, cancer, insulin resistance, and lipodystrophy5–9. However, mechanisms regulating CAV1 trafficking and function remain poorly understood. Here, we show that seipin, a crucial lipid droplet (LD) biogenesis factor10, modulates CAV1 trafficking. Deletion of seipin resulted in the accumulation of saturated lipids, leading to ceramide and sphingomyelin overproduction, which disrupted the membrane order of the trans-Golgi network (TGN). In seipin deficiency, CAV1 location to the plasma membrane (PM) was impaired, reducing caveolae. Instead, CAV1 accumulated in TGN and late endosome compartments, which fused with LDs and delivered the protein. In wild-type (WT) cells, this process was minimal but significantly enhanced by treatment with palmitate, ceramide, or Stearoyl-CoA desaturase-1 (SCD1) inhibition. Conversely, in seipin-deficient cells, inhibiting Fatty Acid Synthase (FASN) or overexpressing SCD1 restored CAV1 localization to the PM and reduced its accumulation in LDs. Our findings reveal that seipin controls the funneling of palmitate toward glycerolipids synthesis and storage in LDs versus conversion to ceramides in the ER. This balance is crucial to cellular protein trafficking by controlling the TGN membrane order. Therefore, our study identifies seipin as a critical regulator of cellular lipid metabolism, protein trafficking, and organelle homeostasis. These findings shed light on the processes regulating CAV1 trafficking and show that convergent pathophysiological mechanisms associated with defects in CAV1 and seipin contribute to metabolic disorders, including insulin resistance and lipodystrophies11–14.
Network-based estimation of therapeutic efficacy and adverse reaction potential for prioritisation of anti-cancer drug combinations
Authors: Ghosh Arindam , Fortino Vittorio 
Published: September 2024

ABSTRACTDrug combinations, although a key therapeutic agent against cancer, are yet to reach their full applicability potential due to the challenges involved in the identification of effective and safe drug pairs.In vitroorin vivoscreening would have been the optimal approach if combinatorial explosion was not an issue.In silicomethods, on the other hand, can enable rapid screening of drug pairs to prioritise for experimental validation. Here we present a novel network medicine approach that systematically models the proximity of drug targets to disease-associated genes and adverse effect- associated genes, through the combination of network propagation algorithm and gene set enrichment analysis. The proposed approach is applied in the context of identifying effective drug combinations for cancer treatment starting from a training set of drug combinations curated from DrugComb and DrugBank databases. We observed that effective drug combinations usually enrich disease-related gene sets while adverse drug combinations enrich adverse-effect gene sets. We use this observation to systematically train classifiers distinguishing drug combinations with higher therapeutic effects and no known adverse reaction from combinations with lower therapeutic effects and potential adverse reactions in six cancer types. The approach is tested and validated using drug combinations curated fromin vitroscreening data and clinical reports. Trained classification models are also used to identify novel potential anti-cancer drug combinations for experimental validation. We believe our framework would be a key addition to the anti-cancer drug combination identification pipeline by enabling rapid yet robust estimation of therapeutic efficacy or adverse reaction potential.