bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mobilization of nuclear antiviral factors by Exportin XPO1 via the actin network inhibits RNA virus replication
Authors: Sun Biao , Wu Cheng-Yu , Gonzalez Paulina Alatriste , Nagy Peter D. 
Published: December 2024

ABSTRACTThe intricate interplay between +RNA viruses and their hosts involves the exploitation of host resources to build virus-induced membranous replication organelles (VROs) in cytosol of infected cells. Previous genome- and proteome-wide approaches have identified numerous nuclear proteins, including restriction factors that affect replication of tomato bushy stunt virus (TBSV). However, it is currently unknown how cells mobilize nuclear antiviral proteins and how tombusviruses manipulate nuclear-cytoplasmic communication. The authors discovered that XPO1/CRM1 exportin plays a central role in TBSV replication in plants. Based on knockdown, chemical inhibition, transient expression and in vitro experiments, we show that XPO1 acts as a cellular restriction factor against TBSV. XPO1 is recruited by TBSV p33 replication protein into the cytosolic VROs via direct interaction. Blocking nucleocytoplasmic transport function of XPO1 inhibits delivery of several nuclear antiviral proteins into VROs resulting in dampened antiviral effects. The co-opted actin network is critical for XPO1 to deliver nuclear proteins to VROs for antiviral activities. We show that XPO1 and XPO1-delivered restriction factors accumulate in vir-condensates associated with membranous VROs. Altogether, the emerging theme on the role of vir-condensates is complex: we propose that vir-condensate serves as a central battleground between virus and the host for supremacy in controlling virus infection. It seems that the balance between co-opted pro-viral and antiviral factors within vir-condensates associated with membranous VROs could be a major determining factor of virus replication and host susceptibility. We conclude that XPO1 and nuclear antiviral cargos are key players in nuclear-cytoplasmic communication during cytosolic +RNA virus replication.SignificanceTomato bushy stunt virus (TBSV), similar to other (+)RNA viruses, replicates in the cytosol and exploits organellar membrane surfaces to build viral replication organelles (VROs) that represent the sites of virus replication. The authors discovered that XPO1 exportin nuclear shuttle protein inhibited TBSV replication in plants. The conserved XPO1 is a central protein interaction nod, which propelled nucleocytoplasmic transport of several viral restriction factors into the cytosolic VROs that restricted tombusviruses replication. The delivered virus restriction factors provided inhibitory functions within virus-induced condensates associated with membranous VROs. The authors propose that the VRO-associated condensate serves as a central battleground between virus and the host for supremacy in controlling virus infection. Altogether, XPO1 is a critical protein interaction hub with major implications in viral replication. The authors conclude that XPO1 and its nuclear antiviral cargos are key players in nuclear-cytoplasmic communication during cytosolic (+)RNA virus replication.
Convergent Evolution of the Antimycobacterial Lasso Peptide Triculamin
Authors: Merrild Aske , Svenningsen Tiziana , Chevrette Marc G , Tørring Thomas 
Published: December 2024

AbstractTriculamin is a ribosomally synthesized and post-translationally modified peptide (RiPP) lasso peptide with potent antimycobacterial activity, produced by an unusual, non-canonical biosynthetic gene cluster (BGC). In this study, we elucidate the biosynthetic pathway of triculamin through heterologous expression and show that the biosynthesis proceeds in the presence of a precursor (triA), macrocyclase (triC), and acetyltransferase (triT). Throughin vitrotriT acetylation and bioactivity assays, we show that acetylation functions as a resistance mechanism. Genomic searches of triculamin BGC genes across bacteria show that triculamin is more widely distributed than previously anticipated, as triculamin-like core peptides are found in at least three phyla in contrast to previously described lasso peptides that are typically restricted to one phylum. Triculamin BGCs with both canonical and non-canonical RiPP biosynthetic genes were identified. Two strains containing canonical triculamin-like BGCs were chemically characterized and shown to produce the novel triculamin-like lasso peptides palmamin and gelatinamin, the latter of which appears to have an unprecedented additional ring formation. Detailed phylogenetic investigation of the macrocyclases from triculamin-like BGCs suggests that these molecules are products of convergent evolution. These findings broaden the evolutionary and functional landscape of lasso peptides, revealing their unexpected diversification and cross-phylum distribution.
The PH domain in the ArfGAP ASAP1 drives catalytic activation through an unprecedented allosteric mechanism
Authors: Soubias Olivier , Foley Samuel L. , Jian Xiaoying , Jackson Rebekah A. , Zhang Yue , Rosenberg Eric M. , Li Jess , Heinrich Frank , Johnson Margaret E. , Sodt Alexander J. , Randazzo Paul A. , Byrd R. Andrew 
Published: December 2024

AbstractASAP1 is a multidomain Arf GTPase-activating protein (ArfGAP) that catalyzes GTP hydrolysis on the small GTPase Arf1 and is implicated in cancer progression. The PH domain of ASAP1 enhances its activity greater than 7 orders of magnitude but the underlying mechanisms remain poorly understood. Here, we combined Nuclear Magnetic Resonance (NMR), Molecular Dynamic (MD) simulations and mathematical modeling of functional data to build a comprehensive structural-mechanistic model of the complex of Arf1 and the ASAP1 PH domain on a membrane surface. Our results support a new conceptual model in which the PH domain contributes to efficient catalysis not only by membrane recruitment but by acting as a critical component of the catalytic interface, binding Arf·GTP and allosterically driving it towards the catalytic transition state. We discuss the biological implications of these results and how they may apply more broadly to poorly understood membrane-dependent regulatory mechanisms controlling catalysis of the ArfGAP superfamily as well as other peripheral membrane enzymes.
Enterobactin carries iron intoC. elegansand mammalian intestinal cells by a mechanism independent of divalent metal transporter DMT1
Authors: Sewell Aileen K. , Cui Mingxue , Zhu Mengnan , Host Miranda R. , Han Min 
Published: December 2024

AbstractThe diverse microbiota of the intestine is expected to benefit the host, yet the beneficial metabolites derived from the microbiota are still poorly understood. Enterobactin (Ent) is a well- known secreted iron-scavenging siderophore made by bacteria to fetch iron from the host or environment. Little was known about a positive role of Ent until a recent discovery in the nematodeC. elegansindicated a beneficial role of Ent in promoting mitochondrial iron level in the animal intestine. To solidify this new paradigm, we further tested this role inC. elegansand multiple mammalian cell models and its relationship with the primary iron transporter DMT1/SMF-3 and several other iron-related genes. Here we show that ferric enterobactin (FeEnt) supplementation promotes whole organism development inC. elegans, increases iron uptake in caco-2 human intestinal epithelial cells, and supports iron-dependent differentiation of murine erythroid progenitor cells, indicating that the FeEnt complex can effectively enter these cells and be bioavailable. Our data in multiple models demonstrate that FeEnt-mediated iron transport is independent of all tested iron transporters. In addition, FeEnt supplementation robustly suppresses the developmental defects of ahif-1mutant under low iron condition, suggesting the critical role in iron homeostasis for this well-known hypoxia regulator. These results suggest that FeEnt can effectively enter animal cells and their mitochondria through a previously unknown mechanism that may be leveraged as a therapeutic ferric iron carrier for the treatment of DMT1- or HIF-1-related iron deficiency and anemia.
Mapping histologic and functional maturation of human endocrine pancreas across early postnatal periods
Authors: Saunders Diane C. , Hart Nathaniel , Pan Fong Cheng , Reihsmann Conrad V. , Hopkirk Alexander L. , Izmaylov Nike , Mei Shaojun , Sherrod Brandon A. , Davis Corey , Duryea Jeff , Haliyur Rachana , Aramandla Radhika , Durai Heather , Poffenberger Greg , Martin Alexandra , Posgai Amanda L. , Kusmartseva Irina , Beery Maria L. , Yang Mingder , Kang Hakmook , Greiner Dale L. , Shultz Leonard D. , Cartailler Jean-Philippe , Aamodt Kristie I. , Bottino Rita , Atkinson Mark A. , Wright Christopher V.E. , Powers Alvin C. , Brissova Marcela 
Published: December 2024

ABSTRACTHuman endocrine cell differentiation and islet morphogenesis play critical roles in determining islet cell mass and function, but the events and timeline of these processes are incompletely defined. To better understand early human islet cell development and maturation, we collected 115 pediatric pancreata and mapped morphological and spatiotemporal changes from birth through the first ten years of life. Using quantitative analyses and a combination of complementary tissue imaging approaches, including confocal microscopy and whole-slide imaging, we developed an integrated model for endocrine cell formation and islet architecture, including endocrine cell type heterogeneity and abundance, endocrine cell proliferation, and islet vascularization and innervation. We also assessed insulin and glucagon secretory profiles in isolated islet preparations from pediatric donors aged 2 months to 10 years and found a temporal difference in the maturation of insulin secretion compared to glucagon secretion. This comprehensive summary of postnatal and pediatric pancreatic islet development provides a framework for future studies and integration of emerging genetic and genomic data related to islet biology and diabetes risk.
MSH2 is not required for either maintenance of DNA methylation or repeat contraction at theFMR1locus in fragile X syndrome
Authors: Grant-Bier Jessalyn , Ruppert Kathryn , Hayward Bruce , Usdin Karen , Kumari Daman 
Published: December 2024

AbstractBackgroundRepeat-induced epigenetic changes are observed in many repeat expansion disorders (REDs). These changes result in transcriptional deficits and/or silencing of the associated gene. MSH2, a mismatch repair protein that is required for repeat expansion in the REDs, has been implicated in the maintenance of DNA methylation seen in the region surrounding expanded CTG repeats at theDMPKlocus in myotonic dystrophy type 1 (DM1). Here, we investigated the role of MSH2 in aberrant DNA methylation in two additional REDs, fragile X syndrome (FXS) that is caused by a CGG repeat expansion in the 5’ untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, and Friedreich’s ataxia (FRDA) that is caused by GAA repeat expansion in intron 1 of thefrataxin(FXN) gene.ResultsIn contrast to what is seen at theDMPKlocus in DM1, loss of MSH2 did not decrease DNA methylation at theFMR1promoter in FXS embryonic stem cells (ESCs) or increaseFMR1transcription. This difference was not due to the differences in the CpG density of the two loci as a decrease in DNA methylation was also not observed in a less CpG dense region upstream of the expanded GAA repeats in theFXNgene in MSH2 null induced pluripotent stem cells (iPSCs) derived from FRDA patient fibroblasts. Surprisingly given previous reports, we found thatFMR1reactivation was associated with a high frequency of MSH2- independent repeat contractions that resulted a permanent loss of DNA methylation.ConclusionsOur results suggest that there are mechanistic differences in the way that DNA methylation is maintained in the vicinity of expanded repeats among different REDs even though they share a similar mechanism of repeat expansion. The high frequency of transcription- induced MSH2-independent contractions we have observed may contribute to the mosaicism that is frequently seen in carriers ofFMR1alleles with expanded CGG-repeat tracts. Given the recent interest in the therapeutic use of transcription-driven repeat contractions, our data may have interesting mechanistic, prognostic, and therapeutic implications.Graphical abstract
In vivochanges in zebrafish anesthetic sensitivity in response to the loss ofkif5Aaare associated with the alteration of mitochondrial motility
Authors: Dubey Priya , Datta Roshni , Eckenhoff Roderic G , Bedell Victoria M 
Published: December 2024

AbstractAnesthetic and sedative drugs are small compounds known to bind to hundreds of proteins. One intriguing binding partner of propofol is the kinesin motor domain, kif5A, a neuronal mitochondrial transport protein. Here, we used zebrafish WT andkif5AaKO larval behavioral assays to assess anesthetic sensitivity and combined that with zebrafish primary neuronal cell culture to probe for alteration in mitochondrial motility. We found that the loss ofkif5Aaincreases behavioral sensitivity to propofol and etomidate, with etomidate hypersensitivity greater than propofol. In contrast,kif5AaKO animals were resistant to the behavioral effects of dexmedetomidine. Finally, WT andkif5AaKO larvae responded similarly to the behavioral effects of ketamine. Propofol inhibited the anterograde motility of mitochondria in WT zebrafish neurons, while etomidate inhibited mitochondrial motility in both anterograde and retrograde directions; neither drug altered mitochondrial motility in thekif5Aaknockout (KO) neurons. In contrast, dexmedetomidine enhanced retrograde mitochondrial motility in both WT andkif5AaKO animals. Finally, ketamine had little significant effect on mitochondrial motility in either mutant or WT animals. These data demonstrate that each anesthetic/sedative drug affects the motor protein machinery uniquely and is associated with unique changes in behavior. Understanding how different anesthetic compounds alter neuron motor proteins will be important in defining how anesthetics alter neuronal signaling and energetic dynamics.
Biologically Plausible Neural Networks for Simulating Brain Dynamics and Inferring Connectivity
Authors: Gupta Aarush 
Published: December 2024

AbstractWe present Cerebrum, a novel framework that bridges biologically plausible neural networks with rigorous mathematical modeling. By grounding neural network simulations in a range of empirically-founded neuronal models (Hodgkin–Huxley, Izhikevich, and Adaptive Exponential Integrate-and-Fire), Cerebrum captures dynamics from intricate ion channel kinetics to general, large-scale network behavior. Our methodology integrates these mathematical models within a unified simulation pipeline, featuring mechanisms for short-term synaptic plasticity, precise state integration via the Runge-Kutta and Euler methods, and refractory spike regulation. We use a Graph Attention Network (GAT), to infer synaptic connectivity directly from dynamic activity patterns. This approach not only ensures biological realism but also facilitates robust connectivity reconstruction across diverse network topologies, including Erdős–Rényi, Small-World, and Scale-Free architectures. Results demonstrate that our framework reliably reproduces key neuronal firing patterns and synchronization phenomena, while its modular design paves the way for scalable investigations into the interplay between network structure and neural dynamics. Cerebrum thus offers a powerful tool for advancing both theoretical and applied aspects of computational neuroscience.
A targetable developmental program co-regulates angiogenesis and immune evasion
Authors: Berico Pietro , Yanke Amanda Flores , Van Rajabpour Fatemeh , Do Catherine , Simonin Wilmer Irving , Sakellaropoulos Theodore , Delclaux Ines , Stagnitta Robert , Vázquez-Cruz Estefania , Osman Iman , Skok Jane , Robles-Espinoza Carla Daniela , Lund Amanda W. , Schober Markus , Hernando Eva 
Published: December 2024

ABSTRACTUltraviolet (UV)-induced DNA mutations produce genetic drivers of cutaneous melanoma initiation and numerous neoantigens that can trigger anti-tumor immune responses in the host. Consequently, melanoma cells must rapidly evolve to evade immune detection by simultaneously modulating cell-autonomous epigenetic mechanisms and tumor-microenvironment interactions. Angiogenesis has been implicated in this process; although an increase of vasculature initiates the immune response in normal tissue, solid tumors manage to somehow enhance blood flow while preventing immune cell infiltration. By comparing the expression of transcription factors (TFs) across early-stage melanoma, naevi, and other cancer types, we found the homeodomain-containing TF HOXD13 drives a melanoblast-like developmental program, which is upregulated in melanoma and strongly correlated with angiogenesis and immune cell exclusion. Using transcriptomics, 3D chromatin profiling, and in vivo models, we demonstrate that HOXD13 upregulation promotes tumor growth in vivo by concomitantly enhancing angiogenesis and suppressing T-cell infiltration. HOXD13 orchestrates 3D chromatin contacts between distal enhancers and promoters, simultaneously activating VEGFA, SEMA3A, and CD73. VEGFA and SEMA3A remodel the tumor vasculature and CD73 elevates extracellular levels of adenosine, a vasodilator and immune suppressor that binds adenosine receptors (AdR) on endothelial and T cells. In line with these findings, HOXD13-induced growth advantage in vivo was significantly reversed by the concomitant administration of VEGFR and AdR inhibitors. By revealing a dual pro-angiogenic and immunosuppressive HOXD13-CD73/VEGF gene regulatory axis, we identify a subset of patients who might benefit from combinations of AdR and VEGFR inhibitors which are both currently being tested in clinical trials.
Double crossed? Structural and computational studies of an unusual crosslinked heme inMethylococcus capsulatuscytochrome P460
Authors: Pfalzgraf Hans E. , Rao Aditya G. , Sen Kakali , Adams Hannah R. , Edwards Marcus , Lu You , Yong Chin , Jaho Sofia , Tosha Takehiko , Sugimoto Hiroshi , Horrell Sam , Beilsten-Edmands James , Owen Robin L. , Andrew Colin R. , Worrall Jonathan A. R. , Tews Ivo , Mulholland Adrian J. , Hough Michael A. , Keal Thomas W. 
Published: December 2024

AbstractCytochromes P460 oxidise hydroxylamine within the nitrogen cycle and contain as their active site an unusual catalytic c-type heme where the porphyrin is cross-linked to the protein via a lysine residue in addition to the canonical cross links from cysteine residues. Understanding how enzymes containing P460 heme oxidise hydroxylamine into either nitrous oxide or nitric oxide has implications for climate change. Interestingly the P460 containing hydroxylamine oxidoreductase utilises a tyrosine cross link to heme and performs similar chemistry. Previous crystal structures of cytochrome P460 fromNitrosomonas europaea(NeP460) clearly show the existence of a single crosslink between the Nz atom of lysine and the heme porphyrin with mutagenesis studies indicating roles for the crosslink in positioning a proton transfer residue and/or influencing the distortion of the heme. Here we describe the evidence for a novel double cross link between lysine and heme in the cytochrome P460 fromMethylococcus capsulatus(Bath). In order to understand the complexities of this enzyme system we applied high resolution structural biology approaches at synchrotron and XFEL sources paired with crystal spectroscopies. Linked to this we carried out QM/MM simulations that enabled the prediction of electronic absorption spectra providing a crucial validation to linking simulations and experimental structures. Our work demonstrates the feasibility of a double crosslink in McP460 and provides an opportunity to investigate how simulations can interact with experimental structures.
Conversion of silent synapses to AMPA receptor-mediated functional synapses in human cortical organoids
Authors: Nishimura Masatoshi , Kodera Tomoki , Adachi Shota , Sato Akinori Y. , Takeuchi Ryosuke F. , Nonaka Hiroshi , Hamachi Itaru , Osakada Fumitaka 
Published: December 2024

AbstractDespite the crucial role of synaptic connections and neural activity in the development and organization of cortical circuits, the mechanisms underlying the formation of functional synaptic connections in the developing human cerebral cortex remain unclear. We investigated the development of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission using human cortical organoids (hCOs) derived from induced pluripotent stem cells. Two-photon Ca2⁺ imaging revealed an increase in the frequency and amplitude of spontaneous activity in hCOs on day 80 compared to day 50. Additionally, spontaneous neural activity in late-stage hCOs, but not in early-stage hCOs, was blocked by N-methyl-D-aspartate receptor (NMDAR) and AMPAR antagonists. However, transsynaptic circuit tracing with G-deleted rabies viral vectors indicated a similar number of synaptic connections in early- and late-stage hCOs. Notably, chemical labeling demonstrated a significant increase in AMPAR expression on the postsynaptic membrane and colocalization with NMDAR in late-stage hCOs. These results suggest that hCOs progressively organize excitatory synaptic transmission, concurrent with the transition from silent synapses lacking AMPARs to functional synapses containing NMDARs and AMPARs. Thisin vitromodel of human cortical circuits derived from induced pluripotent stem cells reflects the developmental programs underlying physiological transitions, providing valuable insights into human corticogenesis and neurodevelopmental disorders.Abstract Figure
Effortful control and cortical brain structure in 5-year-old children: findings from the FinnBrain birth cohort study
Authors: Frantti Meri , Tuulari Jetro J. , Nolvi Saara , Nordenswan Elisabeth , Copeland Anni , Kumpulainen Venla , Silver Eero , Merisaari Harri , Saukko Ekaterina , Kataja Eeva-Leena , Korja Riikka , Karlsson Linnea , Karlsson Hasse , Pulli Elmo P. 
Published: December 2024

AbstractThe aim of this study was to explore the associations between an aspect of self-regulation (SR), effortful control (EC), and cortical brain structure in 5-year-old children. Efficient EC is a predictor of many attributes and important outcomes in life, such as social-emotional functioning, psychiatric and somatic health, finance, and criminal activity. The early brain correlates of EC are not widely studied, while a better understanding of them would aid in recognizing individuals at risk for maladaptive outcomes. Participants (N = 155) were a part of the FinnBrain Birth Cohort Study in Finland. T1-weighted brain magnetic resonance images were processed using FreeSurfer. The data was statistically analysed with a vertex-wise general linear model. At the age of 5 years, EC and its subscales, Attentional focusing, Inhibitory control (INH), Low intensity pleasure (LIP) and perceptual sensitivity, were assessed via parental report using The Children’s Behaviour Questionnaire. We found positive associations between overall EC and cortical volume in the left superior parietal region and in the right inferior temporal region. We also found positive associations between EC and surface area on the left hemisphere in the superior parietal region. The findings were driven by the EC subscales of INH and LIP with INH linking positively with left surface area and volume, and LIP linking with left cortical volume. We extended the previous literature by shedding light on early structural brain correlates of EC in a large sample of typically developing 5-year-olds. The results differed significantly from previous findings in older children, highlighting the need for longitudinal studies to better understand the neural underpinnings of SR throughout development.