bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroanatomical pathways of TMS therapy for depression
Authors: Seguin Caio , Mansour Sina , Betzel Richard F , Chumin Evgeny , Puxeddu Maria Grazia , Lv Jinglei , Parkes Linden , Cocchi Luca , Fitzgerald Paul B , Cash Robin F , Zalesky Andrew
Published: February 2025

TMS therapy for depression delivered to the dorsolateral prefrontal cortex (DLPFC) aims to modulate activity in the subgenual cingulate cortex (SGC). However, these regions lack direct axonal connections, and the neuroanatomical mechanisms underlying the therapy's efficacy remain unknown. Here, we use connectome modelling to map polysynaptic fibre pathways from the DLPFC to the SGC that are associated with TMS treatment response in depression. We show that polysynaptic communication through the structural connectome is correlated with treatment response in two independent cohorts of patients treated with TMS to the left DLPFC (r = -0.56, p = 0.0018; r = -0.52, p = 0.0047), and that DLPFC sites of stronger negative functional connectivity to the SGC are connected to it via shorter fibre pathways. Our results shed light onto the neuroanatomical basis of TMS therapy for depression and pave the way for brain stimulation protocols based on polysynaptic communication via the connectome.
Brucellaproline racemase protein A targets Tpl2 to promote IL-10 secretion for establishment of chronic infection
Authors: Zhang Huan , Wang Yuanzhi , Wang Yueli , Hou Huilin , Wang Yaqian , Deng Xiaoyu , Xu Zhenyu , Xia Xujin , Xu Mingguo , Wang Zhen , Wang Yong , Zhang Changsuo , Zhumanov Kait , Sheng Jinliang , Zhang Hui , Ma Zhongchen , Yi Jihai , Chen Chuangfu
Published: February 2025

IL-10, an anti-inflammatory cytokine, plays a crucial role in limiting immune responses to pathogens, preventing host damage. However, the mechanisms underlyingBrucella-mediated IL- 10 production remain incompletely understood. In this study, we demonstrate that the proline racemase protein A (PrpA) ofBrucella melitensisM5-90 induces macrophages to secrete IL-10 by activating the Tpl2-ERK signaling pathway, thereby promoting chronic infection. Moreover,Tpl2deletion impairs macrophage bactericidal ability, accompanied by reduced TNF-α and IL-1β but unaffected IL-10 levels. Additionally, Trp309, Glu103, and Glu129 of PrpA participate in interaction with Tpl2, but these residues do not influence PrpA-mediated IL-10 production in macrophages.PrpAdeletion enhances IFN-γ levels, specific anti-BrucellaIgG, and CD4+ and CD8+ T cell numbers in mice. Furthermore, theBrucella melitensisM5-90prpAmutant provides higher protection than the parental strain against virulentBrucella melitensisM28 infection in mice. Our findings suggest thatBrucellaPrpA promotes IL-10 secretion by macrophages through Tpl2 activation for bacterial survival and persistent infection, making theBrucella melitensisM5-90prpAmutant a promising vaccine for enhanced protection.

Author Summary

IL-10, an anti-inflammatory cytokine, is exploited byBrucellafor survival. We identifiedBrucellaPrpA as a potent IL-10 inducer, activating the Tpl2-ERK signaling pathway.Tpl2deletion increasedBrucellasurvival in macrophages, accompanied by reduced TNF-α and IL-1β but unaffected IL-10 secretion. Residues (Trp309, Glu103, and Glu129) of PrpA were crucial for interaction with Tpl2, yet did not impact PrpA-mediated IL-10 production. TheB. melitensisM5-90prpAmutant induced higher anti-BrucellaIgG, IFN-γ, and CD4+ and CD8+ T cell numbers in mice, providing better protection thanB. melitensisM5-90. These findings unveil PrpA’s role in IL-10 production and highlight the potential of theB. melitensisM5-90prpAmutant as a promising vaccine for further evaluation.
Complex Human Hair Bearing Skin Organoids as Model for Herpes Simplex Virus 1 Infection in the Skin
Authors: Wyler Emanuel , Albertini Silvia , Friedel Caroline C. , Manukyan Artür , Huang Jiabin , Krasemann Susanne , Plumbom Izabela , Altmüller Janine , Conrad Thomas , Radbruch Helena , Hafezi Wali , Hansen Arne , Grundhoff Adam , Landthaler Markus , Fischer Nicole , Czech-Sioli Manja
Published: February 2025

For Herpes Simplex Virus 1 (HSV-1) the skin is the primary site of infection. After the primary lytic infection, the virus enters the peripheral nervous system where it establishes latency. Spontaneous reactivation from the latently infected neurons leads to the typical HSV-1-induced diseases like cold sores. Modelling HSV-1-induced skin pathologies is challenging due to the variety of different cell types and structures in the skin and human-specific responses to the infection. Nevertheless, studies using monolayer cell lines, raft cultures,ex vivoskin and mouse models provided an immense contribution to our understanding of HSV-1 infection in the skin. However, the contribution of many skin-specific structures, especially hair follicles, to primary infection and reactivation remains unclear. In this study, we used complex human hair bearing skin organoids that were derived from induced pluripotent stem cell as a model for HSV-1 infection. We performed microscopy, bulk and spatial transcriptomics with single cell resolution to gain new insights into the cell-type specific viral life cycle and host responses. We show a restricted viral infection in keratinocytes of the epidermis and specific cell types of hair follicles. We show a cell type specific induction of interferon-stimulated genes and the TNF pathway. We can follow paracrine signaling through the tissue, showing that TNF response genes are upregulated in adjacent cells. Taken together, the skin organoids in combination with novel spatial transcriptomics techniques provide a physiologically highly relevant model system for HSV-1 infection in the skin.
Age-Dependent Patterns of GutBifidobacteriumMicrobiome Diversity across child Cohorts in a Multi-Ethnic population, Western China
Authors: Huang Jian , Chu Yuxin , Zhixuan Liang , Zhang Huimin , Zhao Quanhao , Tian Fengwei , Ni Yongqing
Published: February 2025

High-throughput sequencing has provided unprecedented opportunities to elucidate the role of human gut microbiota. However, current studies have primarily focused on infant and adult cohorts, leaving biomarkers associated with the development of transitional children unclear, particularly in revealing geographic, multi-ethnic group underrepresented. Here, we analyzed fecal samples from 776 infants and children aged 0 to 15 years with amplicon sequencing of the 16S rRNA andgroELgene, representing multi-ethnic groups from different residential locations in the Yining region of Xinjiang. First, we systematically characterized the gut microbiota Spectrum of children in the Ili region. As age increases, the diversity and functional composition of the microbiota become richer and more stable, withBifidobacteriumconsistently dominating the community. Utilizing Bayesian regression models, we identified a cluster of microbiota strongly associated with growth and development in children, which phylogenetically corresponds toBifidobacterium breve. Finally, we included another similar study in the species-level ofBifidobacterium, and metrics of the age-related effect sizes showed heterogeneity across ethnic groups (Uyghur vs Han: βDeming= 4.40 and Kazakh vs Han: βDeming= 4.33). In conclusion, this study provides novel insights into the developmental trajectories of the gut microbiome in children and its relationship with health.

IMPORTANCE

The intestinal microbial markers associated with the development of geographically diverse, multi-ethnic children, particularly those represented by Bifidobacterium species, have been elucidated in this study. Through the application of Bayesian regression models, we identified a microbiome profile closely linked to childhood growth and development, specifically phylogenetically aligned withBifidobacterium breve. When incorporating a comparable study conducted at the species level of anotherBifidobacterium, it was observed that age-related effect sizes varied among different ethnic groups, offering novel insights into the developmental trajectory of children’s gut microbiota and its implications for health.
Spatially distinct cellular and molecular landscapes define prognosis in triple negative breast cancer
Authors: Mukund Kavitha , Veraksa Darya , Frankhouser David , Yang Lixin , Tomsic Jerneja , Pillai Raju , Atti Srijan , Mesrizadeh Zahra , Schmolze Daniel , Wu Xiao-Cheng , LeBlanc Mary-Anne , Miele Lucio , Ochoa Augusto , Seewaldt Victoria , Subramaniam Shankar
Published: February 2025

Background

Triple-negative breast cancer is a prevalent breast cancer subtype with the lowest 5-year survival. Several factors contribute to its treatment response, but the inherent molecular and cellular tumor heterogeneity are increasingly acknowledged as crucial determinants.

Methods

Spatial transcriptomic profiling was performed on FFPE tissues from a retrospective, treatment-naive group of women with differential prognoses (17 with >15 years survival-good prognosis (GPx) and 15 with <3 years survival-poor prognosis (PPx)) using GeoMX®Digital Spatial Profiler. Regions of interest were segmented on pan-cytokeratin and analyzed for tumor and stromal components, probed using GeoMx human whole transcriptome atlas (WTA) panel. Data quality control, normalization, and differential analysis was performed in R using GeomxTools and linear mixed models. Additional analyses including cell-type deconvolution, spatial entropy, functional enrichment, TF-target / ligand-receptor analysis and convolution neural networks were employed to identify significant gene signatures contributing to differential prognosis.

Results

Here we report on the spatial and molecular heterogeneity underlying differential prognosis. We observe that the state of the epithelia and its microenvironment (TME) are transcriptionally distinct between the two groups. Invasive epithelia in GPx show a significant increase in immune transcripts with the TME exhibiting increased immune cell presence (via IF), while in PPx they are more metabolically and translationally active, with the TME being more mesenchymal/fibrotic. Specifically, pre-cancerous epithelia in PPx display a prescience of aggressiveness as evidenced by increased EMT-signaling. We identify distinct epithelial gene signatures for PPx and GPx, that can, with high accuracy, classify samples at the time of diagnosis and likely inform therapy.

Conclusions

To the best of our knowledge, this is the first study to leverage spatial transcriptomics for an in-depth delineation of the cellular and molecular underpinnings of differential prognosis in TNBC. Our study highlights the potential of spatial transcriptomics to not only uncover the molecular drivers of differential prognosis in TNBC but also to pave the way for precision diagnostics and tailored therapeutic strategies, transforming the clinical landscape for this aggressive breast cancer subtype.
Cryo-EM ligand building using generative AI and molecular dynamics
Authors: Haloi Nandan , Howard Rebecca J. , Lindahl Erik
Published: February 2025

Resolving protein-ligand interactions in atomic detail is key to understanding how small molecules regulate macromolecular function. Although recent break-throughs in cryogenic electron microscopy (cryo-EM) have enabled high-quality reconstruction of numerous complex biomolecules, the resolution of bound ligands is often relatively poor. Furthermore, automated methods for building and refining molecular models into cryo-EM maps have largely focused on proteins and may not be optimized for the diverse properties of small-molecule ligands. Here, we present an approach that integrates generative artificial intelligence (AI) with cryo-EM density-guided simulations to fit ligands into experimental maps. Using three inputs: 1) a protein amino acid sequence, 2) a ligand specification, and 3) an experimental cryo-EM map, we validated our approach on a set of biomedically relevant protein-ligand complexes including kinases, GPCRs, and solute transporters, none of which were present in the AI training data. In cases for which generative AI was not sufficient to predict experimental poses outright, integration of flexible fitting into molecular dynamics simulations improved ligand model-to-map cross-correlation relative to the deposited structure from 40–71% to 82–95%. This work offers a straightforward template for integrating generative AI and density-guided simulations to automate model building in cryo-EM maps of ligand-protein complexes, with potential applications for characterization and design of novel modulators and drugs.
Chimeric infective particles expand species boundaries in phage inducible chromosomal island mobilization
Authors: He Lingchen , Patkowski Jonasz B. , Miguel-Romero Laura , Aylett Christopher H S , Fillol-Salom Alfred , Costa Tiago R. D. , Penadés José R
Published: February 2025

Some mobile genetic elements spread among unrelated bacterial species through unknown mechanisms. Recently, we discovered that identical capsid-forming phage-inducible chromosomal islands (cf-PICIs), a new family of phage satellites, are present across multiple species and genera, raising questions about their widespread dissemination. Here we have identified and characterized a new biological entity enabling this transfer. Unlike other satellites, cf-PICIs produce their own capsids and package their DNA, relying solely on phage tails for transfer. Remarkably, cf-PICIs release non-infective, tail-less capsids containing their DNA into the environment. These subcellular entities then interact with phage tails from various species, forming chimeric particles that inject DNA into different bacterial species depending on the tail present. Additionally, we elucidated the structure of the tail-less cf-PICIs and the mechanism behind their unique capsid formation. Our findings illuminate novel mechanisms used by satellites to spread in nature, contributing to bacterial evolution and the emergence of new pathogens.
Functional Dynamics Reveal the Response of the Crabapple (Malussp.) Phyllosphere Microbiome toGymnosporangium yamadaeInfection
Authors: Xu Qianran , Zhang Yonghua , Tao Siqi
Published: February 2025

The plant microbiome is crucial for maintaining plant health under disease stress. While considerable research has focused on belowground systems, the phyllosphere microbiome remains underexplored, particularly regarding its functional responses to pathogen infection. In this study, we investigated the phyllosphere microbiome dynamics of crabapple (Malus‘Kelsey’) infected byGymnosporangium yamadaeusing metatranscriptomic sequencing across six stages of rust disease progression. Our analysis revealed a general increase in the diversity of fungi, bacteria and viruses in infected leaves. Notably, fungal diversity negatively correlated with bacterial diversity, reflecting competitive interactions during disease development. Microbial taxa in diseased leaves exhibited heightened expression activity compared to healthy leaves, with fungi progressively dominating the microbial community. Functional co-occurrence networks of the phyllosphere microbiome in infected leaves were more complex than in healthy leaves, suggesting adaptive reorganization in response to pathogen invasion. Differentially expressed genes at each stage were significantly enriched in carbohydrate metabolism pathways and gene regulation-related functions, enabling functional adaptations to rust diseases. Random forest modeling identified key microbial transcripts associated with pathogen abundance, including beneficial microbes likeSaitozyma podzolica, which secretes glucan-degrading enzymes, andMortierella elongata, involved in sterol biosynthesis and plant resistance. Conversely,Alternaria alternataemerged as a major pathobiome contributor, secreting enzymes that degrade plant cell wall components (e.g., pectin, cellulose, lignin, and xylan), and engaging in MAPK signaling pathways critical for pathogenesis. Our findings underscore the vital role of the phyllosphere microbiome in mediating plant-pathogen interactions and shaping disease progression, providing a foundation for microbiome-based strategies to enhance plant resilience.

Importance

Our findings reveal the dynamic shifts in the expression patterns and adaptive functional strategies of crabapple phyllosphere microbiome in response to theGymnosporangium yamadaeinfection. We identified several key microbes that may play vital roles in pathogenesis and speculated on their roles and functions in plant-pathogen interactions. In conclusion, our study highlights the potential of the phyllosphere microbiome in regulating plant health.
A prevalent Krt8-to-Krt5 cellular state transition in skin is co-opted by p63 for enamel organ development
Authors: Tang Qinghuang , Lee Jung-Mi , Li Liwen , Cai Chunmiao , Jung Hunmin , Kwon Hyuk-Jae Edward
Published: February 2025

Tooth enamel, the hardest tissue in vertebrates, is crucial for mastication and dental protection. Its formation depends on the enamel organ (EO), a specialized epithelial structure derived from oral epithelium. A fundamental question persists: how does uniform oral epithelium differentiate into diverse EO cell types? While p63, a master regulator of ectodermal development, coordinates multiple signaling pathways essential for dental placode formation, its specific roles in EO development remain unclear due to the early developmental arrest inp63knockout mice. Using single-cell RNA sequencing data from mouse incisors, we demonstrate thatp63is expressed across all EO cell types, serving both shared and distinct functions. Through trajectory reconstruction, we identify the role of p63 in regulating both amelogenic (AmG) and non-AmG lineage commitment during EO development. Our comparative transcriptome analyses reveal that p63 regulates the Krt8-to-Krt5 transition during AmG cell differentiation, paralleling its function in skin development. This parallel is reinforced by comparative motif discovery, revealing shared transcription factor usage, particularly p63 and AP-2 family members, in both AmG and skin epidermal cells during this transition. Chromatin accessibility analysis further illustrate that p63 mediates this transition through chromatin landscape remodeling. Together, these findings demonstrate that p63 co-opts the Krt8-to-Krt5 transition mechanism from skin development for EO development, providing novel insights into the molecular mechanisms underlying EO development and potential therapeutic targets for enamel disorders.
Gpnmb Defines a Phagocytic State of Microglia Linked to Neuronal Loss in Prion Disease
Authors: Caredio Davide , Mariutti Giovanni , Cerisoli Martina , Polzer Lisa , Laimeche Yasmine , Miracca Giulia , Emmenegger Marc , Schmitz Matthias , Zerr Inga , De Cecco Elena , Aguzzi Adriano
Published: February 2025

The reaction of different cell types to prion infections is highly heterogeneous. While neurons experience spine retraction and eventually death, astrocytes and microglia undergo strong activation and proliferation. Here we analyzed the cell-type specific responses to prion diseases by establishing a spatiotemporal transcriptomic atlas of mice infected with RML prion strain. Brain areas with severe neuronal loss, such as the thalamus and cerebellum, experienced intense microgliosis. Starting from 30 weeks post-inoculation, we observed the accumulation of a novel microglial subpopulation characterized by strong expression ofGpnmbin these brain regions. The molecular profile ofGpnmb+microglia reflected a state of enhanced phagocytic activity with upregulation of genes associated with lysosomal function and degradation, including vacuolar ATPase V0 domain subunit d2 (Atp6v0d2) and Galectin-3 (Lgals3). In microglial-like, murine BV2 cells, Gpnmb upregulation was induced by soluble find-me signals released during apoptosis, but not by apoptotic bodies or prion accumulation. Gpnmb ablation in BV2 cells impaired their ability to phagocytose apoptotic cells, underscoring its essential role in maintaining microglial phagocytosis. Our findings defineGpnmb⁺ microglia as a distinct, apoptosis-driven phagocytic state, linking neuronal loss to microglial activation in prion disease. The upregulation of GPNMB in sCJD patients, along with its role in apoptotic clearance and lysosomal function, positions it as both a key regulator of microglial responses and a potential biomarker of disease progression.
ReaxFF-guided Optimisation of VIRIP-based HIV-1 Entry Inhibitors
Authors: Zech Fabian , Jung Christoph , Rodríguez-Alfonso Armando Alexei , Köhler Janet , Ständker Ludger , Weidinger Gilbert , Jacob Timo , Kirchhoff Frank
Published: February 2025

Peptides hold great promise for safe and effective treatment of viral infections. However, their use is often constrained by limited efficacy and high production costs, especially for long or complex peptide chains. Here, we used ReaxFF molecular dynamics (MD) simulations to optimize the size and activity of VIRIP (Virus Inhibitory Peptide), a naturally occurring 20-residue fragment of α1-antitrypsin that binds the HIV-1 GP41 fusion peptide (FP), thereby blocking viral fusion and entry into host cells. Specifically, we used the NMR structure of the complex between an optimized VIRIP derivative (VIR-165) and the HIV-1 gp41 FP for ReaxFF-guidedin silicoanalysis, evaluating the contribution of each amino acid in the interaction of the inhibitor with its viral target. This approach allowed us to reduce the size of the HIV-1 FP inhibitor from 20 to 10 amino acids (2.28 to 1.11 kDa). HIV-1 infection assays showed that the size-optimized VIRIP derivative (soVIRIP) retains its broad-spectrum anti-HIV-1 capability and is non-toxic in the vertebrate zebrafish model. Compared to the original VIRIP, soVIRIP displayed more than 100-fold higher antiviral activity (IC50of ∼120 nM). Thus, it is more potent than a dimeric 20-residue VIRIP derivative (VIR-576) that was proven safe and effective in a phase I/II clinical trial. Our results show that ReaxFF-based MD simulations represent a suitable approach for the optimization of therapeutic peptides.
Cryo-EM analysis of theBacillus thuringiensisextrasporal matrix identifies F-ENA as a widespread family of endospore appendages across the Firmicutes phylum
Authors: Sleutel Mike , Sogues Adrià , Gerven Nani Van , Jonsmoen Unni Lise , Molle Inge Van , Fislage Marcus , Theunissen Laurent Dirk , Bellis Nathan F. , Baquero Diana P. , Egelman Edward H. , Krupovic Mart , Wang Fengbin , Aspholm Marina , Remaut Han
Published: February 2025

For over 100 years,Bacillus thuringiensis(Bt) has been used as an agricultural biopesticide to control pests caused by insect species in the orders of Lepidoptera, Diptera and Coleoptera. Under nutrient starvation, Bt cells differentiate into spores and associated toxin crystals that can adopt biofilm-like aggregates. We reveal that such Bt spore/toxin biofilms are embedded in a fibrous extrasporal matrix (ESM), and using cryoID, we resolved the structure and molecular identity of an uncharacterized type of pili, referred to here asFibrillarENdosporeAppendages or ‘F-ENA’. F-ENA are monomolecular protein polymers tethered to the exosporium of Bt and are decorated with a flexible tip fibrillum. Phylogenetic analysis reveals that F-ENA is widespread not only in the class Bacilli, but also in the class Clostridia, and the cryoEM structures of F-ENA filaments fromBacillus, AnaerovoraxandPaenibaccilusreveal subunits with a generic head-neck domain structure, where the β-barrel neck of variable length latch onto a preceding head domain through short N-terminal hook peptides. InBacillus, two collagen-like proteins (CLP) respectively tether F-ENA to the exosporium (F-Anchor), or constitute the tip fibrillum at the distal terminus of F-ENA (F-BclA). Sedimentation assays point towards F-ENA involvement in spore-spore clustering, likely mediated via F-BclA contacts and F-ENA bundling through the antiparallel interlocking of the head-neck units.
The Influence of Spatial Frequencies, Orientation and Familiarity on Face Stimuli Integration
Authors: Cuomo Maria , Federico Giovanni , Fracasso Alessio , Buonocore Antimo
Published: February 2025

When we observe an object, our visual system identifies its shape and integrates it with specific details to form a coherent representation. Thiscoarse-to-fineapproach involves rapid processing of low spatial frequency (LSF) content to generate a basic template, which aids the integration of the more detailed high spatial frequency (HSF) information. Here we explore with two experiments how the contribution of LSF and HSF integration extends to face processing. To do so, we leveraged the face inversion effect, whereby inverted faces are more difficult to recognize than upright ones. In Experiment 1, ten participants matched two familiar faces displayed in rapid succession (template and probe face, respectively). The template and the probe shared either the same SF (congruent) or had complementary SF (incongruent). In congruent conditions, HSF templates yielded better matching accuracy than LSF templates. However, in incongruent conditions, mapping LSF probes onto HSF templates was more effective, but only for upright faces. We propose that, depending on the task, holistic processing may be facilitated by detailed information. In Experiment 2, twelve participants performed the same task with both familiar and unfamiliar faces. While for familiar faces the effects were the same as Experiment 1, for unfamiliar faces the overall accuracy was better for congruent than incongruent conditions, and, crucially, it was independent of the template SF. Our results challenge the view that LSF content provides a foundational template for integrating HSF information, and instead suggest a flexible encoding of SF information, that depends on image contingencies.
Mouse scalp development requires Rac1 and SRF for the maintenance of mechanosensing mesenchyme
Authors: Rathnakar Bharath H. , Rackley Alex , Kwon Hae Ryong , Berry William L. , Olson Lorin E.
Published: February 2025

Regulation of essential cellular responses like proliferation, migration, and differentiation is crucial for normal development. Rac1, a ubiquitously expressed small GTPase, executes these responses under the regulation of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GTPases). Mutations in specific GEFs (DOCK6) and GTPases (AHGAP31) that regulate Rac1 are associated with Adams-Oliver syndrome (AOS), a developmental syndrome characterized by congenital scalp defects and limb truncations. Genetic ablation ofRac1in the mouse embryonic limb ectoderm results in limb truncation. However, the etiology of Rac1-associated cranial defects is unknown. To investigate the origin and nature of cranial defects, we used a mesenchymal Cre line (Pdgfra-Cre) to deleteRac1in cranial mesenchyme.Rac1-KO mice died perinatally and lacked the apical portion of the calvarium and overlying dermis, resembling cranial defects seen in severe cases of AOS. In control embryos, α-smooth muscle actin (αSMA) expression was spatially restricted to the apical mesenchyme, suggesting a mechanical interaction between the growing brain and the overlying mesenchyme. InRac1-KO embryos there was reduced proliferation of apical mesenchyme, and reduced expression of αSMA and its regulator, serum response factor (SRF). Remarkably,Srf-KO mice generated withPdgfra-Crerecapitulated the cranial phenotype observed inRac1-KO mice. Together, these data suggest a model where Rac1 and SRF are critical to maintaining apical fibroblasts in a mechano-sensitive and proliferative state needed to complete cranial development.
Disruption of Mitochondrial Dynamics and Stasis Leads to Liver Injury and Tumorigenesis
Authors: Ma Xiaowen , Wei Xiaoli , Niu Mengwei , Zhang Chen , Peng Zheyun , Liu Wanqing , Yan Junrong , Su Xiaoyang , Lu Shaolei , Cui Wei , Sesaki Hiromi , Zong Wei-Xing , Ni Hong-Min , Ding Wen-Xing
Published: February 2025

Background & Aims

Mitochondrial dysfunction has been implicated in aging and various cancer development. As highly dynamic organelles, mitochondria constantly undergo fission, mediated by dynamin-related protein 1 (DRP1, gene nameDnm1l), and fusion, regulated by mitofusin 1 (MFN1), MFN2, and optic atrophy 1 (OPA1). However, whether and how dysregulation of mitochondria dynamics would be involved in liver pathogenesis and tumorigenesis is unknown.

Methods

Dnm1lFlox/Flox (Dnm1lF/F),Mfn1F/FandMfn2F/Fmice were crossed with albumin-Cre mice to generate liver-specificDnm1lknockout (L-Dnm1lKO), L-Mfn1KO, L-Mfn2KO, L-Mfn1, Mfn2double KO (DKO), and L-Mfn1, Mfn2, Dnm1ltriple KO (TKO) mice. These mice were housed for various periods up to 18 months. Some mice also received hydrodynamic tail vein injections of a Sleeping Beauty transposon-transposase plasmid system withc-MYCandYAP. Blood and liver tissues were harvested for biochemical and histological analysis.

Results

L-Dnm1lKO mice had elevated serum alanine aminotransferase levels and increased hepatic fibrosis as early as two months of age. By 12 to 18 months, male L-Dnm1lKO mice developed spontaneous liver tumors, primarily hepatocellular adenomas. While female L-Dnm1lKO mice also developed liver tumors, their incidence was much lower.

In contrast, neither L-Mfn1KO nor L-Mfn2KO mice had notable liver injury or tumorigenesis. However, a small portion of DKO mice developed tumors at 15-18 month-old. Increased DNA damage, senescence and compensatory proliferation were observed in L-Dnm1lKO mice but were less evident in L-Mfn1KO, L-Mfn2KO or DKO mice, indicating that mitochondrial fission is more important to maintain hepatocyte homeostasis and prevent liver tumorigenesis. Interestingly, further deletion ofMfn1andMfn2in L-Dnm1lKO mice markedly abolished liver injury, fibrosis, and both spontaneous and oncogene-induced tumorigenesis. RNA sequencing and metabolomics analysis revealed significant activation of the cGAS-STING-interferon pathway and alterations in the tumor microenvironment pathways, alongside increased pyrimidine synthesis and metabolism in the livers of L-Dnm1lKO mice. Notably, the changes in gene expression and pyrimidine metabolism were considerably corrected in the TKO mice.

Conclusions

Mitochondrial dynamics and stability are essential for maintaining hepatic mitochondrial homeostasis and hepatocyte functions. Loss of hepatic DRP1 promotes liver tumorigenesis by increasing pyrimidine metabolism and activating the cGAS-STING-mediated innate immune response.
Processingof Clostridium perfringensEnterotoxin by Intestinal Proteases
Authors: Shrestha Archana , Gonzales Jessica L. , Beingesser Juliann , Uzal Francisco A. , McClane Bruce A.
Published: February 2025

C. perfringenstype F isolates are a leading cause of food poisoning and antibiotic-associated diarrhea. Type F isolate virulence requires production ofC. perfringensenterotoxin [CPE], which acts by forming large pore complexes in host cell plasma membranes. During disease, CPE is produced in the intestines when type F strains undergo sporulation. The toxin is then released into the intestinal lumen when the mother cell lyses at the completion of sporulation. Once present in the lumen, CPE encounters intestinal proteases. This study examinedin vitro,ex vivoandin vivoprocessing of CPE by intestinal proteases and the effects of this processing on CPE activity. Results using purified trypsin or mouse intestinal contents detected rapid cleavage of CPE to a major band of ∼32 kDa and studies with Caco-2 cells showed this processed CPE still forms large complexes and retains cytotoxic activity. When mouse small intestinal loops were challenged with CPE, the toxin caused intestinal histologic damage despite rapid proteolytic processing of most CPE to 32 kDa within 15 min. Intestinal large CPE complexes became more stable with longer treatment times. These results indicate that CPE processing involving trypsin occurs in the intestines and the processed toxin retains enterotoxicity.
Borax-Based Gel Electrophoresis: A Novel Approach for RNA Integrity Analysis
Authors: Albaser Abdulhadi
Published: February 2025

This study explores the feasibility of using borax-based agarose gel electrophoresis for RNA integrity assessment. Multiple independent experiments demonstrated that borax, in addition to its buffering properties, exhibits denaturing-like behavior, effectively separating RNA molecules with comparable resolution to formaldehyde-based methods. This finding is surprising, given that theoretically, no evidence for borax denaturing activity exists, as it is typically considered a non-denaturing buffer. This method offers a compelling alternative to traditional formaldehyde-based methods for RNA analysis in various research and clinical settings, offering several advantages, including enhanced safety, simplified protocols, and reduced electrophoresis time. By eliminating the need for pre-treatment steps and utilizing borax as both a buffer and denaturant, this method simplifies RNA analysis. While the precise mechanism underlying this denaturing-like effect remains to be elucidated, further studies are needed to fully characterize these properties and explore its broader applicability.
Enhanced Neural Plasticity of the Primary Visual Cortex in Visual Snow Syndrome: Evidence from MEG Gamma Oscillations
Authors: Orekhova E.V. , Naumova S.M , Obukhova T.S. , Plieva A.M. , Prokofiev A.O. , Petrokovskaia A.V. , Artemenko A.R. , Stroganova T.A.
Published: February 2025

Visual Snow Syndrome (VSS) is a neurological disorder characterized by persistent visual disturbances and associated symptoms. Although the neural basis of VSS remains poorly understood, it may involve increased neuronal excitability and/or altered neuroplasticity in the visual cortex, which could, in turn, affect visual gamma oscillations. An altered excitation-inhibition (E-I) balance is hypothesized to alter the modulation of gamma power and frequency by stimulation intensity, while maladaptive neuroplasticity may impact time-dependent changes in gamma power during repeated stimulation.

To investigate potential alterations in E-I balance and neuroplasticity in VSS, we magnetoencephalography to record visual gamma oscillations in 26 VSS patients and 27 healthy controls. Participants were exposed to repeatedly presented high-contrast annular gratings, which were either static or drifting at varying speeds to systematically manipulate stimulation intensity. We also measured heart rate variability (HRV) during rest and repetitive visual stimulation to explore the relationship between time-dependent gamma changes and parasympathetic activation, which is known to promote activity-dependent plasticity.

Our results showed no significant group differences in gamma power or frequency, nor in their modulation by drift rate, suggesting that the excitation-inhibition (E-I) balance in the primary visual cortex remains largely intact in VSS. Both groups exhibited an initial brief decrease in gamma power followed by a sustained linear increase with stimulus repetition, likely reflecting activity-dependent plasticity. HRV parameters were comparable across groups, with the parasympathetic-sympathetic balance index correlating with repetition-related increase in gamma power, further supporting the link between time-dependent gamma changes and neuroplasticity. Notably, VSS patients exhibited a steeper repetition-related increase in gamma power, indicating atypically heightened activity-dependent plasticity in this group.

These findings provide the first experimental evidence suggesting that altered activity-dependent neuroplasticity plays a role in the pathophysiology of VSS. Furthermore, they identify repetition-related increases in gamma power as a potential biomarker of aberrant neuroplasticity, offering novel insights into VSS pathophysiology and potential avenues for targeted therapeutic interventions.
High-energy-density acoustofluidic device using a double-parabolic ultrasonic transducer
Authors: Corato Enrico , Jakobsson Ola , Qiu Wei , Morita Takeshi , Augustsson Per
Published: February 2025

High-acoustic-energy-density acoustofluidic devices are necessary to make this technology a viable option for clinical applications in the biomedical field. We present a mechanical interface that enables delivery of a high-amplitude acoustic field inside a fluid cavity by translating the vibrations from two large piezoelectric elements into a microfluidic chip. The study comprises both experimental characterization of a double-parabolic metallic acoustic waveguide and simulations of its working mechanism in two dimensions. We could focus 4.9-µm polystyrene particles at a flowrate of 5 ml/min, corresponding to an average retention time of 13.5 ms for particles in the actuated area. Moreover, we measured the acoustic energy density in the channel at stopped-flow condition, obtaining an average value of 1207 J/m3 and a maximum value of 2977 J/m3 with an input electrical power of 1.5 W. By comparing the simulation results with laser-Doppler vibrometer measurements, we confirmed that transverse sound waves play a significant role in the working mechanism of the double-parabolic structure, thus paving the way for further future optimization of the waveguide design.

Published by the American Physical Society
2025
Spin-split Andreev bound states and diode effect in an Ising superconductor Josephson junction
Authors: Patil Sourabh , Tang Gaomin , Belzig Wolfgang
Published: February 2025

The transition-metal dichalcogenides featuring Ising spin-orbit coupling in so-called Ising superconductors offer a unique system to study the interplay of singlet and triplet superconductivity. The presence of high critical fields, spectral properties such as the mirage gap, and field-tunable charge and spin currents in Ising superconductor Josephson junctions are some of the important features. In this Letter, we study an Ising superconductor Josephson junction with a transparent interface and show that Andreev bound states are spin split due to a relative misorientation of in-plane fields in the superconducting contacts. Correspondingly, supercurrent-phase relations display a strongly nonsinusoidal behavior. Introducing additional spin-polarized channels with low transmission results in a nonreciprocal current-phase relation with a diode effect that can be tuned by the in-plane exchange fields. The diode efficiency reaches high values of the order of 40% and is not sensitive to disorder in the junction. Such structures can be realized in van der Waals heterostructures of two-dimensional superconductors and magnets.

Published by the American Physical Society
2025
Chiral perturbation theory and Bose-Einstein condensation in QCD
Authors: Andersen Jens O. , Johnsrud Martin Kjøllesdal , Yu Qing , Zhou Hua
Published: February 2025

We present recent results in three-flavor chiral perturbation theory at finite isospin μI and strangeness μS chemical potentials at zero temperature. The tree-level spectrum for the mesons and gauge bosons in the pion-condensed phase is derived. The phase diagram to O(p2) in the μI–μS plane is mapped out with and without electromagnetic effects. The phase diagram consists of a vacuum phase and three Bose-condensed phases with condensates of π±, K±, and

K

0

/

K

¯

0

, respectively. Including electromagnetic interactions, the charged Bose-condensed phases become Higgs phases via the Higgs mechanism. We calculate the pressure, energy density, isospin density, and speed of sound in the pion-condensed phase to O(p4). The results are compared with recent lattice simulations and the agreement is very good for isospin chemical potentials up to approximately 180 MeV. Moreover, by integrating out the s-quark, we show that the thermodynamic quantities can be mapped onto their two-flavor counterparts with renormalized parameters. The breaking of the U(1) symmetry in the Bose-condensed phases gives rise to a Goldstone boson, whose dispersion is linear for small momenta. We use Son’s prescription to construct an effective theory for the Goldstone mode in the pion-condensed phase, which is valid for momenta p≪μI. It is shown that its damping rate is of order p5 in the nonrelativistic limit, which is Beliaev’s result for a dilute Bose gas. It is also shown that in the nonrelativistic limit the energy density can be matched onto the classic result by Lee, Huang and Yang (LHY) for a dilute Bose, with an s-wave scattering length that includes radiative corrections.

Published by the American Physical Society
2025
Low scale leptogenesis under neutrino
μ−τ
reflection symmetry
Authors: Shao Yan , Zhao Zhen-hua
Published: February 2025

In the literature, the neutrino μ−τ reflection symmetry (which has the interesting predictions θ23=π/4 and δ=±π/2 for the atmospherical neutrino mixing angle and Dirac CP phase) is an attractive and widely studied candidate for the flavor symmetries in the neutrino sector. However, it is known that, when the seesaw model is furnished with this symmetry, the leptogenesis mechanism (which provides an elegant explanation for the baryon-antibaryon asymmetry of the Universe) can only work in the two-flavor regime (which only holds for the right-handed neutrino masses in the range 109–1012  GeV). This prohibits us to have a low scale seesaw model (which has the potential to be directly accessed by running or upcoming collider experiments) that can have the μ−τ reflection symmetry and successful leptogenesis simultaneously. In this paper, for the first time, we demonstrate that the successful leptogenesis may also be achieved in low scale seesaw models furnished with the μ−τ reflection symmetry, by means of the flavor nonuniversality of the conversion efficiencies from the flavored lepton asymmetries to the baryon asymmetry via the sphaleron process. We perform the study in both the resonant leptogenesis regime and the leptogenesis via oscillations (Akhmedov-Rubakov-Smirnov leptogenesis) regime.

Published by the American Physical Society
2025
Neutral Sulfur Atom Formation in Decay of Deep Core Holes in
SF6
Authors: Travnikova Oksana , Trinter Florian , Agåker Marcus , Visentin Giorgio , Andersson Joakim , Kjellsson Ludvig , Ismail Iyas , Velasquez Nicolas , Koulentianos Dimitris , Harder Manuel , Yin Zhong , Söderström Johan , Marchenko Tatiana , Guillemin Renaud , McGinnis O. Dennis , Ågren Hans , Fritzsche Stephan , Simon Marc , Rubensson Jan-Erik , Nordgren Joseph
Published: February 2025

Dissociation upon sulfur K-shell excitation or ionization of SF6 is studied by sulfur L-shell emission spectroscopy using synchrotron radiation and multiconfiguration Dirac-Hartree-Fock calculations of emission energies and transition rates. The decay path involves in particular Auger emission with the ejection of one or more electrons, leading to singly or multiply charged intermediate states. Nevertheless, the results of the study show that the observed photon emission at 151–152 eV following excitation at 2485–2489 eV originates dominantly from transitions in neutral sulfur. This clearly indicates that the central atom retains its electrons in a dissociation process where all fluorine atoms detach before the S 2p decay.

Published by the American Physical Society
2025
Layered aquatic microenvironments control fluctuations generated by active carpets
Authors: Barros Felipe A. , Ulloa Hugo N. , Aguayo Gabriel , Mathijssen Arnold J. T. M. , Guzmán-Lastra Francisca
Published: February 2025

In Earth's aquatic environments and the human body, microbial swimmers often accumulate at interfaces within layered systems, forming colonies known as . These bioactive layers enhance mass transport and diffusion in fluid media. Here we study the hydrodynamic behavior induced by within confined semi-infinite fluid layers, such as the one found in the sea surface microlayer. By deriving analytical expressions and performing numerical simulations, we explore how geometrical and viscous confinement (layer thickness and viscosity ratio) influence hydrodynamic fluctuations and passive tracer dynamics. Our findings reveal anisotropic distributions of fluctuations, characterized by three distinct regions: near the and fluid-fluid interface (Region I), vertical fluctuations dominate; in an intermediate region (Region II), fluctuations become isotropic; and near the free surface (Region III), horizontal fluctuations prevail. The results also demonstrate the emergence of coherent vortical structures in highly confined systems, with roll-like patterns governed by the thickness of the confined layer and the sharpness in viscosity transitions. The insights provided by this work have implications for understanding biogenic flow patterns and transport processes in natural and engineered environments, offering potential applications in areas such as microbial ecology, biofilm management, and microfluidic technologies.

Published by the American Physical Society
2025
Linear-optical approach to encoding qubits into harmonic-oscillator modes via quantum walks
Authors: Wu Jun-Yi , Wu Shin-Tza
Published: February 2025

We propose a linear-optical scheme that allows encoding grid-state quantum bits (qubits) into a bosonic mode using cat state and postselection as sources of non-Gaussianity in the encoding. As a linear-optical realization of the quantum-walk encoding scheme in [Lin , ], we employ the cat state as a quantum coin that enables encoding approximate Gottesman-Kitaev-Preskill qubits through quantum walk of a squeezed vacuum state in phase space. We show that the conditional phase-space displacement necessary for the encoding can be realized through a Mach-Zehnder interferometer (MZI) assisted with ancillary cat-state input under appropriate parameter regimes. By analyzing the fidelity of the MZI-based displacement operation, we identify the region of parameter space over which the proposed linear-optical scheme can generate grid-state qubits with high fidelity. With adequate parameter setting, our proposal should be accessible to current optical and superconducting-circuit platforms in preparing grid-state qubits for bosonic modes in the, respectively, optical and microwave domains.

Published by the American Physical Society
2025
Depinning, melting, and sliding of generalized Wigner crystals in Moiré systems
Authors: Reichhardt C. , Reichhardt C. J. O.
Published: February 2025

We numerically examine the depinning, sliding, and melting of commensurate and incommensurate Wigner crystals on two-dimensional hexagonal periodic substrates near fillings of 1/3,1/2, and 2/3 to model the dynamics of generalized Wigner crystals in moiré heterostructures. At low temperatures where thermal fluctuations are irrelevant, for commensurate fillings we find a strongly pinned state that depins into a sliding crystal, while at incommensurate fillings the depinning threshold is strongly reduced. For fillings below 1/2, the depinning occurs in a two-step process. Above the first depinning threshold, there is an extended range of drives where the conduction occurs via the sliding of antikinks along the charge stripes, followed by a second threshold where all the charges begin to slide. At finite temperatures, the external driving reduces the effective melting temperature at commensurate fillings and enhances creep at incommensurate fillings. We show that depinning into different sliding states, such as moving fluids or moving crystals, produces nonlinear features in the transport curves. We also show that transport is asymmetric on either side of a commensurate filling due to the different dynamics for interstitials versus holes in the commensurate structure. A variety of sliding states should be accessible for generalized Wigner crystals at finite temperatures even for low drives. If experiments can realize sliding dynamics in moiré systems, it would open another class of commensurate and incommensurate phases for study. Additionally, the sliding dynamics and antikink flow could provide unique functionalities for charge transport in moiré heterostructures.

Published by the American Physical Society
2025