bluuebunny/crossref_metadata_2025 huggingface dataset:
Rprot-Vec: A deep learning approach for fast protein structure similarity calculation
Authors: Zhang Yichuan , Zhang Wen
Published: January 2025

The prediction of structural similarity and homology detection of protein sequences has always been a very challenging and valuable research. Based on protein structure similarity, rapid and accurate detection of homologous proteins can infer the functions of newly discovered or unannotated proteins. If we can use a method to quickly predict the structural similarity between two proteins, we can achieve the task of homologous detection of protein sequences. By using this method with partially known protein structures, we can quickly infer the functions of more unknown proteins. In this article, we propose an enhanced model Rprot-vec (Rapid Protein Vector) based on deep learning, which improves existing methods. It can quickly calculate the structural similarity of proteins and perform protein homology detection using only protein sequences. Meanwhile, our model can also be used to simulate proteins to accomplish more downstream tasks related to proteins. Our model performs well within the very important TM-score range, with an accurate similarity prediction rate of 65.3% for homologous proteins. In addition, for all protein pairs within the TM-score range, the average prediction error is 0.0561, indicating good performance. The superiority of our model can be demonstrated from various aspects. In addition, we have also supplemented the dataset in this field, providing data support for future researchers studying this field simultaneously.

Contact

zhangyichuan09@gmail.com

Supplementary information

https://github.com/SuperZyccc/RProt-vec/
Multi-species integration, alignment and annotation of single-cell RNA-seq data with CAMEX
Authors: Guo Zhen-Hao , Huang De-Shuang , Zhang Shihua
Published: January 2025

Single-cell RNA-seq (scRNA-seq) data from multiple species present remarkable opportunities to explore cellular origins and evolution. However, integrating and annotating scRNA-seq data across different species remains challenging due to the variations in sequencing techniques, ambiguity of homologous relationships, and limited biological knowledge. To tackle the above challenges, we introduce CAMEX, a heterogeneous Graph Neural Network (GNN) tool that leverages many-to-many homologous relationships for multi-species integration, alignment, and annotation of scRNA-seq data from multiple species. Notably, CAMEX outperforms state-of-the-art methods integration on various cross-species benchmarking datasets (ranging from one to eleven species). Besides, CAMEX facilitates the alignment of diverse species across different developmental stages, significantly enhancing our understanding of organ and organism origins. Furthermore, CAMEX enables the detection of species-specific cell types and marker genes through cell and gene embedding. In short, CAMEX holds the potential to provide invaluable insights into how evolutionary forces operate across different species at single-cell resolution.
A highly efficient CRISPR-Cas9-based gene editing system in oat (Avena sativa)
Authors: Mehtab-Singh  , Kaye Cali , Kaur Rajvinder , Singh Jaswinder
Published: January 2025

Cultivated oat (Avena sativa) is an emerging cereal for healthy lives owing to its unique characteristics, such as high β-glucan and oil content, distinctive fatty acid composition, and gluten-free nature. The recent unravelling of the 12.5 Gb hexaploid oat genome underlined breeding barriers caused by ancestral translocations and inversions, leading to recombination suppression and pseudo-linkage further hindering conventional trait introgression. Over the past decade, the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system has been extensively used for crop improvement and functional genomics in all other cereals except oats. Its large repetitive genome with three sub-genomes, lack of efficient transformation, recalcitrant nature, and complex molecular screening due to gene redundancy have been major obstacles to gene editing success in oat. We report the first successful CRISPR-Cas9-based gene editing in oat in three genes —AsTLP8, AsVRN3andAsVRN3Dwith gene-editing efficiency of up to 41.1%. The gene-edited plants for all the genes carried deletions and/or one base insertion. Further analysis ofVRN3T1and T2mutants revealed bent leaves in heterozygous knockouts (AACCdD), while an extended vegetative growth phase was seen in the T1homozygous and biallelic mutants (aaccdd), accentuating the important role ofVRN3in oat development. We are confident that this highly efficient oat gene editing system will pave the way for a deeper molecular understanding of this healthy cereal, deciphering oat’s functional genomics, and creating genetic diversity at the cold spots of recombination in oat.
SARS-CoV-2 cellular coinfection is limited by superinfection exclusion
Authors: Sims Anna , Weir Daniel J. , Cole Sarah J. , Hutchinson Edward
Published: January 2025

The coinfection of individual cells is a requirement for exchange between two or more virus genomes, which is a major mechanism driving virus evolution. Coinfection is restricted by a mechanism known as superinfection exclusion (SIE), which prohibits the infection of a previously infected cell by a related virus after a period of time. SIE regulates coinfection for many different viruses, but its relevance to the infection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was unknown. In this study, we investigated this using a pair of SARS-CoV-2 variant viruses encoding distinct fluorescent reporter proteins. We show for the first time that SARS-CoV-2 coinfection of individual cells is limited temporally by SIE. We defined the kinetics of the onset of SIE for SARS-CoV-2 in this system, showing that the potential for coinfection starts to diminish within the first hour of primary infection, and then falls exponentially as the time between the two infection events is increased. We then asked how these kinetics would affect the potential for coinfection with viruses during a spreading infection. We used plaque assays to model the localised spread of SARS-CoV-2 observed in infected tissue, and showed that the kinetics of SIE restrict coinfection, and therefore sites of possible genetic exchange, to a small interface of infected cells between spreading viral infections. This indicates that SIE, by reducing the likelihood of coinfection of cells, likely reduces the opportunities for genetic exchange between different strains of SARS-CoV-2 and therefore is an underappreciated factor in shaping SARS-CoV-2 evolution.
Clinical performance evaluation of a tiling amplicon panel for whole genome sequencing of respiratory syncytial virus
Authors: Nunley B. Ethan , Weixler Amelia , Kim Hyeong Geon , Xie Hong , Sereewit Jaydee , Hajian Pooneh , Ellis Sean E , Mills Margaret G , Perez-Osorio Ailyn C , Goya Stephanie , Gov Jolene , Dewar Rebecca , Fernandes Goncalo , Templeton Kate E , Maloney Daniel M , Greninger Alexander L. , Roychoudhury Pavitra
Published: January 2025

Accurate genomic characterization of respiratory syncytial virus (RSV) is crucial for studies of epidemiology and viral evolution, and monitoring potential escape from newly authorized vaccines and antivirals. We adapted a viral whole genome tiling amplicon panel (UW-ARTIC) and developed a custom bioinformatic pipeline for high-throughput, cost-effective sequencing of RSV-A and RSV-B. We established genome acceptability criteria and determined the performance characteristics of the panel including assay sensitivity, specificity, breadth of genome recovery, accuracy, and precision using contrived and remnant clinical specimens. High-quality genomes (>95% genome completeness; >500X and >1000X average depth for whole genome and fusion gene respectively) were recovered from samples with Ct ≤ 30 (~594 and 2,004 copies per reaction for RSV-A and RSV-B respectively). Minor variants were accurately identified in sample mixtures of 5:95 and higher. The assay showed high accuracy when compared against Sanger, shotgun metagenomic, and hybridization capture-based sequencing; and high repeatability and reproducibility. The UW-ARTIC RSV panel has utility in genomic surveillance, clinical and research applications. It has been used to generate FDA-reportable data for clinical trials of RSV antiviral products, with robust performance characteristics in samples from around the globe from as recently as the 2023/24 season. Continued genomic surveillance and future updates to primer sets will be essential for continued recovery of genomes as RSV continues to evolve.
Rhamnose-mediated modulation of hair follicle growth: insights from chemical genomics
Authors: Li Xiu , Liu Ying , Li Lu , Jiang Wenjie , Ma Shize , Cao Rui , Zhang Yi , Xiao Ran , Wang Dong , Yang Zhigang
Published: January 2025

Pursuing compounds capable of stimulating hair follicle growth or regeneration presents a significant challenge in dermatological research. Dermal papilla (DP) cells, which serve as a dynamic niche for hair follicle stem cells, are often used to identify hair growth-promoting agents as a screening model. Here, we integrated human scalp single-cell RNA sequencing data with human DP cells (hDPCs) gene expression profiles to develop a gene panel for assessing hair follicle inductive potential, then applied a high-throughput sequencing-based high-throughput screening (HTS2) method to quantify the gene expressions of hDPCs perturbed by over 2000 small molecules. Notably, rhamnose was identified as a compound that restored the expression of hair-inducing genes in hDPCs. More importantly, the topical application of rhamnose accelerated hair follicle regeneration by promoting hair cycle into the anagen phase. Transcriptome and central carbon metabolism analyses revealed that rhamnose induced glucose metabolism remodeling favoring glycolysis in mice. A similar phenotype was also observed in rhamnose-treated hDPCs, as demonstrated by glycolysis and mitochondrial stress tests. The present study introduces a novel methodology for evaluating hair-inducing agents and provides valuable insights into the cellular and molecular mechanisms underlying the hair growth-promoting effects of rhamnose. These findings highlight the potential for the therapeutic application of rhamnose in the treatment of alopecia.
Dynamics of biofilm-formingBacillus subtilisinCaenorhabditis elegansgut
Authors: Saitoh Yasuaki , Qiu Tian (Autumn)
Published: January 2025

Biofilm-formingBacillus subtilisstrain NCIB3610 has been reported to show biofilm-mediated beneficial effects when fed toCaenorhabditis elegans, including enhanced stress resistance, extended lifespan, and protection against neurotoxic agents. However, biofilm-formingB. subtilispresents multiple cell types, and thus a thorough characterization ofB. subtiliscell dynamics in theC. elegansgutin vivois necessary to understand mechanisms of the biofilm-mediated beneficial effects. In this study, we utilized an isogenic NCIB3610 strain expressing a biofilm reporter PtapA-mKate2to monitor matrix-producing components inC. elegansgut. Interestingly, our results revealed that in liveC. elegansgut, noB. subtilisbiofilms were formed but only free spores and diffused fluorescence, which were likely from dietary matrix-producing cells crushed by the pharynx. Additional data showed that spores can geminate into motile cells but not matrix-producing cells in livingC. elegansgut. Biofilm formation was found in gut afterC. elegansdeath, indicating that mechanistically, life-dependent functions of the worm inhibit the formation of matrix-producing cells in gut. These findings resolved a key piece of puzzle in understanding the fundamental mechanisms ofC. elegans-B. subtilisinteraction and highlighted the importance of characterizing cell dynamicsin vivoin host-microbe interaction research.
Long- term improvement in Alzheimer’s Disease with Transcranial Direct Current Stimulation
Authors: Aggarwal Anu
Published: January 2025

The goal of this work was to integrate results from clinical trials related to transcranial direct current stimulation (tDCS) treatment of Alzheimer’s disease (AD) into a machine learning model of the disease to understand its impact on disease progression over a decade. Themain contributionsof this work are- firstly, extension of otherwise sparse clinical data for tDCS stimulation in AD patients to predict patient outcomes over a decade. Secondly, it provides evidence of long-term improvement in AD with tDCS. Thirdly, it calculates an optimal tDCS regimen for improvement in cognitive function for patients with AD. This paper integrates data from an emerging field of research (tDCS treatment) into general guidelines for best stimulation practices and potential outcomes which can be replicated to other diseases and treatments.
Ovarian cancer cell cluster inhibits pancreatic cancer progression
Authors: Liang Maodi , Fan Rui , Wang Cuizhe , Gong Kejian , Lin Xiao , Zhao Mengyuan , Zhang Huizi , Xu Lili , Liu Qin , Su Yurui , Cui Chunmei , Liu Xingkai , Zhang Jun , Cui Qinghua
Published: January 2025

Pancreatic cancer is the most lethal cancer and all of the current cancer treatment strategies fail at this disease. It is thus urgently important to explore novel therapeutics. We previously revealed that it can be significantly inhibited by ovarian cancer cell by bothin vitroandin vivoexperiments. It was reported that cancer cell cluster can greatly enhance the efficiency in metastasis model compared to single cancer cell. Given this observation, here we proposed that ovarian cancer cell cluster could inhibit pancreatic cancer more efficiently than single ovarian cancer cell. As a result, animal experiments demonstrated that the injection of both low and high doses of SKOV3 ovarian cancer cluster show significantly higher efficiency in inhibiting pancreatic cancer xenografts than single SKOV3 ovarian cancer cell. Moreover, single cell RNA-sequencing analysis revealed that ovarian cancer cell cluster treatment inhibited pancreatic cancer by promoting inflammation response by both activating the NF-κB pathway in pancreatic cancer cells and substantially shifting macrophages in tumor microenvironments (TME) to M1 phenotype. In summary, this study proposed and validated a novel potential therapeutic for pancreatic cancer.
Multiple losses of ecdysone receptor genes in nematodes: an alternative evolutionary scenario of molting regulation
Authors: Yamakawa Shumpei , Barf Lisa-Marie , Hejnol Andreas
Published: January 2025

Molting is a hallmark feature of ecdysozoans, including arthropods, tardigrades, and nematodes. Ecdysone hormones play a crucial role in regulating the molting process of different ecdysozoan taxa. Interestingly, despite this highly conserved function of ecdysone, the model nematodeCaenorhabditis eleganshas lost the ecdysone receptor (ECR) genes and their molting appears to be ecdysone-independent. The loss ofecrhas only been reported inCaenorhabditiswithin ecdysozoans, and the evolutionary background behind this loss has remained enigmatic. Here, we show that loss ofecris not exceptional inCaenorhabditis, but has occurred at least three times in Rhabditina and Tylenchina nematodes. Our genome-wide analysis of 160 nematode species revealed the multiple losses ofecrand its typical heterodimer partneruspduring nematode evolution. Furthermore, using genomic and transcriptomic analyses, we identified two factors that likely underlie and buffer the loss of ECR gene/function: molting regulation by an alternative nuclear receptor HR3 (NHR-23) and a lineage-specific expansion of nuclear receptors in theecr-deficient taxa. Taken together, it is suggested that ecdysone/ECR function in nematodes is only minor or redundant. We propose a novel scenario for the evolution of molting regulation, highlighting the importance of HR3 as the potential core regulator.
Slow oscillation-sleep spindle coupling is associated with fear extinction retention in trauma-exposed individuals
Authors: Denis Dan , Bottary Ryan , Cunningham Tony J. , Davidson Per , Yuksel Cagri , Milad Mohammed R. , Pace-Schott Edward F.
Published: January 2025

Posttraumatic stress disorder (PTSD) can be characterized as a disorder of fear learning and memory, in which there is a failure to retain memory for the extinction of conditioned fear. Sleep has been implicated in successful extinction retention. The coupling of sleep spindles to slow oscillations (SOs) during non-rapid eye movement sleep has been shown to broadly underpin sleep’s beneficial effect on memory consolidation. However, the role of this oscillatory coupling in the retention of extinction memories is unknown. In a large sample of 124 trauma-exposed individuals, we investigated SO-spindle coupling in relation to fear extinction memory. We found that participants with a PTSD diagnosis, relative to trauma-exposed controls, showed significantly altered SO-spindle timing, such that PTSD participants exhibited spindle coupling further away from the peak of the SO. Across participants, the amount of coupling significantly predicted extinction retention, with coupled spindles uniquely predicting successful extinction retention compared to uncoupled spindles. These results suggest that SO-spindle coupling is critical for successful retention of extinguished fear, and that SO-spindle coupling dynamics are altered in PTSD. These alterations in the mechanics of sleep may have substantial clinical implications, meriting further investigation.
Self-Contemplating In-Context Learning Enhances T Cell Receptor Generation for Novel Epitopes
Authors: Zhang Pengfei , Bang Seojin , Lee Heewook
Published: January 2025

Computational design of T cell receptors (TCRs) that bind to epitopes holds the potential to revolutionize targeted immunotherapy. However, computational design of TCRs for novel epitopes is challenging due to the scarcity of training data, and the absence of known cognate TCRs for novel epitopes. In this study, we aim to generate high-quality cognate TCRs particularly fornovel epitopeswith no known cognate TCRs, a problem that remains under-explored in the field. We propose to incorporate in-context learning, successfully used with large language models to perform new generative tasks, to the task of TCR generation for novel epitopes. By providing cognate TCRs as additional context, we enhance the model’s ability to generate high-quality TCRs for novel epitopes. We first unlock the power of in-context learning by training a model to generate new TCRs based on both a target epitope and a small set of its cognate TCRs, so-called in-context training (ICT). We then self-generate its own TCR contexts based on a target epitope, as novel epitopes lack known binding TCRs, and use it as an inference prompt, referred to as self-contemplation prompting (SCP). Our experiments first demonstrate that aligning training and inference distribution by ICT is critical for effectively leveraging context TCRs. Subsequently, we show that providing context TCRs significantly improves TCR generation for novel epitopes. Furthermore, we show TCR generation using SCP-synthesized context TCRs achieves performance comparable to, and sometimes surpassing, ground-truth context TCRs, especially when combined with refined prompt selection based on binding affinity and authenticity metrics.
Cross-species comparative modelling of antimicrobial host responsesex vivoin human and murine precision cut lung slices andin vivoin mice
Authors: Choltus Hélèna , Prados Julien , Bianchi Niccolo , Heikkila Nelli , Beinier Veronique Serre , Karenovics Wolfram , Bédat Benoit , Eberhardt Christiane , Becattini Simone , Schmolke Mirco
Published: January 2025

In biomedical infectious disease research new models to bridge preclinical and clinical research are needed. Mouse models are still one of the most-interrogated experimental systems with the caveat of biological differences in pathogen-host-interaction for some human-relevant pathogens and increasing ethical concerns. Arguably one of the most complex cell culture models are precision cut organ slices, volume defined tissue blocks which can be cultured ex vivo and exposed to various stimuli including human pathogens. They could be applied as 3R model system. However, their response to infectious agents in comparison toin vivomodels is understudied. To understand species and model specific differences in the host response (here: influenza A virus (IAV) andStreptococcus pneumoniae(Spn)), we interrogate here the transcriptional reaction of human PCLS (hPCLS) compared to that of murine precision cut lung slices (mPCLS) and a murinein vivoinfection model. A direct comparison of hPCLS and mPCLS revealed a more complex early innate immune response against viral and bacterial pathogens in the human model, which beyond this informs about secondary cell-to-cell communicationin situand bystander cell responses to proinflammatory and antiviral cytokines secreted by tissue resident immune cells. In contrast, the murine PCLS model revealed substantial deficits in responding to viral challenge, reproducing only a small fraction of the murinein vivohost response. Our study provides the first cross-species comparison of early transcriptomic responses to relevant human pathogens.
Neuronal Decoding of Temperature Signals inCaenorhabditis elegans
Authors: Batra Abhilasha , Sharma Rati
Published: January 2025

Neural processing in animals facilitate sensory adaptation by eliciting appropriate responses to changing environmental stimuli. Although sensory adaptation is well recognized, the specific role of individual neurons in these adaptive mechanisms remains poorly understood from a theoretical standpoint. Specifically, it is unclear how single neurons influence the processing of sensory information and modulate their responses to environmental changes. InCaenorhabditis elegans(C. elegans), the primary AFD thermosensory neurons respond to external thermal stimuli incorporating experience-dependent temperature response thresholds. While extensive experimental studies have highlighted the functional features of the AFD neurons, mathematical understanding of their responses is still not well established. In this study, we develop a theoretical framework that captures how a single pair of AFD neurons encodes sensory information and regulates their responses to thermal warming signals, with a focus on how prior environmental experiences influence these responses. Through this framework we find that the interaction between two key entitiesi.e. cGMP and calcium, plays a crucial role in processing sensory information and fine-tuning neuronal responses to thermal changes. In addition to reproducing experimentally known trends, our results show that growth conditions such as cultivation temperature of the worms significantly shape the neurons’ functional properties, including their operating range, activation thresholds and response start time and duration. The findings in this work, therefore, enhance the overall understanding of how environmental experiences by single neuron shape sensory systems and provide a deeper connection between experimental data and quantitative models.
Comparative Evaluation of Targeted RNA Sequencing Protocols for Gene Expression Quantification With and Without Unique Molecular Indices (UMIs)
Authors: Gosch Annica , Courts Cornelius
Published: January 2025

Interest in forensic RNA analysis has increased over the last years. RNA molecules present in forensic samples can accurately be quantified via quantitative PCR (qPCR), however, due to the limited number of markers that can be assayed simultaneously per reaction, qPCR is less suitable for applications requiring gene expression quantification of large marker sets. Few years ago, massively parallel targeted RNA-sequencing (targRNAseq) allowing to simultaneously and accurately quantify several hundreds of markers has been added to the forensic genetic tool set. However, typical targRNAseq protocols include a multiplex-PCR-step to amplify selected targets which potentially introduces bias and limits accurate gene expression quantification.

Unique Molecular Indices (UMIs) have been invented to overcome this limitation and have been implemented in protocols from some vendors.

In this study, we compared two targeted RNAseq protocols assaying expression of a set of 121 forensically relevant mRNA biomarkers: The Ion Ampliseq targeted RNA sequencing panel (Thermo Fisher Scientific), which employs a multiplex-PCR without the use of UMIs, and the QIAseq targeted RNA panel (QIAGEN), which uses UMIs prior to multiplex amplification.

Both protocols were tested on replicated samples and dilution series and compared with respect to sensitivity and accuracy of gene expression quantification.

The UMI-based protocol exhibited decreased sensitivity in comparison to the non-UMI-based alternative, however, making use of UMI technology greatly improved gene expression quantification accuracy. We thus recommend the use of UMI-based protocols for targeted RNA sequencing for applications requiring accurate gene expression quantification.
Large interspecific and intraspecific variation in seed longevity in storage
Authors: Klepka Lea , Liepelt Sascha , Bucharova Anna
Published: January 2025

Premise

Conservation seed banks are an essential tool for plant ex-situ conservation. However, seeds stored for long periods of time slowly deteriorate and lose viability. While seed longevity is known to vary between species, the extent of variability within species and the factors driving it remain unclear.

Methods

We focused on both inter- and intraspecific variability in seed longevity and its determinants. We studied 41 common grassland species and 188 seed accessions from across Europe. We exposed the seeds to artificial ageing conditions (60% RH, 45°C) and estimated the seed longevity (p50), defined as the time required for viability to decline to 50% of the initial viability. We then tested the relationships between seed longevity and both species- and origin-specific factors.

Results

Variability in seed longevity was only slightly greater between species than within species, with species identity explaining 51.9% of the total variation in seed longevity among seed accessions, leaving 48.1% of the variation within species. In interspecific species comparison, seed viability was predicted only by initial seed viability, but unrelated to species-specific seed mass or seed chemical composition. Within species, seed longevity increased with the initial viability of the seed accession and mean annual temperature at the accession origin, but was unrelated to seed mass or precipitation in the origin, and the residual variance was substantial.

Conclusion

Our findings highlight that seed longevity on the level of individual seed accessions remains challenging to predict.
Role of Age in Mediating the Association Between the Vaginal Microbiota and Preterm Birth
Authors: Xie Yun , Wang Qi , Li Dan , Jia Fengan , Chang Fan , Zhang Zhen , Sun Yanmei , Wang Shiwei
Published: January 2025

The vaginal microbiota plays a crucial role in vaginal health and pregnancy outcomes. However, the influence of maternal characteristics, especially age, on the relationship between the vaginal microbiota and preterm birth is poorly understood. This study quantifies the effects of race, maternal age, and gestational age on vaginal microbiota composition. Our results demonstrate stronger associations between preterm birth and a less optimal vaginal microbiota in White and Asian women compared to Black or African American women. The microbiota difference between preterm and term births was more pronounced in older reproductive-age women, withLactobacillusspecies increasing with age only in term births. Additionally, lower alpha diversity was observed in term pregnancies compared to preterm during both early and late pregnancy, particularly in women aged above 25 years. These findings highlight the mediating role of age in the relationship between the vaginal microbiota and preterm birth.
Single-Cell Multimodal Profiling Reveals a Novel CD26+Fibroblast Subpopulation in Atherosclerosis
Authors: Bashore Alexander C. , Coronel Johana , Xue Chenyi , Zhu Lucie Y. , Reilly Muredach P.
Published: January 2025

Background

Atherosclerosis involves complex interactions between lipids, immune cells, vascular smooth muscle cells (VSMCs), and fibroblasts within the arterial wall. While significant advances in single-cell technologies have shed light on the roles of immune cells and VSMCs in plaque development, fibroblasts remain underexplored, leaving critical gaps in understanding their contributions to disease progression and plaque stability. Comprehensive characterization of fibroblast phenotypes in atherosclerosis is essential to unravel their diverse functions and to distinguish between subsets that may play protective versus pathogenic roles in the disease process.

Methods

Here, we utilized CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) to comprehensively profile fibroblast diversity in a mouse model of atherosclerosis. Mice were fed an atherogenic diet for 0, 8, 19, and 26 weeks, representing distinct stages of disease progression, enabling a detailed phenotypic characterization of fibroblasts throughout the course of atherosclerosis development.

Results

We identified four distinct fibroblast subpopulations, including a myofibroblast population closely resembling VSMC-derived chondromyocytes. The proportions of these fibroblast subsets exhibited a modest decline as atherosclerosis progressed. Through multimodal analysis, we identified CD26 as a highly expressed and specific marker for one of these fibroblast subpopulations, distinguishing it from other subsets. Using a combination of flow cytometry and immunohistochemistry, we demonstrated that CD26+fibroblasts predominantly reside in the adventitia of healthy arteries. During atherosclerosis progression, these cells expand into the intima and primarily localize within the fibrous cap of the lesion.

Conclusions

Our multi-omic analysis highlights the phenotypic diversity and dynamic changes of fibroblasts during atherosclerosis progression. Among these, CD26+ fibroblasts emerge as a distinct subpopulation that expands within atherosclerotic lesions and may play a critical role in promoting plaque stability through their migration into the fibrous cap.
ArtSymbioCyc, a metabolic network database collection dedicated to arthropod symbioses: a case study, the tripartite cooperation inSipha maydis
Authors: Baa-Puyoulet Patrice , Gerlin Léo , Parisot Nicolas , Peignier Sergio , Renoz François , Calevro Federica , Charles Hubert
Published: January 2025

Most arthropods live in close association with bacteria. The genomes of associated partners have co-evolved creating situations of interdependence that are complex to decipher despite the availability of their complete sequences. We developed ArtSymbioCyc, a metabolism-oriented database collection gathering genomic resources for arthropods and their associated bacteria. ArtSymbioCyc uses the powerful tools of the BioCyc community to produce high quality annotations and to analyze and compare metabolic networks on a genome-wide scale. We used ArtSymbioCyc to study the case of the tripartite symbiosis of the cereal aphidSipha maydisfocusing on amino acid and vitamin metabolisms, as these compounds are known to be important in this strictly phloemophagous insect. We showed how the metabolic pathways of the insect host and its two obligate bacterial associates are interdependent and specialized in the exploitation of Poaceae phloem, for example for the biosynthesis of sulfur-containing amino acids and most vitamins. This demonstrates that ArtSymbioCyc does not only reveal the individual metabolic capacities of each partner and their respective contributions to the holobiont they constitute, but also allows to predict the essential inputs that must come from host nutrition.

IMPORTANCE

Evolution has driven the emergence of complex arthropod-microbe symbiotic systems, whose metabolic integration is difficult to unravel. With its user-friendly interface, ArtSymbioCyc (https://artsymbiocyc.cycadsys.org) eases and speeds up the analysis of metabolic networks by enabling precise inference of compound exchanges between associated partners, and helps unveil the adaptive potential of arthropods in contexts such as conservation or agricultural control.
A cross-species multimodal database of gene expression in cardiac hypertrophy
Authors: Sandmann Christoph , Lanzer Jan D , Stein Frank , Malovrh Ellen , Rüdinger Nicholas , Frey Norbert , Saez-Rodriguez Julio , Völkers Mirko
Published: January 2025

Changes in gene expression determine the pathophysiological response of the heart during increased workload and biomechanical stress.1,2Understanding the complex gene expression regulation during physiological and pathological stress provides insight into mechanisms that mediate the transition from cardiac hypertrophy to heart failure. We curated and generated a multi-omics database of cardiac hypertrophy and heart failure and exemplified its usage by evaluating the regulation of UCK2, a gene that belongs to a conserved cardiomyocyte hypertrophy gene expression signature with unknown function in heart disease. To provide the community with simple access to the database, we developed CHEERIO (Cardiac HypErtrophy gEne expRessIOn Database), a free and easy-to-use interactive web application to explore rodent and human gene expression during early, late, physiological and pathological cardiac hypertrophy, as well as heart failure at transcriptome, translatome, proteome, bulk and single-cell resolution. CHEERIO is freely available athttps://voelkerslab.shinyapps.io/CHEERIO/.
An anti-amyloidogenic approach to specifically block memory consolidation in mice for therapeutic intervention
Authors: López-García Paula , McGreevy Kerry R. , Vaquero Maria Eugenia , Ramírez de Mingo Daniel , Pallé Anna , Popiel Helena Akiko , Santi Andrea , Nagai Yoshitaka , Trejo José Luis , Carrión-Vázquez Mariano
Published: January 2025

Post-traumatic stress disorder (PTSD) is a mental health disorder triggered by the exposure to a traumatic event, which manifests with anguish, intrusive memories, and negative mood changes. So far, there is no efficient treatment for PTSD other than symptomatic palliative care. However, the cytoplasmic polyadenylation element binding protein-3 (CPEB3) has been recently associated to a potential risk gene for PTSD. Considering that CPEB3 protein is a functional amyloid whose importance for long-term memory consolidation in mammals is well established, we propose the active (amyloid) state of CPEB3 as a promising therapeutic target to block the consolidation of traumatic memories through by the anti-amyloidogenic polyglutamine binding peptide 1 (QBP1).

Here we report a preclinical development in mice of this pharmacological treatment for PTSD based on the action of the QBP1 peptide. We first characterized the human CPEB3 (hCPEB3) proteinin vitro, showing how its amyloid aggregation is inhibited by the active core of QBP1 (QBP1-M8) without affecting other self-assembly processes such as phase separation. Then, we generated and characterized a novel transgenic mouse that constitutively expresses QBP1 in tandem (TgQBP1). TgQBP1 mice have shown that the consolidation of simple learning is impaired after 24 h for both hippocampal-dependent and aversive memories and that it is limited to new learned memories and has no effect on short-term memory. Furthermore, fear induced anxiety was reduced in comparison to WT mice, suggesting that PTSD-like symptoms are also being ameliorated. Intriguingly, we found that aversive memories seem to be more strongly affected in younger mice. Finally, the analysis of CPEB3 amyloid presence in hippocampal extracted samples showed a correlative decrease in murine CPEB3 oligomerization in the TgQBP1 mice. Taking together, these results strongly suggest that the amyloidogenic blockage of CPEB3 by QBP1 peptide is a potential drug for the prevention and treatment of PTSD.
Emergence of Lignin-Carbohydrate Interactions During Plant Stem Maturation Visualized by Solid-State NMR
Authors: Xiao Peng , Pfaff Sarah A. , Zhao Wancheng , Debnath Debkumar , Liu Chang-Jun , Cosgrove Daniel J. , Wang Tuo
Published: January 2025

Lignification waterproofs and strengthens the secondary plant cell wall, while increasing the energy cost associated with releasing sugars for biofuel production. The physical association between lignin and the carbohydrate scaffold that accommodates lignin polymerization, as well as the temporally distinct roles of different lignin units and carbohydrate partners during lignification, remain largely unclear. Here we map the lignin-carbohydrate interactions by solid-state NMR in13C-labeledArabidopsis inflorescence stems as secondary cell walls are formed. Analysis includes wild-type and two mutants that either selectively or globally disrupt lignin biosynthesis. Mature cell walls in the basal regions of older stems are enriched in S-lignin and carbohydrate-lignin interactions. Acetylated xylan is the dominant mediator of interactions with S-lignin, while methylated pectin unexpectedly interacts with G-lignin during early-stage lignification. The critical role of S-lignin in stabilizing carbohydrate-lignin interface is emphasized by the weak lignin-carbohydrate interactions and compromised mechanical properties of a low-Sfah1mutant, whereas theref3mutant, with low overall lignin content but a higher S/G ratio, remained unaffected. These findings demonstrate that the molecular mixing pattern, rather than lignin content, is a key determinant of the structure and properties of lignocellulosic materials.
R2TP-like Quaternary Chaperones: a comprehensive overview to understand the dynamic R2SP complex
Authors: Santo Paulo E. , Chagot Marie-Eve , Gizardin-Fredon Hugo , Ley Marie , Chenuel Thomas , Deslignière Evolène , Plassart Laura , Paiva Ana C. F. , Sousa Pedro M. F. , Bertrand Edouard , Charpentier Bruno , Verheggen Céline , Quinternet Marc , Meyer Philippe , Bandeiras Tiago M. , Cianférani Sarah , Plisson-Chastang Célia , Manival Xavier
Published: January 2025

The human R2SP complex belongs to the R2TP-like quaternary chaperone family and consists of RUVBL1, RUVBL2, SPAG1 and PIH1D2. R2SP is crucial for the correct assembly of motile cilia (SPAG1 null mutations cause Primary Ciliary Dyskinesia) and the organization of the synaptic zone. RUVBL1/2 ATPases are the powerhouse of this molecular machinery, while SPAG1 and PIH1D2 would be adaptors that interact with specific clients to promote their quaternary assembly. Despite these functional data, little is known about the structure of R2SP and the precise mode of action of these R2TP-like complexes. We have combined biochemical and structural approaches (NMR, structural mass spectrometry and cryo-EM) to investigate the 3D organization of the human R2SP complex, its mode of assembly and ATPase activity. Our study reveals a three-dimensional structure similar to that of the canonical R2TP complex, but also highlights differences in the mode of action of its RUVBL1/2 ATPase core as well as the binding of its adaptors SPAG1 and PIH1D2.
Resilience to Endoplasmic Reticulum Stress Mitigates Calcium-Dependent Membrane Hyperexcitability Underlying Late Disease Onset in SCA6
Authors: Huang Haoran , Charron Taylor L. , Fu Min , Dunn Miranda , Jones Deborah M. , Kumar Praveen , Kulkarni Ashwinikumar , Konopka Genevieve , Shakkottai Vikram G.
Published: January 2025

An enduring puzzle in many inherited neurological disorders is the late onset of symptoms despite expression of function-impairing mutant protein early in life. We examined the basis for onset of impairment in Spinocerebellar ataxia type 6 (SCA6), a canonical late-onset neurodegenerative ataxia which results from a polyglutamine expansion in the voltage gated calcium channel, Cav2.1. Cerebellar Purkinje cell spiking abnormalities are seen concurrent with motor impairment in SCA6 mice but the basis for these changes in spiking is unknown. We identify endoplasmic reticulum (ER) calcium depletion as the cause for Purkinje cell spiking abnormalities and that the impairments in Purkinje cell spiking are unrelated to Cav2.1 ion-flux function. Further, intact inhibitory neurotransmission in the cerebellar cortex is necessary for Purkinje neurons to exhibit spiking abnormalities in SCA6 mice. Based on serial cerebellar transcriptome analysis, we define a mechanism of disease that is related to ER stress. Further, our studies support a model whereby proteotoxicity from misfolded mutant Cav2.1 is mitigated by a HSP90-dependent unfolded protein response (UPR) and that age-related breakdown of this response causes motor dysfunction and aberrant Purkinje cell spiking. Redundant pathways of the UPR mediate this resilience to ER stress. These studies elucidate a mechanism of resilience connecting aberrant proteostasis and calcium-dependent intrinsic membrane hyperexcitability to explain delayed disease onset more widely in age-dependent neurodegenerative disease.

Significance Statement

Advancing age is the single most important risk factor for neurodegenerative disease. Understanding how age intersects with genetic risk is therefore a critical challenge for neurodegenerative disease research. SCA6, a canonical late-onset degenerative cerebellar ataxia, results from a polyQ expansion in the voltage gated calcium channel, Cav2.1, encoded byCACNA1A. We define a mechanism of disease in SCA6 that is related to ER stress and unrelated to impaired calcium flux function of Cav2.1. Age-related decompensation of a HSP90-dependent unfolded protein response leads to disease onset. Mutant Cav2.1 misfolding as the basis for disease in SCA6 provides insight into a novel role for channelopathies to behave as proteinopathies and helps understand resilience to proteotoxicity more widely in adult-onset neurodegenerative disease.
Thalamic oscillations distinguish natural states of consciousness in humans
Authors: Chowdhury Aditya , Kaufmann Elisabeth , Schreiner Thomas , Koeglsperger Thomas , Mehrkens Jan-Hinnerk , Remi Jan , Vollmar Christian , Staudigl Tobias
Published: January 2025

Abstract

Natural states of consciousness are thought to be regulated by deep brain structures such as the thalamus. However, very little is known about the underlying electrophysiology in humans. Using a rare opportunity to directly record from the human thalamus, we identify a hitherto- unreported brain-state-specific oscillation. We find that the oscillation is present only during Rapid Eye Movement (REM) sleep and wakefulness, while being entirely absent during Non- REM sleep. The oscillation further distinguishes REM sleep microstates, co-occurring with bursts of eye movements, and is specific to the Central Thalamus, a structure implicated in causing global brain state transitions. The discovery of a distinct oscillatory signature in the Central Thalamus that distinguishes conscious states opens up avenues to further investigate thalamic contributions to human consciousness and refine interventions to treat disorders of consciousness.
Astrocytic-supplied cholesterol drives synaptic gene expression programs in developing neurons and downstream astrocytic transcriptional programs
Authors: Vartiainen Emilia , Liyanage Dhara , Mazureac Illinca , Battaglia Rachel A. , Tegtmeyer Matthew , Xu He Jax , Räsänen Noora , Sealock Julia , McCarroll Steven , Nehme Ralda , Pietiläinen Olli
Published: January 2025

Astrocytes participate in neuronal synaptic programs that are enriched for genetic associations in schizophrenia and autism spectrum disorders (ASD). To better understand how these co-regulated cellular programs are induced during early neuronal development, we studied astrocytes and iPSC-derived neurons in co-cultures and mono-cultures at 16 time points spanning 0.5 hours to 8 days. We found that upregulation in astrocytes of genes involved in cholesterol biosynthesis preceded the activation of synaptic gene programs in neurons and upregulation of the astrocyticNrxn1. Neuronal knockdown of key cholesterol receptors led to downregulation of neuronal synaptic genes and induced a robust transcriptional response in the astrocytes, including further upregulation ofNrxn1. This suggests that astrocyte-supplied cholesterol drives these neuronal changes and that bi-directional signalling is occuring. The genes upregulated in neurons were enriched for deleterious variants in schizophrenia and neurodevelopmental disorders, suggesting that their pathogenic effect may be, in part, mediated by reduced buffering capacity for changes in the astrocyte cholesterol supply to neurons. These findings highlight the critical role of astrocyte-neuron interactions in psychiatric and neurodevelopmental disorders, particularly in relation to lipid metabolism and synaptic plasticity.
Boundaries of universal theories
Authors: McCullough Matthew , Riembau Marc , Ricci Lorenzo
Published: January 2025

Universal theories are a broad class of well-motivated microscopic dynamics of the electroweak sector that go beyond the Standard Model description. The long distance physics is described by electroweak parameters which correspond to local operators in the effective field theory. We show how unitarity and analyticity constrain the space of parameters. In particular, the W and Y parameters are constrained to be positive and are necessarily the leading terms in the low-energy expansion. We assess the impact of unitarity on the interpretation of Drell-Yan data. In passing, we uncover an unexpected Wilson coefficient transcendental cancellation at the O(<10−3) level.

Published by the American Physical Society
2025
Synthesis, crystal structure and Hirshfeld surface analysis of 5-oxo-N-phenyl-3-(thiophen-2-yl)-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxamide
Authors: Aliyeva Khatira N. , Hökelek Tuncer , Khrustalev Victor N. , Rzayev Rovnag M. , Bhattarai Ajaya , Maharramov Abel M. , Shikhaliyev Namig G.
Published: January 2025

The asymmetric unit of the title compound, C23H19NO2S, contains two molecules that differ in the conformation of the two carboxamide moieties. In the crystal, intermolecular N—H...O hydrogen bonds link the molecules into chains propagating parallel to the c-axis direction. Between the molecules, weak C—H...π(ring) interactions are present, whereas π–π interactions are not observed. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions to the crystal packing are from H...H (47.6%), H...C/C...H (33.4%) and H...O/O...H (11.6%) interactions. Orientational disorder is observed for both thiophene rings.