bluuebunny/crossref_metadata_2025 huggingface dataset:
Methanochimaera problematica gen. nov., sp. nov., a novel methanoarchaeon isolated from cold seep sediment and reclassification of Methanomicrobium antiquum as Methanoeremita antiquus gen. nov., comb. nov.
Authors: Zhou Yang-Zhi , Lai Mei-Chin , You Yi-Ting , Lai Shu-Jung , Wu Sue-Yao , Hung Chuan-Chuan , Ding Jiun-Yan , Shih Chao-Jen , Wu Yen-Chi , Zhang Wei-Ling , Chen Sheng-Chung
Published: December 2024

A hydrogenotrophic methanoarchaeon, designated strain FWC-SCC4T, was isolated from cold seep sediment of Four-Way Closure Ridge, offshore southwestern Taiwan. Strain FWC-SCC4Tutilizes H2/CO2 or formate, but not acetate, secondary alcohols, methylamines, methanol or ethanol for growth and methane production. Yeast extract is required for growth. The cell morphology is coccoid, with a diameter of 0.8–1.2 µm, and the cell envelope is composed of S-layer protein with Mr about 137.00 kDa. Cells possess multiple flagella and usually occur singly. Strain FWC-SCC4T grows at a temperature range of 20–40 °C (optimum 37 °C) and a pH range of 5.4–7.2 (optimum 7.0). The NaCl range for growth is 0–0.86 M (optimum 0.09 M). The result of phylogenetic analysis of 16S rRNA gene sequences indicates that the most closely related species are Methanoplanus limicola M3T and Methanoplanus endosymbiosus MC1T, with similarities of 95.95 and 95.63%, respectively. The G+C content of the genomic DNA is 40.3 mol%. The overall genome-relatedness indexes (OGRIs) and concatenated ribosomal protein (RBP) phylogenic analysis indicate that strain FWC-SCC4T is a novel lineage of Methanomicrobiaceae. In addition to strain FWC-SCC4T, the differences between Methanomicrobium antiquum MobHT and Methanomicrobium mobile BPT demonstrated by comparative analysis of genomic G+C content and phylogenetic analysis with non-type strain genomes are enough to support the establishment of a novel genus. In conclusion, strain FWC-SCC4T (BCRC AR10058T= NBRC 114595T) is proposed as the type strain of Methanochimaera problematica gen. nov., sp. nov., and Methanoeremita antiquus gen. nov., comb. nov. is proposed as the new name for Methanomicrobium antiquum MobHT (=DSM 21220T= NBRC 104160T).
Early Diagnosis and Prognostic Prediction of Colorectal Cancer through Plasma Methylation Regions
Authors: Zhu Lingqin , Yang Lang , Men Fangli , Yu Jianwei , Sun Shuyang , Li Chenguang , Ma Xianzong , Xu Junfeng , Li Yangjie , Tian Ju , Wang Xin , Xie Hui , Kang Qian , Duan Linghui , Yi Xiang , Guo Wei , Gong Xueqing , Guo Ni , Lu Youyong , Leung Joseph , He Yuqi , Sheng Jianqiu
Published: December 2024

The methylation of plasma cell-free DNA (cfDNA) has emerged as a valuable diagnostic and prognostic biomarker in various cancers including colorectal cancer (CRC). Currently, there are no biomarkers that serve simultaneously for early diagnosis and prognostic prediction in CRC patients. Herein, we developed a plasma panel (27 DMRs, differential methylated regions) and validated its superior performance across CRC diagnosis and prognosis prediction in an independent cohort. We first conducted a preliminary screening of 119 CRC tissue samples to identify CRC-specific methylation features. Subsequently, a CRC-specific methylation panel was developed by further filtering 161 plasma samples. Then machine learning algorithms were applied to develop diagnosis and prognosis models using cfDNA samples from 51 CRC patients and 33 normal controls. The diagnosis model was tested in a cohort consisting of 30 CRC, 37 advanced adenoma (AA), and 14 healthy plasma samples, independently validated in a cohort consisting of 18 CRC, 91 NAA, 23 AA and 34 healthy plasma samples. In the tissue external validation cohort (GSE48684), the cfDNA methylation diagnosis model conducted with the panel, have the area under the curve (AUC) reached 0.983, and for the plasma cfDNA model in the external validation cohort, the sensitivities for NAA, AA and CRC 0 -Ⅱ are 48.4%. 52.2% and 66.7% respectively, with a specificity of 88%. Additionally, the panel was applied to patient staging and metastasis, performing well in predicting CRC distant metastasis (AUC = 0.955) and prognosis (AUC = 0.867). Using normal samples as control, the changes in methylation score in both tissue and plasma were consistent across different lesions, although the degree of alterations varied with severity. The methylation scores vary between paired tissue and blood samples, suggesting distinct mechanisms of migration from tumor tissue to blood for the 27 DMRs. Together, Our cfDNA methylation models based on 27 DMRs can identify different stages of CRC and predict metastasis and prognosis, ultimately enabling early intervention and risk stratification for CRC patients.
A penalized distributed-lag non-linear model for modeling the joint delayed effect of two predictors: impact of minimum and maximum temperature on mortality
Authors: Rutten Sara , Duarte Elisa , Neyens Thomas , Lauwaet Dirk , Faes Christel
Published: December 2024

Distributed lag non-linear models (DLNMs) offer a flexible approach towards modelling time-delayed exposures. They are popular to study the effect of environmental exposure on health outcomes, such as the effect of temperature on mortality. Conventional distributed lag non-linear models typically focus on a single exposure variable, potentially overlooking complex interactions between multiple predictors. In this paper, we propose a distributed lag non-linear model that captures the joint delayed impact of two exposure variables by incorporating their interaction through a tensor basis constructed from univariate P-splines. This model is compared to a model assuming an additive effect of delayed exposures. Our model is used to examine the joint impacts of maximum and minimum temperatures on all-cause mortality in Flanders during summer. The results show that our model provides a flexible strategy towards the analysis of two predictors with interacting time-delayed effects on an outcome of interest. The importance of both maximum and minimum temperatures in explaining variability in mortality is illustrated, and we show that the interaction effect varies across age and gender groups. A spatial risk analysis at the municipality level reveals that mortality is attributed differently to temperature exposure across different areas, due to temperature variations as well as spatial trends in age and gender.
Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer
Authors: Zhang Yijuan , Ling Li , Maganti Swetha , Hope Jennifer L. , Galapate Cheska Marie , Carrette Florent , Duong-Polk Karen , Bagchi Anindya , Scott David A. , Lowy Andrew M. , Bradley Linda M. , Commisso Cosimo
Published: December 2024

Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and CAFs use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis functions to control CAF subtype identity when glutamine is limiting. Our data demonstrate that metabolic stress leads to an intrinsic inflammatory CAF (iCAF) program driven by MEK/ERK signaling. Utilizingin vivomodels, we find that blocking macropinocytosis alters CAF subtypes and reorganizes the tumor stroma. Importantly, these changes in stromal architecture can be exploited to sensitize PDAC to immunotherapy and chemotherapy. Our findings demonstrate that metabolic stress plays a role in shaping the tumor microenvironment, and that this attribute can be harnessed for therapeutic impact.

Graphical Abstract
Bayesian Least-Squares Supertrees (BLeSS): Flexible Inference of Large Time-Calibrated Phylogenies
Authors: Černý David , Slater Graham J.
Published: December 2024

Abstract

Time-calibrated phylogenies are key to macroevolutionary hypothesis testing and parameter inference, but their estimation is difficult when the number of tips is large. Despite its attractive properties, the joint Bayesian inference of topology and divergence times remains computationally prohibitive for large supermatrices. Historically, supertrees represented a popular alternative to supermatrix-based phylogenetic methods, but most of the existing supertree techniques do not accommodate branch lengths or topological uncertainty, rendering them unfit to supply input for modern comparative methods. Here, we present Bayesian Least-Squares Supertrees (BLeSS), a new approach that takes a profile of time trees with partially overlapping leaf sets as its input, and returns the joint posterior distribution of supertree topologies and divergence times as its output. Building upon the earlier exponential error model and average consensus techniques, BLeSS transforms the profile into path-length distance matrices, computes their arithmetic average, and uses MCMC to sample time-calibrated supertrees according to their least-squares fit to the average distance matrix. We provide a fast, flexible, and validated implementation of BLeSS in the programRevBayes, and test its performance using a comprehensive set of simulations. We show that the method performs well across a wide range of conditions, including variation in missing data treatment and the steepness of the error function. Finally, we apply BLeSS to an empirical dataset comprising 33 time trees for 260 species of carnivorans, illustrating its ability to recover well-supported clades and plausible node ages, and discuss how the method can best be used in practice, outlining possible extensions and performance boosts.
Small RNAs regulation and genomic harmony: insights into allopolyploid evolution in marsh orchids (Dactylorhiza)
Authors: Eriksson Mimmi C. , Thornton Matthew , Trucchi Emiliano , Wolfe Thomas M. , Balao Francisco , Hedrén Mikael , Paun Ovidiu
Published: December 2024

Hybridization and polyploidy are prevalent drivers of speciation, with novel ecological properties potentially arising, among other mechanisms, through changes in gene regulation by small RNAs (smRNAs), linked to transposable element (TE) dynamics. With a common garden set-up, we comparatively investigated smRNA abundance in two young, but widely distributed, ecologically divergent sibling allotetraploid marsh orchids (Dactylorhiza majalisandD. traunsteineri) and their diploid parents. Despite independent origins, the allopolyploids appear to share a substantial portion of smRNA targeting, with transgressive smRNA targeting consistently overexpressed in both, related to key genes regulating transcription, cell division, and biotic and abiotic stress responses. TE-targeting smRNAs also display shared patterns between the sibling allopolyploids, with 20-23 nt smRNAs following the maternal and smaller genome, whereas 24 nt smRNAs targeting typically resembling the level of the paternal and larger genome. However, differences between the allopolyploids are also evident, with the older allopolyploidD. majalisoften showing higher regulation by smRNAs, appearing more focused on fine-tuning gene copy regulation, whereas its younger siblingD. traunsteineriexhibits stronger non-additive expression, more prominently reflecting an apparent ongoing resolution of post-polyploidization meiotic/mitotic challenges. These findings highlight shared and species-specific smRNA dynamics, revealing how allopolyploids balance genomic instability and adaptive regulation during their evolutionary trajectories. In this system, the youngerD. traunsteineriseems to prioritize stabilizing its genome, while the olderD. majalisshifted towards optimizing gene expression. Together, this study emphasizes the role of smRNAs in facilitating ecological novelty and speciation during post-polyploidization evolution, providing insights into molecular mechanisms and adaptive evolution.
Boosting of CAR-T cells with rhabdovirus is limited by type I interferon and rapid contraction
Authors: Burchett Rebecca , Morris Claire G. , Ishak Mira , Cummings Derek , Baker Christopher L. , Marius Ricardo , Kazdhan Natasha , Silvestri Christopher M. , Bell John C. , Lichty Brian D. , Walsh Scott R. , Wan Yonghong , Hammill Joanne A. , Bramson Jonathan L.
Published: December 2024

Rhabdovirus vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing rhabdovirus vaccines to boost adoptively transferred T cells relies ona prioriknowledge of tumour epitopes, isolation of matched epitope-specific T cells, and a personalized vaccine, which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vesicular stomatitis virus (VSV) vaccine encoding the CAR-target. Boosting CAR-engineered tumour-specific T cells with paired VSV vaccines was associated with robust T cell expansion and delayed tumour progression in syngeneic models. CAR-T cell expansion and anti-tumour function was enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with VSV encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells to achieve long-term tumour control.
Identifying novel genetic and phenotypic associations to genomic features by leveraging off-target reads in exome sequencing data
Authors: Ercelen Defne , Caggiano Christa , Border Richard , Sankararaman Sriram , Mangul Serghei , Zaitlen Noah , Thompson Michael
Published: December 2024

Upwards of 40% of reads in sequencing datasets may be unmapped and discarded by standard protocols. Recent work has shown the utility of re-analyzing these unmapped reads to construct meaningful features, such as immune diversity repertoires or copy number variation in mtDNA and rDNA. While previous analyses of these features have produced significant correlations with diverse traits, they have generally been limited to analyses of RNA-sequencing data in phenotype-specific cohorts. Here, we explore whether associations can be identified using population-scale, whole-exome sequencing data in the UK BioBank. Using recently developed tools, we constructed multiple features including T-cell receptor diversity metrics, microbial load, and mtDNA and rDNA copy numbers for nearly 50,000 individuals in the UK BioBank. We first verify the validity of our method by showing that GWAS on these constructed traits results in replication of associations from studies in which the phenotypes were explicitly measured. Next, across several GWAS, we identified 21 novel independent significant loci in 11 genes, most of them in genes implicated in the innate immune response. Finally, we further analyzed the read-constructed features by establishing correlations to other population-level biobank traits such as immune disorders, metabolic disorders, neuropsychiatric disorders, and blood cell counts. Our results suggest that existing tools for feature construction from unmapped reads can offer novel information at the population level, and that these features can be used to establish novel genetic associations.
Automated Cell Type Annotation with Reference Cluster Mapping
Authors: Galanti Valerio , Shi Lingting , Azizi Elham , Liu Yining , Blumberg Andrew J.
Published: December 2024

Single-cell RNA sequencing (scRNA-seq) technologies have revolutionized our understanding of cellular heterogeneity. However, the characterization of scRNA-seq datasets remains challenging. We introduce a novel computational method that significantly enhances the annotation of scRNA clusters of a query dataset using established datasets as references. RefCM leverages optimal transport to measure the similarity in gene expression distributions between clusters and solves an integer program to optimally link the query and reference datasets based on this metric. Our algorithm produces more accurate cross-technology, cross-tissue, and cross-species mappings than any other currently available method. We demonstrate the efficacy of our method on a variety of benchmark datasets, showcasing its robustness and applicability across diverse biological contexts.
Detection of eco-evolutionary dynamics in communities using Joint Species Distribution Models
Authors: Pantel Jelena H. , Hermann Ruben J.
Published: December 2024

2

Biodiversity at the metacommunity scale is typically influenced by a number of environmental, spatial, biotic, and stochastic factors. At the same time, these factors impact the evolution of individual species, as sites present different local selection pressures and connectivity can impact gene flow and genetic drift. Identifying the relative impacts of environmental, spatial, biotic, and other drivers on community composition across spatial and temporal scales has been greatly facilitated by joint species distribution models, but these models have yet to consider the impact of microevolution on community composition. We used Heirarchical Models of Species Communities (HMSC) to analyze simulated data of an populations and communities, including in a large evolving metacommunity model, to establish whether HMSC can sufficiently quantify the contribution of phenotypic evolution for metacommunity composition. The models successfully partitioned variance contributed by environmental, spatial, and evolving phenotypic drivers, and also estimated site-and year-specific covariance. We also applied the HMSC with trait evolution model to an existing dataset studying trait change and community dynamics in an experimental aquatic plant system. The study of eco-evolutionary dynamics may require data that reflects numerous complex, interacting processes and it is necessary to have flexible, generalized statistical models to analyze this data. JSDM models such as HMSC present one promising path for analysis of eco-evolutionary dynamics in multi-species communities.
Dynamic Control of Argonautes by a Rapidly Evolving Immunological Switch
Authors: Ewe Chee Kiang , Teichman Guy , Knott Maximilian M L , Anava Sarit , Gingold Hila , Sarmiento Mario Bardan , Troemel Emily , Rechavi Oded
Published: December 2024

Small RNAs, coupled with Argonuate proteins (AGOs), regulate diverse biological processes, including immunity against nucleic acid parasites.C. eleganspossesses an expanded repertoire of at least 19 AGOs functioning in an intricate gene regulatory network. Despite their crucial roles, little is known about the regulation of AGOs, and whether their expression levels, tissue specificity, and functions change in response to genetic perturbations or environmental triggers. Here, we report that PALS-22, a member of an unusually expanded protein family inC. elegans, acts as a negative regulator of antiviral RNAi involving the RIG-I homolog. The loss ofpals-22leads to enhanced silencing of transgenes and endogenous dsRNAs. We found that PALS-22 normally suppresses the expression of two AGOs, VSRA-1 and SAGO-2, which are activated by bZIP transcription factor ZIP-1. Whenpals-22is eliminated,vsra-1andsago-2are upregulated. These AGOs in turn play key roles in defense against foreign genetic elements and intracellular pathogens, respectively. Surprisingly, while inpals-22mutants immune genes functioning in the intracellular pathogen response (IPR) are upregulated, removing SAGO-2 or the RNA-dependent RNA polymerase RRF-3 in these mutants leads to the downregulation of these genes. This observation contrasts with the typical gene-silencing role of siRNAs. Finally, by analyzingC. eleganswild isolates and lab reference strains, we demonstrate that PALS-22 regulates the expression of several germline AGOs, affecting germline mortality and transgenerational epigenetic inheritance. In summary, PALS-22 is a key genetic node that balances the trade-off between immunity and germline health by modulating the functions of different AGOs, thereby shaping the outputs of the RNAi machinery and the dynamics of epigenetic inheritance.
Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL
Authors: Vareli Aimilia , Narayanan Haripriya Vaidehi , Clark Heather , Jayawant Eleanor , Zhou Hui , Liu Yi , Stott Lauren , Simoes Fabio , Hoffmann Alexander , Pepper Andrea , Pepper Chris , Mitchell Simon
Published: December 2024

In Diffuse Large B-cell Lymphoma (DLBCL), elevated anti-apoptotic BCL2-family proteins (e.g., MCL1, BCL2, BCLXL) and NF-κB subunits (RelA, RelB, cRel) confer poor prognosis. Heterogeneous expression, regulatory complexity, and redundancy offsetting the inhibition of individual proteins, complicate the assignment of targeted therapy. We combined flow cytometry ‘fingerprinting’, immunofluorescence imaging, and computational modeling to identify therapeutic vulnerabilities in DLBCL. The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-κB inhibition (Amgen16). Within the U2932 cell line we identified distinct resistance mechanisms to BCL2 inhibition in cellular sub-populations recapitulating intratumoral heterogeneity. Co-cultures with CD40L-expressing stromal cells, mimicking the tumor microenvironment (TME), induced resistance to BCL2 and BCLXL targeting BH3-mimetics via cell-type specific upregulation of BCLXL or MCL1. Computational models, validated experimentally, showed that basal NF-κB activation determined whether CD40 activation drove BH3-mimetic resistance through upregulation of RelB and BCLXL, or cRel and MCL1. High basal NF-κB activity could be overcome by inhibiting BTK to resensitize cells to BH3-mimetics in CD40L co-culture. Importantly, non-canonical NF-κB inhibition overcame heterogeneous compensatory BCL2 upregulation, restoring sensitivity to both BCL2- and BCLXL-targeting BH3-mimetics. Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-κB inhibitors in DLBCL.
Intraspecific differences in alkaline tolerance in brook stickleback (Culaea inconstans) inhabiting neutral and alkaline lakes
Authors: Zimmer Alex M. , Bernard Charles , Giacomin Marina , Dion-Côté Anne-Marie , Goss Greg G. , Glover Chris N.
Published: December 2024

Exposure to alkaline water (pH > 9.0) is physiologically challenging for fish, yet our understanding of the physiology of alkaline tolerance in fishes is limited to a small number of ihighly specialized species. This study aimed to characterize mechanisms of alkaline tolerance in brook stickleback (Culaea inconstans), a fish species with a broad pH habitat range, including highly alkaline waters such as Buffalo Lake (pH = 9.2) in Alberta, Canada. Stickleback from Buffalo Lake and a neutral reference lake (Buck Lake; pH = 8.2) were collected from the wild and acclimated to common conditions (pH = 8.0) for at least 2 months. Both populations were then exposed to alkaline conditions (pH = 9.5), resulting in a significant decrease in survival (14% by 7 d of exposure) in Buck Lake fish, but no mortality in Buffalo Lake stickleback. In a 4-d exposure to alkaline water, fish from both populations experienced characteristic inhibitions of ammonia excretion followed by subsequent recovery, in conjunction with an accumulation of ammonia within the body. However, no differences were observed between populations. Analysis of tissue Na+and Cl-content showed a more pronounced decrease in Cl-in Buck Lake fish, suggesting that tighter regulation of Cl-homeostasis and/or acid-base balance may be an important feature of alkaline tolerance. RNA-sequencing analysis highlighted large differences in gene expression between the alkaline and neutral lake populations, and in response to alkaline exposure. Few of these changes in the expression involved genes known to be associated with nitrogen, ion, or acid-base balance. These data indicate that alkaline tolerance is higher in brook stickleback resident to an alkaline lake than those sourced from a neutral lake, a trait that may be related to differences in physiological and transcriptomic responses to alkaline exposure.
Cluster Formation and Phase Separation Driven by Mobile Myosin Motors in the Motility Assay
Authors: Slater Brandon , Sciortino Alfredo , Bausch Andreas R. , Kim Taeyoon
Published: December 2024

Interactions between F-actin and myosin are critically important for a wide range of biological processes, including cell migration, cytokinesis, and morphogenesis. The motility assay with myosin motors fixed on a surface has been utilized for understanding various phenomena emerging from the interactions between F-actin and myosin. For example, F-actin in the motility assay exhibited distinct collective behaviors when actin concentration was above a critical threshold. Recent studies have performed the myosin motility assay on a lipid bilayer, meaning that myosin motors anchored on the fluid-like membrane have mobility. Interestingly, mobile motors led to very different collective behaviors of F-actin compared to those induced by stationary motors. However, the dynamics and mechanism of the unique collective behaviors have remained elusive. In this study, we employed our cutting-edge computational model to simulate the motility assay with mobile myosin motors. We reproduced the formation of actin clusters observed in experiments and showed that F-actin within clusters exhibits strong polar ordering and leads to phase separation between myosin motors and F-actin. The cluster formation was highly dependent on the average length and concentration of F-actin. Our study provides insights into understanding the collective behaviors of F-actins that could emerge under more physiological conditions.
Accurate and General DNA Representations Emerge from Genome Foundation Models at Scale
Authors: Ellington Caleb N. , Sun Ning , Ho Nicholas , Tao Tianhua , Mahbub Sazan , Li Dian , Zhuang Yonghao , Wang Hongyi , Song Le , Xing Eric P.
Published: December 2024

Language models applied to protein sequences have become a panacea, enabling therapeutics development, materials engineering, and core biology research. Despite the successes of protein language models, genome language models remain nascent. Recent studies suggest the bottleneck is data volume or modeling context size, since long-range interactions are widely acknowledged but sparsely annotated. However, it may be the case that even short DNA sequences are modeled poorly by existing approaches, and current models are unable to represent the wide array of functions encoded by DNA. To study this, we develop AIDO.DNA, a pretrained module for DNA representation in an AI-driven Digital Organism [1]. AIDO.DNA is a seven billion parameter encoder-only transformer trained on 10.6 billion nucleotides from a dataset of 796 species. By scaling model size while maintaining a short context length of 4k nucleotides, AIDO.DNA shows substantial improvements across a breadth of supervised, generative, and zero-shot tasks relevant to functional genomics, synthetic biology, and drug development. Notably, AIDO.DNA outperforms prior encoder-only architectureswithoutnew data, suggesting that new scaling laws are needed to achieve computeoptimal DNA language models. Models and code are available through Model-Generator inhttps://github.com/genbio-ai/AIDOand on Hugging Face athttps://huggingface.co/genbio-ai.
RNA-binding proteins control the G2-M checkpoint of the germinal centre B cell
Authors: Salerno Fiamma , Whale Alex J. , Matheson Louise S. , Foster William S. , Stammers Melanie , Bell Sarah E. , Hodson Daniel J. , Linterman Michelle A. , Houseley Jonathan , Turner Martin
Published: December 2024

How germinal centre (GC) B cells undergo rapid cell division while maintaining genome stability is poorly understood. Here, we show that the RNA-binding proteins ZFP36L1 and ZFP36L2 act downstream of antigen-sensing and protect GC B cells from replication stress by controlling a cell cycle-related RNA post-transcriptional regulon. ZFP36L1 and ZFP36L2 safeguard faithful completion of mitosis by restraining the expression of CDK1 and cyclin B1, whilst controlling their activity through regulation of a p21-mediated negative feedback loop. In the absence of ZFP36L1 and ZFP36L2, GC B cells arrest in G2-M and die by apoptosis, resulting in curtailed GC responses. This is associated with stalling of the DNA replication fork at active replication initiation zones, which causes replication stress and increased activity of the ATR/CHK1 DNA damage response. Our findings reveal that gene regulation by RNA-binding proteins is essential for a functional G2-M checkpoint to operate in GC B cells.
Discovery of Thermodynamic Control Variables that Independently Regulate Healthspan and Maximum Lifespan
Authors: Denisov Kirill A. , Gruber Jan , Fedichev Peter O.
Published: December 2024

The question, “Can aging be modified, delayed, or reversed?” has profound social and economic implications for rapidly aging societies today. Interventions, ideally, would intercept functional decline and extend healthspan by delaying late-life morbidity (known as “squaring the curve”). These have proven elusive, but examples of differential aging in the animal world abound, suggesting aging itself is a malleable process. We present a novel multi-scale theoretical framework for entropic aging, and apply it to recently published DNA methylation data from 348 evolutionarily distant mammalian species. Our analysis identified modules or correlated DNA methylation changes associated with reversible pathway activation in key biological processes. We discovered a single species-dependent scaling factor controlling the magnitude of fluctuations across biological pathways. It acts as the organism’s “effective temperature”, quantifying intrinsic biological noise within networks and is unrelated to physical body temperature. Furthermore, we find a distinct stochastic damage signature and an associated extreme value (Gumbel) distribution of activation barriers controlling site-specific damage rates of individual CpG sites. This implies that aging is driven by rare, high-energy transitions on rugged energy landscape, most likely simultaneous and hence practically irreversible failures in highly redundant systems. While the overall rate of damage accumulation and hence the maximum lifespan does not depend on the effective temperature driving the noise in leading pathways, effective temperature does influence both initial mortality rate and the mortality rate doubling time – thereby shaping the survival curve. Lowering effective temperature must, therefore, be a promising Geroscience strategy, aimed directly at squaring the curve of aging. The example shows that targeting the thermodynamic forces driving mammalian aging may provide powerful strategies for the development of truly meaningful interventions to combat aging in humans.
A negative binomial latent factor model for paired microbiome sequencing data
Authors: Kim Hyotae , Siddiqui Nazema , Karstens Lisa , Ma Li
Published: December 2024

Motivation

Microbiome compositional data are often collected from several body sites and exhibit dependency among them. Analyzing microbial compositions from different sites jointly allows for effective borrowing of information by exploiting the underlying cross-site correlation, which can lead to more effective statistical analysis, especially when the sample size at one or both sites is limited. To this end, we introduce a joint model for microbiome compositions at two (or more) sites within the same subjects. Our model incorporates (i) latent factors shared across two body sites to explain the common subject effects and to serve as the source of correlation between the two sites; and (ii) mixtures of latent factors to allow heterogeneity among the samples in their level of cross-site association. The model is illustrated with synthetic data and we apply it in a case study involving samples of the urinary and vaginal microbiome collected from women.

Results

Simulation studies show how common subject effects influence regression analysis results; a stronger association between two sites in the data causes a greater degree of bias in the analysis. The model with latent factors mitigates the bias present in the model without latent factors, whereas the two models perform comparably for the data set without paired associations. In a case study involving samples collected from a study on the female urogenital microbiome with aging (e.g., the UMICRO study), our model leads to the detection of covariate associations of the vaginal and urinary microbiome composition that are otherwise not statistically significant under a similar regression model applied to the two sites separately. Our model also enables prediction of the microbial abundance at one site based on observations from another site. We also consider a model extension that allows the clustering of subjects (samples) and cluster-specific levels of paired association. Under the extended modeling framework, the clusters can be classified according to their association strengths.
Alpha-synuclein knockout impairs melanoma development and alters DNA damage repair in the TG3 mouse model in a sex-dependent manner
Authors: Arnold Moriah R. , Chen Suzie , Unni Vivek K.
Published: December 2024

Strong evidence suggests links between Parkinson’s Disease (PD) and melanoma, as studies have found that people with PD are at an increased risk of developing melanoma and those with melanoma are at increased risk of developing PD. Although these clinical associations are well-established, the cellular and molecular pathways linking these diseases are poorly understood. Recent studies have found a previously unrecognized role for the neurodegeneration-associated protein alpha-synuclein (αSyn) in melanoma; the overexpression of αSyn promotes melanoma cell proliferation and metastasis. However, to our knowledge, no studies have investigated the role of αSyn inin vivomelanoma models outside of a xenograft paradigm. Our study created and characterizedSncaknockout in the spontaneously developing melanoma TG3 mouse line, TG3+/+Snca-/-. We show that αSyn loss-of-function significantly delays melanoma onset and slows tumor growthin vivo. Furthermore, decreased tumor volume is correlated with a decreased DNA damage signature and increased apoptotic markers, indicating a role for αSyn in modulating the DNA damage response (DDR) pathway. Overall, our study provides evidence that targeting αSyn and its role in modulating the DDR and melanomagenesis could serve as a promising new therapeutic target.
Marine medaka responds differently to dioxin compared with its close freshwater relative, the Japanese medaka: the AHR molecular mechanism
Authors: Zhang Wanglong , Zong Yanjiao , Sun Ruize , Xue Zhenhong , Wan Wenhui , Ren Anran , Ma Yongchao , Tian Wenjing , Wang Renjun
Published: December 2024

The global water pollution now calls for precise risk assessment of chemicals, e.g., dioxins and the emerging dioxin-like compounds (DLCs). The freshwater and marine medaka have been widely implemented in the toxicity testing, and perhaps give mechanistic information for comparative biology. The question that ‘will they report equal results due to their close phylogenetic relation’ has been raised, therefore, we explored their physiological and molecular responses to dioxin. As the mediator of the dioxin toxicity, the aryl hydrocarbon receptor (AHR) of marine medaka (Oryzias melastigma) has not been functionally characterized and might be species-specific. In terms of sensitivity to dioxin—2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the EC50values of omeAHR1a (0.16±0.12 nM), omeAHR1b (2.96±2.96 nM), omeAHR2a (0.44±0.30 nM), and omeAHR2b (9.00±6.88 nM) exhibit marked variations. The omeAHR2a and omeAHR1a display heightened sensitivity compared to the freshwater Japanese medaka (Oryzias latipes) counterparts olaAHR2a and olaAHR1a, respectively. The results indicate the in vitro sensitivity of AHR among species can vary by one or two orders of magnitude. Physiologically, the marine medaka (LC50: 1.64 ng/L (95% CI: 1.05-2.55 ng/L)) also exhibits a pronounced sensitivity to TCDD than Japanese medaka (LC50: 3.42 ng/L (95% CI: 1.37-6.48 ng/L), aligning with the in vitro AHR sensitivity. Further mechanistic investigations using additional ligands and computational modeling reveal that: 1) most of omeAHR2a, olaAHR2a, dreAHR2, and hsaAHR interact with ligands in the affinity order of TCDD > PCB126 > BNF > indole, mirroring their AHR transactivation potency, but the docking poses and dynamics can vary; 2) one AHR subform’s high sensitivity to dioxin—TCDD may extend to DLCs but not to other types of ligands. These insights underscore the difference of AHR biology among species even the close relative species, and finger out the necessity for meticulous consideration when evaluating the toxicity of compounds and when extending predictive toxicity assessments to more species.
Ultra-early hematoma expansion is associated with ongoing hematoma growth and poor functional outcome
Authors: Mutimer Chloe A. , Wu Teddy Y. , Zhao Henry , Churilov Leonid , Campbell Bruce C.V. , Cheung Andrew , Meretoja Atte , Kleinig Timothy J. , Choi Philip M. , Ma Henry , Cloud Geoffrey C. , Grimley Rohan , Shah Darshan , Ranta Annemarei , Mahawish Karim , Yogendrakumar Vignan , Sharma Gagan , Donnan Geoffrey A. , Davis Stephen M. , Yassi Nawaf
Published: December 2024

INTRODUCTION

There are limited data on ultra-early hematoma growth dynamics and their clinical impact in primary intracerebral hemorrhage (ICH). We aimed to (a) estimate the incidence of hematoma expansion within the hyperacute period of ICH, (b) describe hematoma dynamics over time, (c) investigate the associations between ultra-early hematoma expansion and clinical outcomes after ICH, and (d) assess the effect of tranexamic acid on ultra-early hematoma expansion.

METHODS

We performed a planned secondary analysis of the STOP-MSU international multicenter randomized controlled trial. The trial compared tranexamic acid with placebo in 201 patients with primary ICH presenting within 2 hours of symptom onset. Repeat CT imaging ∼1 hour after treatment commencement was encouraged.

Patients who underwent re-imaging up to 3 hours from baseline imaging were included in this descriptive study. Hematoma expansion was defined as either a ≥33% or ≥6 ml increase from baseline hematoma volume.

RESULTS

We included 105 of the 201 patients who had 1-hour imaging (median age 66 years, 40% female, 53% tranexamic acid). Median time from onset to baseline imaging was 74min (IQR 56-87 min), and between baseline and 1-hour imaging was 95 min (IQR 74-132 min). Forty-one patients (39%) had ultra-early hematoma expansion. These patients had larger baseline hematoma volumes (15.9 ml vs 9.1 ml, p=0.03) compared to those with no early hematoma expansion.

Hematoma growth rate declined over time compared to the onset-to-baseline imaging period (clustered median regression p<0.01). In 92 patients with both 1-hour and 24-hour re-imaging, 9/31 (29%) of those with ultra-early hematoma expansion had further expansion between the 1-hour and 24-hour scan, compared to only 4/61(6.6%) without ultra-early expansion (p<0.01). Of those 61 patients, there were 10 (16.4%) who fulfilled the expansion definition by 24 hours.

Ultra-early hematoma expansion was associated with poor functional outcomes (mRS 3-6; aOR 3.87 [1.21-12.40], p=0.02) and mortality (aOR 6.16 [95% CI 2.15-17.68], p<0.01), adjusted for treatment group.

There was no observed effect of tranexamic acid treatment on ultra-early hematoma expansion (41% vs. 37%, p=0.65).

CONCLUSIONS

Most hematoma growth occurs in the ultra-early period. The presence of hyperacute hematoma expansion is associated with ongoing hematoma growth, poor functional outcomes and mortality, and represents a target for therapeutic intervention.
Yo-yo dieting deregulates feeding behavior in mice via the induction of durable gut dysbiosis
Authors: Fouesnard Mélanie , Salin Adélie , Ribes Sandy , Monnoye Magali , Champeil-Potokar Gaëlle , Hjeij Marie-Sabelle , Randuineau Gwénaëlle , Gleau Léa Le , Fradj Selma Ben , Philippe Catherine , Benani Alexandre , Denis Isabelle , Douard Véronique , Boudry Gaëlle
Published: December 2024

Background & Aims

Alternating periods of excessive and restrained eating results in weight cycling, a known risk factor for eating behavior dysregulation such as binge eating. Diet alternation also induces changes in intestinal microbiota composition. We tested the hypothesis that recurrent diet alternation alters hedonic feeding regulation by changing either or both intestinal microbiota and brain homeostasis in mouse.

Methods

C57BL/6 mice underwent 3 cycles of 1 week of western diet (WD, 45% kcal from fat) separated by 2 weeks of chow diet (CYCL group) or staid under chow diet (CTRL group). Food intake was monitored after each dietary change. Striatum, hypothalamus, brainstem and caecal content were collected before the third WD introduction in CYCL mice and in CTRL mice. Microbiota transfer from CYCL or CTRL mice into naive recipient mice was performed to investigate whether gut microbiota per se could explain differences in eating behavior during weight cycling.

Results

Diet alternation in CYCL mice resulted in weight cycling, with enhanced weight gain upon each WD feeding phase. CYCL mice increased their energy intake specifically during the first hours following WD re-introduction, reminiscent of binge-eating episodes. Expression of reward-related genes in the striatum and thickness of the astro-glial barrier in the brain stem were enhanced in CYCL compared to CTRL mice. Diet alternation also induced caecal dysbiosis in CYCL mice. Gut microbiota transfer from CYCL mice to naive recipient mice recapitulated the altered eating behavior upon WD exposure.

Conclusions

Alternation between high-energy and standard diet durably remodels the gut microbiota and the brain towards a profile associated with an increase in hedonic appetite. Using gut microbiota transfer, we established that this microbiota signature affects hedonic feeding regulation. These results open the ways to microbiota-targeted strategies to prevent development of eating disorders in weight cycling patients.
The Role of Negatively Charged Groups in Antimicrobial Cationic Peptide Mimics: Insights into Membrane Interactions
Authors: Saiba Roni , Debnath Ananya , Vemparala Satyavani
Published: December 2024

In this study, we explore cationic amphiphilic methacrylate copolymers incorporating both positively charged AEMA and negatively charged PAMA functional groups, focusing on their interactions with bacterial membranes. Aggregation studies reveal that electrostatic interactions drive the formation of stable polymer aggregates, with block copolymers forming micelle-like structures and random copolymers exhibiting a more uniform distribution. These ternary polymers preferentially interact with deep lipid packing defects in bacterial membranes, stabilizing and expanding these defects, while shallow defects remain largely unaffected due to the unfavorable interaction of anionic groups with lipid headgroups. The role of interfacial water is also critical, as hydration layers surrounding anionic groups shield them from electrostatic repulsion, enabling deeper penetration into the membrane. Comparative analyses highlight the advantages of anionic-containing polymers over previously studied polar-containing systems, which predominantly engage shallow defects and exhibit limited structural adaptability near membranes. These findings underscore the role of anionic residues in enabling adaptable AMP conformations, enhanced membrane engagement, and effective disruption mechanisms, providing valuable insights for the design of biomimetic antimicrobial polymers incorporating different functional groups.
Cytokine Dynamics and Oxidative Stress in Host Cells Stimulated with Drug-Resistant and SensitiveMycobacterium tuberculosisIsolates
Authors: Kumar Kavitha , Giribhattanavar Prashant , Sagar B. K. Chandrasekhar , Patil Shripad A.
Published: December 2024

Background

The immune response toMycobacterium tuberculosis(M. tuberculosis) is central to the pathogenesis of tuberculosis (TB), yet the immune dynamics induced by drug-resistant strains remain underexplored. Understanding the host’s immune response to both drug-sensitive and drug-resistantM. tuberculosisisolates is crucial for elucidating the mechanisms of pathogenesis and resistance. This study aims to assess the cellular immune responses, including PBMC proliferation, cytokine secretion (IL-4 and IL-17a), and reactive oxygen species (ROS) production in response to live drug-sensitive and drug-resistantM. tuberculosisclinical isolates.

Methods

Peripheral blood mononuclear cells (PBMCs) from PPD-negative and PPD-positive healthy volunteers were stimulated with liveM. tuberculosisisolates, including MDR, SI-resistant, and sensitive strains. The immune responses were assessed by evaluating cell proliferation, secretion of IL-4 and IL-17a cytokines, and ROS production over a 9-day period.

Results

PBMCs from PPD-positive individuals exhibited a higher proliferative response compared to PPD-negative individuals, indicating more robust immune memory. IL-4 secretion was low but varied among samples, with higher levels observed in response to MDR isolates, suggesting a potential role in immunopathology. IL-17a levels increased over time, particularly in PPD-positive individuals, and MDR strains elicited a stronger response than sensitive isolates. ROS production was significantly elevated in response to resistant strains, reflecting the host’s oxidative defense mechanisms.

Conclusion

This study demonstrates distinct immune responses to drug-resistantM. tuberculosisisolates, with variations in cell proliferation, cytokine secretion, and ROS production. These findings provide insights into the immune dynamics during infection with resistant strains and underscore the importance of genotype-environment interactions in TB pathogenesis.

Graphical Abstract
Uncovering Genes Essential in Domestication and Breeding of Sugar Beet
Authors: Dhiman Amar Singh , Emrani Nazgol , Holtgrewe-Stukenbrock Eva , Varrelmann Mark , Jung Christian
Published: December 2024

The genusBetaencompasses economically important root crops such as sugar and table beet. ABetadiversity set including the wild relativeB. vulgarisssp.maritimawas grown in the field, and a large phenotypic diversity was observed. The genomes of 290 accessions were sequenced, and more than 10 million high-quality SNPs were employed to study genetic diversity. A genome-wide association study was performed, and marker-trait associations were found for nine phenotypic traits. The candidate gene within theMlocus controlling monogermity on chromosome 4 was previously unknown. The most significant association for monogermity was identified at the end of chromosome 4. Within this region, a non-synonymous mutation within the Zinc-Finger domain of theWIP2gene co-segregated with monogermity. This gene plays a regulatory role inAGL8/FULin Arabidopsis. Intriguingly, commercial hybrids are in a heterozygous state at this position. Thus, the long-sought gene for monogermity was identified in this study. Red and yellow pigmentation due to betalain accumulation in shoots and roots is an important characteristic of table and leaf beets. The strongest associations were found upstream or downstream of two genes encoding Cytochrome P450 and anthocyanin MYB-like transcription factor proteins involved in betalain biosynthesis. Significant associations forCercosporaleaf spot resistance were identified on chromosomes 1, 2, 7, and 9. The associated regions harbor genes encoding proteins with leucine-rich repeats and nucleotide binding sites whose homologs are major constituents of plant-pathogen defense.