bluuebunny/crossref_metadata_2025_split huggingface dataset:
A transcription factor toggle switch determines differentiated epidermal cell identities inHydra
Authors: Ferenc Jaroslav , Bonvin Marylène , Papasaikas Panagiotis , Ferralli Jacqueline , Nuninger Clara , Tsiairis Charisios D. 
Published: December 2024

AbstractInHydra, a simple cnidarian model, epithelio-muscular cells play a crucial role in shaping and maintaining the body architecture. These cells are continuously renewed as undifferentiated cells from the body’s mid-region get displaced toward the extremities, replacing shed, differentiated cells and adopting specific identities. This ongoing differentiation, coupled with the maintenance of distinct anatomical regions, provides an ideal system to explore the relationship between cell type specification and axial patterning. However, the molecular mechanisms governing epithelial cell identity inHydraremain largely unknown. In this study, we describe a double-negative feedback loop between the transcription factors Zic4 and Gata3 that functions as a toggle switch to control epidermal cell fate. Zic4 is activated by Wnt signaling from the mouth organizer and triggers battery cell specification in tentacles. In contrast, Gata3 promotes basal disk cell identity at the aboral end. Functional analyses demonstrate that Zic4 and Gata3 are mutually antagonistic; suppression of one leads to the dominance of the other, andvice versa, resulting in ectopic cell specification. Notably, simultaneous knockdown of both factors rescues the phenotype, indicating that it is the balance between these transcription factors, rather than their absolute levels, that dictates cell identity. This study highlights the mechanisms by which distinct cellular identities are established atHydrabody termini and reveals how cell fate decisions are coordinated with axial patterning.
5’ HOXD GENES DIFFERENTIALLY REGULATE GENE EXPRESSION OF SYNOVIAL FIBROBLASTS IN HAND JOINTS
Authors: Mirrahimi Masoumeh , Klein Kerstin , Cebrián Camino Calvo , Khmelevskaya Alexandra , Houtman Miranda , Camarillo Retamosa Eva , Saadat Mohammd Hossein , Ezen Ege , Vogetseder Alexander , Rothenfluh Esin , Berli Martin , Rauer Thomas , Catanzaro Sabrina , Jingyi Wang , Andersson Johan , Distler Oliver , Ospelt Caroline 
Published: December 2024

ABSTRACTWe previously demonstrated that Homeobox (HOX) transcription factors are differentially expressed between joint locations and can accurately assign synovial fibroblasts (SFs) to their correct joint location. We show here that the expression of the 5’HOXD transcription factors HOXD10, HOXD11, and HOXD13 in SFs strikingly overlaps with predilection sites for the development of rheumatoid arthritis (RA). Changes in SFs gene expression after silencing 5’HOXDs aligned with joint-specific differences of RA SFs. In particular, we identify HOXD13 as regulator or primary cilia function in SFs modulating cell cycle, DNA damage and proteasome activity. Accordingly, we show joint specific differences in primary cilia morphology, DNA damage repair and proteasome activity. We thus propose that HOXD13 and primary cilia play a role in shaping joint-specific SFs functions that might underlie the pathognomic pattern of joint involvement in RA.
Age-Related Patterns of DNA Methylation Changes
Authors: Chen Kevin , Wang Wenshu , Suryadevara Hari Naga Sai Kiran , Peng Gang 
Published: December 2024

AbstractDNA methylation is a dynamic process that adds methyl groups to DNA molecules, which plays an important role in gene expression regulation, genome stability, and aging. Epigenetic clocks developed over the past decade have used DNA methylation values at specific CpG sites combined with factors such as environmental influences and lifestyle factors to predict biological age with remarkable accuracy. However, these epigenetic clocks, built using conventional penalized regression models, have several limitations: (1) they assume consistent linear changes in methylation with age, even though methylation patterns may vary at different ages; (2) the selected CpGs in these clocks often lack specific biological significance; and (3) there is minimal overlap among the selected CpGs across different clocks, suggesting that only a small subset of a larger group of age-correlated CpGs is used to build an effective clock. Using data from 4,899 samples across 22 GEO datasets, we first analyzed the methylation patterns of 1,868 CpGs from 9 widely used epigenetic clocks and observed the expected consistently linear patterns in a subcluster. Next, we applied our own CpG selection method, which does not assume a lifelong linear correlation between DNA methylation and age. we divided the lifespan into overlapping age windows— [0, 20], [5, 25], [10, 30] …, [55, 75], [60, 80]— and identified CpGs that showed strong correlations with age within each specific window. Most CpGs were selected in young and old age windows, while few were selected in the middle-aged windows, indicating fast DNA methylation changes during child development and aging. Among the 12,903 unique CpGs selected within any of the windows, we performed clustering and uncovered from main patterns: (1) increase before 20 years old, (2) decrease before 20 years old, (3) increase before 20 and then decrease after 60, and (4) decrease before 20 and then increase after 60. Comparing this to the clock CpGs, both sets contained CpGs that decreased during adolescence. When examining gender differences, we noted that female samples had notably slowed methylation changes in old age windows compared to male samples, possibly due to hormonal changes during menopause. These findings suggest that age-related methylation changes are more complex than previously thought, with implications for refining epigenetic clocks and redefining the way researchers study aging. Future research should explore the biological mechanisms behind these non-linear and sex-specific patterns.
FSTL3 is a biomarker of poor prognosis and is associated with immunotherapy resistance in ovarian cancer
Authors: Chauvin Maeva , Tromelin Estelle , Roche Julien , Lancia Hyshem H , Meinsohn Marie-Charlotte , Coletti Caroline , Phuong Nguyen Ngoc Minh , Lafont Virginie , Michaud Henri-Alexandre , Mishra Ranjan , Gros Laurent , Bonnefoy Nathalie , Pépin David 
Published: December 2024

AbstractHigh-grade serous ovarian carcinoma (HGSOC), is associated with high mortality rates due to late-stage diagnosis and limited treatment options. We investigated the role of FSTL3 in ovarian cancer progression both as a prognostic biomarker and as a potential therapeutic target.We measured levels of follistatin (FST) and follistatin-like 3 (FSTL3) in 96 ovarian cancer patient ascites samples and found that FSTL3 overexpression was more predominant than FST and associated with poorer survival outcomes. Mice implanted with an HGSOC syngeneic cell line bearing common alterations in ovarian cancer (KRASG12V, P53R172H, CCNE1oe, AKT2oe) had increasing levels of FST and FSTL3 in serum during tumor growth. Further alteration of this model to generate a knockout of FST (KPCA.FSTKO) and an overexpression of human FSTL3 (KPCA.FSTKO_hFSTL3), revealed that FSTL3 expression was associated with a more fibrotic tumor microenvironment, correlating with an increased abundance of cancer-associated myofibroblasts (myCAFs), and cancer cells with a more mesenchymal phenotype. Tumors overexpressing FSTL3 had less immunocyte infiltration and a significantly reduced intratumoral T-cell abundance (CD4+, CD8+). FSTL3 overexpression completely abrogated tumor response to PPC treatment (Prexasertib combined with PD-1 and CTLA-4 blockade) compared to controls, suggesting that FSTL3 may be involved in immunotherapy resistance.In conclusion, this study suggests a role for FSTL3 as a prognostic marker and as therapeutic target in HGSOC, where it may play a role in promoting a mesenchymal tumor phenotype, maintaining an immunosuppressive tumor microenvironment, and driving immunotherapy resistance.HighlightsHigh FSTL3 levels are associated with poor outcomes in ovarian cancer.Serum levels of FSTL3 increase during tumor growth and reflect tumor burden and therapy response.Overexpression of FSTL3 in cancer cells promotes a fibrotic tumor microenvironment and immunocyte exclusion.Overexpression of FSTL3 in tumors induces resistance to Chk1 and immune checkpoint inhibitor combination therapy.Graphical abstract
FLEXIBILITY IN GENE COEXPRESSION AT DEVELOPMENTAL AND EVOLUTIONARY TIMESCALES
Authors: Fischer Eva K , Song Youngseok , Zhou Wen , Hoke Kim L 
Published: December 2024

ABSTRACTThe explosion of next-generation sequencing technologies has allowed researchers to move from studying single genes, to thousands of genes, and thereby to also consider the relationships within gene networks. Like others, we are interested in understanding how developmental and evolutionary forces shape the expression of individual genes, as well as the interactions among genes. To this end, we characterized the effects of genetic background and developmental environment on brain gene coexpression in two parallel, independent evolutionary lineages of Trinidadian guppies (Poecilia reticulata). We asked whether connectivity patterns among genes differed based on genetic background and rearing environment, and whether a gene’s connectivity predicted its propensity for expression divergence. In pursuing these questions, we confronted the central challenge that standard approaches fail to control the Type I error and/or have low power in the presence of high dimensionality (i.e., large number of genes) and small sample size, as in many gene expression studies. Using our data as a case study, we detail central challenges, discuss sample size guidelines, and provide rigorous statistical approaches for exploring coexpression differences with small sample sizes. Using these approaches, we find evidence that coexpression relationships differ based on both genetic background and rearing environment. We report greater expression divergence in less connected genes and suggest this pattern may arise and be reinforced by selection.
Stable isotope fingerprinting can directly link intestinal microorganisms with their carbon source and captures diet-induced substrate switchingin vivo
Authors: Mordant Angie , Blakeley-Ruiz J. Alfredo , Kleiner Manuel 
Published: December 2024

AbstractDiet has strong impacts on the composition and function of the gut microbiota with implications for host health. Therefore, it is critical to identify the dietary components that support growth of specific microorganismsin vivo. We used protein-based stable isotope fingerprinting (Protein-SIF) to link microbial species in gut microbiota to their carbon sources by measuring each microbe’s natural13C content (δ13C) and matching it to the13C content of available substrates. We fed gnotobiotic mice, inoculated with a 13 member microbiota, diets in which the13C content of all components was known. We varied the source of protein, fiber or fat to observe13C signature changes in microbial consumers of these substrates. We observed significant changes in the δ13C values and abundances of specific microbiota species, as well as host proteins, in response to changes in13C signature or type of protein, fiber, and fat sources.Using this approach we were able to show that upon switching dietary source of protein, fiber, or fat (1) some microbial species continued to obtain their carbon from the same dietary component (e.g., protein); (2) some species switched their main substrate type (e.g., from protein to carbohydrates); and (3) some species might derive their carbon through foraging on host compounds. Our results demonstrate that Protein-SIF can be used to identify the dietary-derived substrates assimilated into proteins by microbes in the intestinal tract; this approach holds promise for the analysis of microbiome substrate usage in humans without the need of substrate labeling.SignificanceThe gut microbiota plays a critical role in the health of animals including humans, influencing metabolism, the immune system, and even behavior. Diet is one of the most significant factors in determining the function and composition of the gut microbiota, but our understanding of how specific dietary components directly impact individual microbes remains limited. We present the application of an approach that measures the carbon isotope “fingerprint” of proteins in biological samples. This fingerprint is similar to the fingerprint of the substrate used to make the proteins. We describe how we used this approach in mice to determine which dietary components specific intestinal microbes use as carbon sources to make their proteins. This approach can directly identify components of an animal’s diet that are consumed by gut microbes.
Deciphering enzymatic potential in metagenomic reads through DNA language model
Authors: Prabakaran R , Bromberg Y 
Published: December 2024

AbstractEarth’s microbial world plays a fundamental role in shaping the biosphere, steering global processes, soil rejuvenation, and ecological fortification. An overwhelming majority of microbial entities, however, remain un(der)studied. Metagenomics stands to elucidate this microbial “dark matter” by directly sequencing the microbial community DNA from environmental samples. Yet, our ability to explore metagenomic sequences is mostly limited to establishing their similarity to curated datasets of organisms or genes/proteins. Aside from the difficulties in establishing such similarity, the reference-based approaches, by definition, forgo discovery of any entities sufficiently unlike the reference collection.Presenting a paradigm shift, language model-based methods, offer promising avenues for reference-free analysis of metagenomic reads. Here, we introduce two language models, a pretrained foundation model REMME, aimed at understanding the DNA context of metagenomic reads, and the fine-tuned REBEAN model for predicting the enzymatic potential encoded within the read-corresponding genes. By emphasizing function recognition over gene identification, REBEAN is able to label molecular functions carried both by previously explored genes and by new (orphan) sequences. Inherently, REBEAN identifies the functionally relevant parts of a gene even though it is not explicitly trained to do so. It thus expands enzymatic annotation of unassembled metagenomic reads from extreme environments while maintaining consistency with available annotation methods. Here, our comprehensive analysis highlights our models’ potential for metagenomic read annotation and unearthing of novel enzymes, thus enriching our understanding of microbial communities.
Cells Prioritize the Regulation of Cell Mass Density
Authors: Fu Jinyu , Ni Qin , Wu Yufei , Gupta Anoushka , Ge Zhuoxu , Yang Hongru , Afrida Yasin , Barman Ishan , Sun Sean X. 
Published: December 2024

AbstractA cell’s global physical state is characterized by its volume and dry mass. The ratio of cell mass to volume is the cell mass density (CMD), which is also a measure of macromolecular crowding and concentrations of all proteins. Using the Fluorescence eXclusion method (FXm) and Quantitative Phase Microscopy (QPM), we investigate CMD dynamics after exposure to sudden media osmolarity change. We find that while the cell volume and mass exhibit complex behavior after osmotic shock, CMD follows a straightforward monotonic recovery in 48 hours. The recovery is cell-cycle independent and relies on a coordinated adjustment of protein synthesis and volume growth rates. Surprisingly, we find that the protein synthesis rate decreases when CMD increases. This result is explained by CMD-dependent nucleoplasm-cytoplasm transport, which serves as negative regulatory feedback on CMD. The Na+/H+exchanger NHE plays a role in regulating CMD by affecting both protein synthesis and volume change. Taken together, we reveal that cells possess a robust control system that actively regulates CMD during environmental change.
Structure of theStaphylococcus aureusbacteriophage 80α neck shows the interactions between DNA, tail completion protein and tape measure protein
Authors: Kizziah James L. , Mukherjee Amarshi , Parker Laura K. , Dokland Terje 
Published: December 2024

ABSTRACTTailed bacteriophages with double-stranded DNA genomes (classCaudoviricetes) play an important role in the evolution of bacterial pathogenicity, both as carriers of genes encoding virulence factors and as the main means of horizontal transfer of mobile genetic elements (MGEs) in many bacteria, such asStaphylococcus aureus. TheS. aureuspathogenicity islands (SaPIs), including SaPI1, are a type of MGEs are that carry a variable complement of genes encoding virulence factors. SaPI1 is mobilized at high frequency by “helper” bacteriophages, such as 80α, leading to packaging of the SaPI1 genome into virions made from structural proteins supplied by the helper. 80α and SaPI1 virions consist of an icosahedral head (capsid) connected via a unique vertex to a long, non-contractile tail. At one end of the tail, proteins associated with the baseplate recognize and bind to the host. At the other end, a connector or “neck” forms the interface between the tail and the head. The neck consists of several specialized proteins with specific roles in DNA packaging, phage assembly, and DNA ejection. Using cryo-electron microscopy and three-dimensional reconstruction, we have determined the high-resolution structure of the neck section of SaPI1 virions made in the presence of phage 80α, including the dodecameric portal (80α gene product (gp) 42) and head-tail-connector (gp49) proteins, the hexameric head-tail joining (gp50) and tail terminator (gp52) proteins, and the major tail protein (gp53) itself. We were also able to resolve the DNA, the tail completion protein (gp51) and the tape measure protein (gp56) inside the tail. This is the first detailed structural description of these features in a bacteriophage, providing insights into the assembly and infection process in this important group of MGEs and their helper bacteriophages.
GRASP55 Safeguards Proper Lysosome Function by Controlling Sorting of Lysosomal Enzymes at the Golgi
Authors: Nüchel Julian , Omidi Maryam , Fernandes Stephanie A. , Tauber Marina , Pohl Sandra , Plomann Markus , Demetriades Constantinos 
Published: December 2024

SummaryLysosomes are multifunctional organelles that play important roles in cellular recycling, signaling, and homeostasis, relying on precise trafficking and activation of lysosomal enzymes. While the Golgi apparatus plays a central role in lysosomal enzyme sorting, the mechanisms linking Golgi function to lysosomal activity remain incompletely understood. Here, we identify the Golgi-resident protein GRASP55, but not its paralog GRASP65, as a key regulator of lysosome function. More specifically, we demonstrate that loss of GRASP55 expression leads to missorting and secretion of lysosomal enzymes, lysosomal dysfunction and bloating. GRASP55 deficiency also disrupts lysosomal mTORC1 signaling, reducing the phosphorylation of its lysosomal substrates, TFEB and TFE3, while sparing its non-lysosomal targets. Mechanistically, GRASP55 interacts with GNPTAB, a critical enzyme required for mannose 6-phosphate (M6P) tagging of lysosomal enzymes, and is necessary for its correct trafficking and stability. These findings reveal an essential role for GRASP55 in Golgi-lysosome communication and lysosomal enzyme trafficking, and suggest thatGRASP55/GORASP2may act as a susceptibility gene for lysosomal storage disorder (LSD)-like conditions. Overall, this work underscores the importance of Golgi-mediated protein sorting in lysosome function and lysosomal mTORC1 signaling, and provides insights into the molecular basis of LSD-related pathologies.
Estimates of epidemiological parameters for H5N1 influenza in humans: a rapid review
Authors: Ward Jack , Lambert Joshua W. , Russell Timothy W. , Azam James M. , Kucharski Adam J. , Funk Sebastian , Quilty Billy J. , Gressani Oswaldo , Hens Niel , Edmunds W. John 
Published: December 2024

AbstractBackgroundThe ongoing H5N1 panzootic in mammals has amplified zoonotic pathways to facilitate human infection. Characterising key epidemiological parameters for H5N1 is critical should this become widespread.AimTo identify and estimate critical epidemiological parameters for H5N1 from past and current outbreaks, and to compare their characteristics with human influenza subtypes.MethodsWe searched PubMed, Embase, and Cochrane Library for systematic reviews reporting parameter estimates from primary data or meta-analyses. To address gaps, we searched Google Scholar for studies of any design providing relevant estimates. We estimated the basic reproduction number for the outbreak in the US and estimated the serial interval using data from previous household clusters in Indonesia. We also applied a branching process model to simulate transmission chain size and duration to assess if simulated transmission patterns align with observed dynamics.ResultsFrom 32 studies, we identified H5N1’s epidemiological profile as having lower transmissibility (R0 < 0.2) but higher severity compared to human subtypes. Evidence suggests H5N1 has longer incubation (∼4 days vs ∼2 days) and serial intervals (∼6 days vs ∼3 days) than human subtypes, impacting transmission dynamics. Key gaps remain regarding latent and infectious periods.ConclusionsWe characterised critical epidemiological parameters for H5N1 infection. The current U.S. outbreak shows lower pathogenicity but similar transmissibility compared to prior outbreaks. Longer incubation and serial intervals may enhance contact tracing feasibility. These estimates offer a baseline for monitoring changes in H5N1 epidemiology.
Interplay of PD-L1, FOXP3, and CD8 in the Immune Microenvironment of Penile Squamous Cell Carcinoma: Expression Profiles and Correlations
Authors: Canete-Portillo Sofia , Cubilla Antonio L. , Netto George J. , Chaux Alcides 
Published: December 2024

ABSTRACTBackgroundPenile squamous cell carcinoma (PSCC) presents significant challenges in diagnosis and treatment. Understanding the complex immunological landscape, particularly the interaction between PD-L1, FOXP3, and CD8, is crucial for developing effective therapeutic strategies.MethodsWe analyzed 108 PSCC cases through 528 tissue microarray samples. Immunohistochemical staining was performed using standardized protocols to detect PD-L1, FOXP3, and CD8 expression. Expression patterns were evaluated in both tumor and stromal compartments, with assessment of membranous staining for PD-L1 and quantification of FOXP3+ and CD8+ lymphocytes.ResultsPD-L1 expression in tumor cells showed a moderate positive correlation (r=0.477, P<0.001) with CD8+ T-cell infiltration in the tumor compartment, suggesting an adaptive immune resistance mechanism. PD-L1 expression in tumor cells demonstrated a weak positive correlation (r=0.289, P=0.002) with FOXP3 expression in tumor-associated lymphocytes. The strongest correlation observed (r=0.717, P<0.001) was between FOXP3 expression in stromal lymphocytes and CD8+ T-cell presence in stromal areas. PD-L1 expression in lymphocytes showed a significant correlation (r=0.354, P<0.001) with FOXP3 expression in stromal lymphocytes.ConclusionsOur findings reveal complex interactions between PD-L1, FOXP3, and CD8 within the tumor microenvironment of PSCC. The strong correlation between stromal FOXP3+ and CD8+ cells points to a crucial immune regulatory axis that could influence treatment outcomes. These results provide insights for developing targeted therapeutic strategies and improving patient care in PSCC.