Systems Biology

The covariance environment defines cellular niches for spatial inference

Tue, 2024-04-02 06:00

Nat Biotechnol. 2024 Apr 2. doi: 10.1038/s41587-024-02193-4. Online ahead of print.

ABSTRACT

A key challenge of analyzing data from high-resolution spatial profiling technologies is to suitably represent the features of cellular neighborhoods or niches. Here we introduce the covariance environment (COVET), a representation that leverages the gene-gene covariate structure across cells in the niche to capture the multivariate nature of cellular interactions within it. We define a principled optimal transport-based distance metric between COVET niches that scales to millions of cells. Using COVET to encode spatial context, we developed environmental variational inference (ENVI), a conditional variational autoencoder that jointly embeds spatial and single-cell RNA sequencing data into a latent space. ENVI includes two decoders: one to impute gene expression across the spatial modality and a second to project spatial information onto single-cell data. ENVI can confer spatial context to genomics data from single dissociated cells and outperforms alternatives for imputing gene expression on diverse spatial datasets.

PMID:38565973 | DOI:10.1038/s41587-024-02193-4

Categories: Literature Watch

PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress

Tue, 2024-04-02 06:00

Nat Commun. 2024 Apr 2;15(1):2857. doi: 10.1038/s41467-024-47222-7.

ABSTRACT

PARP2 is a DNA-dependent ADP-ribosyl transferase (ARTs) enzyme with Poly(ADP-ribosyl)ation activity that is triggered by DNA breaks. It plays a role in the Base Excision Repair pathway, where it has overlapping functions with PARP1. However, additional roles for PARP2 have emerged in the response of cells to replication stress. In this study, we demonstrate that PARP2 promotes replication stress-induced telomere fragility and prevents telomere loss following chronic induction of oxidative DNA lesions and BLM helicase depletion. Telomere fragility results from the activity of the break-induced replication pathway (BIR). During this process, PARP2 promotes DNA end resection, strand invasion and BIR-dependent mitotic DNA synthesis by orchestrating POLD3 recruitment and activity. Our study has identified a role for PARP2 in the response to replication stress. This finding may lead to the development of therapeutic approaches that target DNA-dependent ART enzymes, particularly in cancer cells with high levels of replication stress.

PMID:38565848 | DOI:10.1038/s41467-024-47222-7

Categories: Literature Watch

Oxytetracycline hyper-production through targeted genome reduction of <em>Streptomyces rimosus</em>

Tue, 2024-04-02 06:00

mSystems. 2024 Apr 2:e0025024. doi: 10.1128/msystems.00250-24. Online ahead of print.

ABSTRACT

Most biosynthetic gene clusters (BGC) encoding the synthesis of important microbial secondary metabolites, such as antibiotics, are either silent or poorly expressed; therefore, to ensure a strong pipeline of novel antibiotics, there is a need to develop rapid and efficient strain development approaches. This study uses comparative genome analysis to instruct rational strain improvement, using Streptomyces rimosus, the producer of the important antibiotic oxytetracycline (OTC) as a model system. Sequencing of the genomes of two industrial strains M4018 and R6-500, developed independently from a common ancestor, identified large DNA rearrangements located at the chromosome end. We evaluated the effect of these genome deletions on the parental S. rimosus Type Strain (ATCC 10970) genome where introduction of a 145 kb deletion close to the OTC BGC in the Type Strain resulted in massive OTC overproduction, achieving titers that were equivalent to M4018 and R6-500. Transcriptome data supported the hypothesis that the reason for such an increase in OTC biosynthesis was due to enhanced transcription of the OTC BGC and not due to enhanced substrate supply. We also observed changes in the expression of other cryptic BGCs; some metabolites, undetectable in ATCC 10970, were now produced at high titers. This study demonstrated for the first time that the main force behind BGC overexpression is genome rearrangement. This new approach demonstrates great potential to activate cryptic gene clusters of yet unexplored natural products of medical and industrial value.IMPORTANCEThere is a critical need to develop novel antibiotics to combat antimicrobial resistance. Streptomyces species are very rich source of antibiotics, typically encoding 20-60 biosynthetic gene clusters (BGCs). However, under laboratory conditions, most are either silent or poorly expressed so that their products are only detectable at nanogram quantities, which hampers drug development efforts. To address this subject, we used comparative genome analysis of industrial Streptomyces rimosus strains producing high titers of a broad spectrum antibiotic oxytetracycline (OTC), developed during decades of industrial strain improvement. Interestingly, large-scale chromosomal deletions were observed. Based on this information, we carried out targeted genome deletions in the native strain S. rimosus ATCC 10970, and we show that a targeted deletion in the vicinity of the OTC BGC significantly induced expression of the OTC BGC, as well as some other silent BGCs, thus suggesting that this approach may be a useful way to identify new natural products.

PMID:38564716 | DOI:10.1128/msystems.00250-24

Categories: Literature Watch

Single-Cell Multi-Omics Map of Cell Type-Specific Mechanistic Drivers of Multiple Sclerosis Lesions

Tue, 2024-04-02 06:00

Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200213. doi: 10.1212/NXI.0000000000200213. Epub 2024 Apr 2.

ABSTRACT

BACKGROUND AND OBJECTIVES: In progressive multiple sclerosis (MS), compartmentalized inflammation plays a pivotal role in the complex pathology of tissue damage. The interplay between epigenetic regulation, transcriptional modifications, and location-specific alterations within white matter (WM) lesions at the single-cell level remains underexplored.

METHODS: We examined intracellular and intercellular pathways in the MS brain WM using a novel dataset obtained by integrated single-cell multi-omics techniques from 3 active lesions, 3 chronic active lesions, 3 remyelinating lesions, and 3 control WM of 6 patients with progressive MS and 3 non-neurologic controls. Single-nucleus RNA-seq and ATAC-seq were combined and additionally enriched with newly conducted spatial transcriptomics from 1 chronic active lesion. Functional gene modules were then validated in our previously published bulk tissue transcriptome data obtained from 73 WM lesions of patients with progressive MS and 25 WM of non-neurologic disease controls.

RESULTS: Our analysis uncovered an MS-specific oligodendrocyte genetic signature influenced by the KLF/SP gene family. This modulation has potential associations with the autocrine iron uptake signaling observed in transcripts of transferrin and its receptor LRP2. In addition, an inflammatory profile emerged within these oligodendrocytes. We observed unique cellular endophenotypes both at the periphery and within the chronic active lesion. These include a distinct metabolic astrocyte phenotype, the importance of FGF signaling among astrocytes and neurons, and a notable enrichment of mitochondrial genes at the lesion edge populated predominantly by astrocytes. Our study also identified B-cell coexpression networks indicating different functional B-cell subsets with differential location and specific tendencies toward certain lesion types.

DISCUSSION: The use of single-cell multi-omics has offered a detailed perspective into the cellular dynamics and interactions in MS. These nuanced findings might pave the way for deeper insights into lesion pathogenesis in progressive MS.

PMID:38564686 | DOI:10.1212/NXI.0000000000200213

Categories: Literature Watch

CoMentG: comprehensive retrieval of generic relationships between biomedical concepts from the scientific literature

Tue, 2024-04-02 06:00

Database (Oxford). 2024 Apr 2;2024:baae025. doi: 10.1093/database/baae025.

ABSTRACT

The CoMentG resource contains millions of relationships between terms of biomedical interest obtained from the scientific literature. At the core of the system is a methodology for detecting significant co-mentions of concepts in the entire PubMed corpus. That method was applied to nine sets of terms covering the most important classes of biomedical concepts: diseases, symptoms/clinical signs, molecular functions, biological processes, cellular compartments, anatomic parts, cell types, bacteria and chemical compounds. We obtained more than 7 million relationships between more than 74 000 terms, and many types of relationships were not available in any other resource. As the terms were obtained from widely used resources and ontologies, the relationships are given using the standard identifiers provided by them and hence can be linked to other data. A web interface allows users to browse these associations, searching for relationships for a set of terms of interests provided as input, such as between a disease and their associated symptoms, underlying molecular processes or affected tissues. The results are presented in an interactive interface where the user can explore the reported relationships in different ways and follow links to other resources. Database URL: https://csbg.cnb.csic.es/CoMentG/.

PMID:38564426 | DOI:10.1093/database/baae025

Categories: Literature Watch

Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction

Tue, 2024-04-02 06:00

Elife. 2024 Apr 2;12:RP90532. doi: 10.7554/eLife.90532.

ABSTRACT

Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.

PMID:38564252 | DOI:10.7554/eLife.90532

Categories: Literature Watch

Protein language model-embedded geometric graphs power inter-protein contact prediction

Tue, 2024-04-02 06:00

Elife. 2024 Apr 2;12:RP92184. doi: 10.7554/eLife.92184.

ABSTRACT

Accurate prediction of contacting residue pairs between interacting proteins is very useful for structural characterization of protein-protein interactions. Although significant improvement has been made in inter-protein contact prediction recently, there is still a large room for improving the prediction accuracy. Here we present a new deep learning method referred to as PLMGraph-Inter for inter-protein contact prediction. Specifically, we employ rotationally and translationally invariant geometric graphs obtained from structures of interacting proteins to integrate multiple protein language models, which are successively transformed by graph encoders formed by geometric vector perceptrons and residual networks formed by dimensional hybrid residual blocks to predict inter-protein contacts. Extensive evaluation on multiple test sets illustrates that PLMGraph-Inter outperforms five top inter-protein contact prediction methods, including DeepHomo, GLINTER, CDPred, DeepHomo2, and DRN-1D2D_Inter, by large margins. In addition, we also show that the prediction of PLMGraph-Inter can complement the result of AlphaFold-Multimer. Finally, we show leveraging the contacts predicted by PLMGraph-Inter as constraints for protein-protein docking can dramatically improve its performance for protein complex structure prediction.

PMID:38564241 | DOI:10.7554/eLife.92184

Categories: Literature Watch

Universal Transitions between Growth and Dormancy via Intermediate Complex Formation

Tue, 2024-04-02 06:00

Phys Rev Lett. 2024 Mar 15;132(11):118401. doi: 10.1103/PhysRevLett.132.118401.

ABSTRACT

A simple cell model consisting of a catalytic reaction network with intermediate complex formation is numerically studied. As nutrients are depleted, the transition from the exponential growth phase to the growth-arrested dormant phase occurs along with hysteresis and a lag time for growth recovery. This transition is caused by the accumulation of intermediate complexes, leading to the jamming of reactions and the diversification of components. These properties are generic in random reaction networks, as supported by dynamical systems analyses of corresponding mean-field models.

PMID:38563921 | DOI:10.1103/PhysRevLett.132.118401

Categories: Literature Watch

Glycolytic activity and in vitro effect of the pyruvate kinase activator AG-946 in red blood cells from low-risk myelodysplastic syndromes patients: A proof-of-concept study

Tue, 2024-04-02 06:00

Am J Hematol. 2024 Apr 2. doi: 10.1002/ajh.27300. Online ahead of print.

ABSTRACT

Glycolytic activity and in vitro effect of the pyruvate kinase activator AG-946 in red blood cells from low-risk myelodysplastic syndromes patients. Data showed decreased glycolytic activity in red blood cells of 2/3 of patients with lower-risk MDS. These results highlight a potential effect of the PK activator in this setting.

PMID:38563490 | DOI:10.1002/ajh.27300

Categories: Literature Watch

Predictability of cortico-cortical connections in the mammalian brain

Tue, 2024-04-02 06:00

Netw Neurosci. 2024 Apr 1;8(1):138-157. doi: 10.1162/netn_a_00345. eCollection 2024.

ABSTRACT

Despite a five order of magnitude range in size, the brains of mammals share many anatomical and functional characteristics that translate into cortical network commonalities. Here we develop a machine learning framework to quantify the degree of predictability of the weighted interareal cortical matrix. Partial network connectivity data were obtained with retrograde tract-tracing experiments generated with a consistent methodology, supplemented by projection length measurements in a nonhuman primate (macaque) and a rodent (mouse). We show that there is a significant level of predictability embedded in the interareal cortical networks of both species. At the binary level, links are predictable with an area under the ROC curve of at least 0.8 for the macaque. Weighted medium and strong links are predictable with an 85%-90% accuracy (mouse) and 70%-80% (macaque), whereas weak links are not predictable in either species. These observations reinforce earlier observations that the formation and evolution of the cortical network at the mesoscale is, to a large extent, rule based. Using the methodology presented here, we performed imputations on all area pairs, generating samples for the complete interareal network in both species. These are necessary for comparative studies of the connectome with minimal bias, both within and across species.

PMID:38562298 | PMC:PMC10861169 | DOI:10.1162/netn_a_00345

Categories: Literature Watch

Functional associations of evolutionarily recent human genes exhibit sensitivity to the 3D genome landscape and disease

Mon, 2024-04-01 06:00

bioRxiv [Preprint]. 2024 Mar 17:2024.03.17.585403. doi: 10.1101/2024.03.17.585403.

ABSTRACT

Genome organization is intricately tied to regulating genes and associated cell fate decisions. In this study, we examine the positioning and functional significance of human genes, grouped by their evolutionary age, within the 3D organization of the genome. We reveal that genes of different evolutionary origin have distinct positioning relationships with both domains and loop anchors, and remarkably consistent relationships with boundaries across cell types. While the functional associations of each group of genes are primarily cell type-specific, such associations of conserved genes maintain greater stability across 3D genomic features and disease than recently evolved genes. Furthermore, the expression of these genes across various tissues follows an evolutionary progression, such that RNA levels increase from young genes to ancient genes. Thus, the distinct relationships of gene evolutionary age, function, and positioning within 3D genomic features contribute to tissue-specific gene regulation in development and disease.

PMID:38559085 | PMC:PMC10980080 | DOI:10.1101/2024.03.17.585403

Categories: Literature Watch

Escape from X inactivation is directly modulated by levels of Xist non-coding RNA

Mon, 2024-04-01 06:00

bioRxiv [Preprint]. 2024 Mar 12:2024.02.22.581559. doi: 10.1101/2024.02.22.581559.

ABSTRACT

In placental females, one copy of the two X chromosomes is largely silenced during a narrow developmental time window, in a process mediated by the non-coding RNA Xist1. Here, we demonstrate that Xist can initiate X-chromosome inactivation (XCI) well beyond early embryogenesis. By modifying its endogenous level, we show that Xist has the capacity to actively silence genes that escape XCI both in neuronal progenitor cells (NPCs) and in vivo, in mouse embryos. We also show that Xist plays a direct role in eliminating TAD-like structures associated with clusters of escapee genes on the inactive X chromosome, and that this is dependent on Xist's XCI initiation partner, SPEN2. We further demonstrate that Xist's function in suppressing gene expression of escapees and topological domain formation is reversible for up to seven days post-induction, but that sustained Xist up-regulation leads to progressively irreversible silencing and CpG island DNA methylation of facultative escapees. Thus, the distinctive transcriptional and regulatory topologies of the silenced X chromosome is actively, directly - and reversibly - controlled by Xist RNA throughout life.

PMID:38559194 | PMC:PMC10979913 | DOI:10.1101/2024.02.22.581559

Categories: Literature Watch

Multiscale computational model predicts how environmental changes and drug treatments affect microvascular remodeling in fibrotic disease

Mon, 2024-04-01 06:00

bioRxiv [Preprint]. 2024 Mar 22:2024.03.15.585249. doi: 10.1101/2024.03.15.585249.

ABSTRACT

Investigating the molecular, cellular, and tissue-level changes caused by disease, and the effects of pharmacological treatments across these biological scales, necessitates the use of multiscale computational modeling in combination with experimentation. Many diseases dynamically alter the tissue microenvironment in ways that trigger microvascular network remodeling, which leads to the expansion or regression of microvessel networks. When microvessels undergo remodeling in idiopathic pulmonary fibrosis (IPF), functional gas exchange is impaired due to loss of alveolar structures and lung function declines. Here, we integrated a multiscale computational model with independent experiments to investigate how combinations of biomechanical and biochemical cues in IPF alter cell fate decisions leading to microvascular remodeling. Our computational model predicted that extracellular matrix (ECM) stiffening reduced microvessel area, which was accompanied by physical uncoupling of endothelial cell (ECs) and pericytes, the cells that comprise microvessels. Nintedanib, an FDA-approved drug for treating IPF, was predicted to further potentiate microvessel regression by decreasing the percentage of quiescent pericytes while increasing the percentage of pericytes undergoing pericyte-myofibroblast transition (PMT) in high ECM stiffnesses. Importantly, the model suggested that YAP/TAZ inhibition may overcome the deleterious effects of nintedanib by promoting EC-pericyte coupling and maintaining microvessel homeostasis. Overall, our combination of computational and experimental modeling can explain how cell decisions affect tissue changes during disease and in response to treatments.

PMID:38559112 | PMC:PMC10979947 | DOI:10.1101/2024.03.15.585249

Categories: Literature Watch

Strain engineering of Bacillus coagulans with high osmotic pressure tolerance for effective L-lactic acid production from sweet sorghum juice under unsterile conditions

Mon, 2024-04-01 06:00

Bioresour Technol. 2024 Mar 30:130648. doi: 10.1016/j.biortech.2024.130648. Online ahead of print.

ABSTRACT

Open unsterile fermentation of the low-cost non-food crop, sweet sorghum, is an economically feasible lactic acid biosynthesis process. However, hyperosmotic stress inhibits microbial metabolism and lactic acid biosynthesis, and engineering strains with high osmotic tolerance is challenging. Herein, heavy ion mutagenesis combined with osmotic pressure enrichment was used to engineer a hyperosmotic-tolerant Bacillus coagulans for L-lactic acid production. The engineered strain had higher osmotic pressure tolerance, when compared with the parental strain, primarily owing to its improved properties such as cell viability, cellular antioxidant capacity, and NADH supply. In a pilot-scale open unsterile fermentation using sweet sorghum juice as a feedstock, the engineered strain produced 94 g/L L-lactic acid with a yield of 91 % and productivity of 6.7 g/L/h, and optical purity of L-lactic acid at the end of fermentation was 99.8 %. In short, this study provided effective and low-cost approach to produce polymer-grade L-lactic acid.

PMID:38561153 | DOI:10.1016/j.biortech.2024.130648

Categories: Literature Watch

Resource allocation modeling for autonomous prediction of plant cell phenotypes

Mon, 2024-04-01 06:00

Metab Eng. 2024 Mar 30:S1096-7176(24)00054-5. doi: 10.1016/j.ymben.2024.03.009. Online ahead of print.

ABSTRACT

Predicting the plant cell response in complex environmental conditions is a challenge in plant biology. Here we developed a resource allocation model of cellular and molecular scale for the leaf photosynthetic cell of Arabidopsis thaliana, based on the Resource Balance Analysis (RBA) constraint-based modeling framework. The RBA model contains the metabolic network and the major macromolecular processes involved in the plant cell growth and survival and localized in cellular compartments. We simulated the model for varying environmental conditions of temperature, irradiance, partial pressure of CO2 and O2, and compared RBA predictions to known resource distributions and quantitative phenotypic traits such as the relative growth rate, the C:N ratio, and finally to the empirical characteristics of CO2 fixation given by the well-established Farquhar model. In comparison to other standard constraint-based modeling methods like Flux Balance Analysis, the RBA model makes accurate quantitative predictions without the need for empirical constraints. Altogether, we show that RBA significantly improves the autonomous prediction of plant cell phenotypes in complex environmental conditions, and provides mechanistic links between the genotype and the phenotype of the plant cell.

PMID:38561149 | DOI:10.1016/j.ymben.2024.03.009

Categories: Literature Watch

Interactive effects between water temperature, microparticle compositions, and fiber types on the marine keystone species Americamysis bahia

Mon, 2024-04-01 06:00

Environ Pollut. 2024 Mar 30:123906. doi: 10.1016/j.envpol.2024.123906. Online ahead of print.

ABSTRACT

Recently, there has been an increasing emphasis on examining the ecotoxicological effects of anthropogenic microparticles (MPs), especially microplastic particles, and related issues. Nevertheless, a notable deficiency exists in our understanding of the consequences on marine organisms, specifically in relation to microfibers and the combined influence of MPs and temperature. In this investigation, mysid shrimp (Americamysis bahia), an important species and prey item in estuarine and marine food webs, were subjected to four separate experimental trials involving fibers (cotton, nylon, polyester, hemp; 3 particles/ml; approximately 200 μm in length) or fragments (low-density Polyethylene: LDPE, polylactic acid: PLA, and their leachates; 5, 50, 200, 500 particles/ml; 1-20 μm). To consider the effects in the context of climate change, three different temperatures (22, 25, and 28 °C) were examined. Organismal growth and swimming behavior were measured following exposure to fragments and microfibers, and reactive oxygen species and particle uptake were investigated after microfiber exposure. To simulate the physical characteristics of MP exposure, such as microfibers obstructing the gills, we also assessed the post-fiber-exposure swimming behavior in an oxygen-depleted environment. Data revealed negligible fragment, but fiber exposure effects on growth. PLA leachate triggered higher activity at 25 °C and 28 °C; LDPE exposures led to decreased activity at 28 °C. Cotton exposures led to fewer behavioral differences compared to controls than other fiber types. The exposure to hemp fibers resulted in significant ROS increases at 28 °C. Microfibers were predominantly located within the gastric and upper gastrointestinal tract, suggesting extended periods of residence and the potential for obstructive phenomena over the longer term. The combination of increasing water temperatures, microplastic influx, and oxidative stress has the potential to pose risks to all components of marine and aquatic food webs.

PMID:38561036 | DOI:10.1016/j.envpol.2024.123906

Categories: Literature Watch

Complexity of avian evolution revealed by family-level genomes

Mon, 2024-04-01 06:00

Nature. 2024 Apr 1. doi: 10.1038/s41586-024-07323-1. Online ahead of print.

ABSTRACT

Despite tremendous efforts in the past decades, relationships among main avian lineages remain heavily debated without a clear resolution. Discrepancies have been attributed to diversity of species sampled, phylogenetic method, and the choice of genomic regions 1-3. Here, we address these issues by analyzing genomes of 363 bird species 4 (218 taxonomic families, 92% of total). Using intergenic regions and coalescent methods, we present a well-supported tree but also a remarkable degree of discordance. The tree confirms that Neoaves experienced rapid radiation at or near the Cretaceous-Paleogene (K-Pg) boundary. Sufficient loci rather than extensive taxon sampling were more effective in resolving difficult nodes. Remaining recalcitrant nodes involve species that challenge modeling due to extreme GC content, variable substitution rates, incomplete lineage sorting, or complex evolutionary events such as ancient hybridization. Assessment of the impacts of different genomic partitions showed high heterogeneity across the genome. We discovered sharp increases in effective population size, substitution rates, and relative brain size following the K-Pg extinction event, supporting the hypothesis that emerging ecological opportunities catalyzed the diversification of modern birds. The resulting phylogenetic estimate offers novel insights into the rapid radiation of modern birds and provides a taxon-rich backbone tree for future comparative studies.

PMID:38560995 | DOI:10.1038/s41586-024-07323-1

Categories: Literature Watch

DNA Methylation in the Adaptive Response to Exercise

Mon, 2024-04-01 06:00

Sports Med. 2024 Apr 2. doi: 10.1007/s40279-024-02011-6. Online ahead of print.

ABSTRACT

Emerging evidence published over the past decade has highlighted the role of DNA methylation in skeletal muscle function and health, including as an epigenetic transducer of the adaptive response to exercise. In this review, we aim to synthesize the latest findings in this field to highlight: (1) the shifting understanding of the genomic localization of altered DNA methylation in response to acute and chronic aerobic and resistance exercise in skeletal muscle (e.g., promoter, gene bodies, enhancers, intergenic regions, un-annotated regions, and genome-wide methylation); (2) how these global/regional methylation changes relate to transcriptional activity following exercise; and (3) the factors (e.g., individual demographic or genetic features, dietary, training history, exercise parameters, local epigenetic characteristics, circulating hormones) demonstrated to alter both the pattern of DNA methylation after exercise, and the relationship between DNA methylation and gene expression. Finally, we discuss the changes in non-CpG methylation and 5-hydroxymethylation after exercise, as well as the importance of emerging single-cell analyses to future studies-areas of increasing focus in the field of epigenetics. We anticipate that this review will help generate a framework for clinicians and researchers to begin developing and testing exercise interventions designed to generate targeted changes in DNA methylation as part of a personalized exercise regimen.

PMID:38561436 | DOI:10.1007/s40279-024-02011-6

Categories: Literature Watch

Prestalk-like positioning of de-differentiated cells in the social amoeba Dictyostelium discoideum

Mon, 2024-04-01 06:00

Sci Rep. 2024 Apr 1;14(1):7677. doi: 10.1038/s41598-024-58277-3.

ABSTRACT

The social amoeba Dictyostelium discoideum switches between solitary growth and social fruitification depending on nutrient availability. Under starvation, cells aggregate and form fruiting bodies consisting of spores and altruistic stalk cells. Once cells socially committed, they complete fruitification, even if a new source of nutrients becomes available. This social commitment is puzzling because it hinders individual cells from resuming solitary growth quickly. One idea posits that traits that facilitate premature de-commitment are hindered from being selected. We studied outcomes of the premature de-commitment through forced refeeding. Our results show that when refed cells interacted with non-refed cells, some of them became solitary, whereas a fraction was redirected to the altruistic stalk, regardless of their original fate. The refed cells exhibited reduced cohesiveness and were sorted out during morphogenesis. Our findings provide an insight into a division of labor of the social amoeba, in which less cohesive individuals become altruists.

PMID:38561423 | DOI:10.1038/s41598-024-58277-3

Categories: Literature Watch

A guide to selecting high-performing antibodies for Rab1A and Rab1B for use in Western Blot, immunoprecipitation and immunofluorescence

Mon, 2024-04-01 06:00

F1000Res. 2023 Dec 28;12:1578. doi: 10.12688/f1000research.143928.2. eCollection 2023.

ABSTRACT

Rab1 is a highly conserved small GTPase that exists in humans as two isoforms: Rab1A and Rab1B, sharing 92% sequence identity. These proteins regulate vesicle trafficking between the endoplasmic reticulum (ER) and Golgi and within the Golgi stacks. Rab1A and Rab1B may be oncogenes, as they are frequently dysregulated in various human cancers. Moreover, they contribute to the progression of Parkinson's disease. The availability of high-quality antibodies specific for Rab1A or Rab1B is essential to understand the distinct functions of these Rab1 proteins in both health and diseaseand to enhance the reproducibility of research involving these proteins. In this study, we characterized seven antibodies targeting Rab1A and five antibodies targeting Rab1B for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a much larger, collaborative initiative seeking to address the antibody reproducibility issue by characterizing commercially available antibodies for human proteins and publishing the results openly as a valuable resource for the scientific community. While uses of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

PMID:38559361 | PMC:PMC10979127 | DOI:10.12688/f1000research.143928.2

Categories: Literature Watch

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