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

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

bioRxiv [Preprint]. 2024 Mar 17:2024.03.17.585262. doi: 10.1101/2024.03.17.585262.

ABSTRACT

Age is the strongest risk factor for developing Alzheimer's disease, the most common neurodegenerative disorder. However, the mechanisms connecting advancing age to neurodegeneration in Alzheimer's disease are incompletely understood. We conducted an unbiased, genome-scale, forward genetic screen for age-associated neurodegeneration in Drosophila to identify the underlying biological processes required for maintenance of aging neurons. To connect genetic screen hits to Alzheimer's disease pathways, we measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease. We further identified Alzheimer's disease human genetic variants that modify expression in disease-vulnerable neurons. Through multi-omic, multi-species network integration of these data, we identified relationships between screen hits and tau-mediated neurotoxicity. Furthermore, we computationally and experimentally identified relationships between screen hits and DNA damage in Drosophila and human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to attenuate the effects of age on neurodegeneration and Alzheimer's disease.

PMID:38559190 | PMC:PMC10980014 | DOI:10.1101/2024.03.17.585262

bioRxiv [Preprint]. 2024 Mar 17:2024.03.15.585236. doi: 10.1101/2024.03.15.585236.

ABSTRACT

The reproducibility of computational biology models can be greatly facilitated by widely adopted standards and public repositories. We examined 50 models from the BioModels Database and attempted to validate the original curation and correct some of them if necessary. For each model, we reproduced these published results using Tellurium. Once reproduced we manually created a new set of files, with the model information stored by the Systems Biology Markup Language (SBML), and simulation instructions stored by the Simulation Experiment Description Markup Language (SED-ML), and everything included in an Open Modeling EXchange (OMEX) file, which could be used with a variety of simulators to reproduce the same results. On the one hand, the validation procedure of 50 models developed a manual workflow that we would use to build an automatic platform to help users more easily curate and verify models in the future. On the other hand, these exercises allowed us to find the limitations and possible enhancement of the current curation and tooling to verify and curate models.

AUTHOR SUMMARY: Public repositories with models deposited using standard formats are an important activity in computational systems biology, which allows scientists to easily find, access, and reuse them to rerun simulations or derive new ones using compatible software or tools. Common standards and public repositories can facilitate the reuse and regeneration of computational biology models beyond the software originally used to perform the simulations. As an exercise to validate and correct the current curation, we examined a selection of models in the BioModels Database. For each model, we reproduced some published results in the corresponding papers by a certain software. Once reproduced we manually created a standard file package using the model and its simulation information stored in the standard formats. These exercises not only allowed us to develop a workflow that we would use to develop an automatic online platform to help users more easily curate models for existing or future databases and repositories but also allowed us to find the limitations and possible enhancement of the current curation and tooling to verify and curate models.

PMID:38559029 | PMC:PMC10979985 | DOI:10.1101/2024.03.15.585236

PLoS Comput Biol. 2024 Apr 1;20(4):e1011993. doi: 10.1371/journal.pcbi.1011993. Online ahead of print.

ABSTRACT

The intensification of intervention activities against the fatal vector-borne disease gambiense human African trypanosomiasis (gHAT, sleeping sickness) in the last two decades has led to a large decline in the number of annually reported cases. However, while we move closer to achieving the ambitious target of elimination of transmission (EoT) to humans, pockets of infection remain, and it becomes increasingly important to quantitatively assess if different regions are on track for elimination, and where intervention efforts should be focused. We present a previously developed stochastic mathematical model for gHAT in the Democratic Republic of Congo (DRC) and show that this same formulation is able to capture the dynamics of gHAT observed at the health area level (approximately 10,000 people). This analysis was the first time any stochastic gHAT model has been fitted directly to case data and allows us to better quantify the uncertainty in our results. The analysis focuses on utilising a particle filter Markov chain Monte Carlo (MCMC) methodology to fit the model to the data from 16 health areas of Mosango health zone in Kwilu province as a case study. The spatial heterogeneity in cases is reflected in modelling results, where we predict that under the current intervention strategies, the health area of Kinzamba II, which has approximately one third of the health zone's cases, will have the latest expected year for EoT. We find that fitting the analogous deterministic version of the gHAT model using MCMC has substantially faster computation times than fitting the stochastic model using pMCMC, but produces virtually indistinguishable posterior parameterisation. This suggests that expanding health area fitting, to cover more of the DRC, should be done with deterministic fits for efficiency, but with stochastic projections used to capture both the parameter and stochastic variation in case reporting and elimination year estimations.

PMID:38557869 | DOI:10.1371/journal.pcbi.1011993

Brief Bioinform. 2024 Mar 27;25(3):bbae136. doi: 10.1093/bib/bbae136.

ABSTRACT

Disease ontologies facilitate the semantic organization and representation of domain-specific knowledge. In the case of prostate cancer (PCa), large volumes of research results and clinical data have been accumulated and needed to be standardized for sharing and translational researches. A formal representation of PCa-associated knowledge will be essential to the diverse data standardization, data sharing and the future knowledge graph extraction, deep phenotyping and explainable artificial intelligence developing. In this study, we constructed an updated PCa ontology (PCAO2) based on the ontology development life cycle. An online information retrieval system was designed to ensure the usability of the ontology. The PCAO2 with a subclass-based taxonomic hierarchy covers the major biomedical concepts for PCa-associated genotypic, phenotypic and lifestyle data. The current version of the PCAO2 contains 633 concepts organized under three biomedical viewpoints, namely, epidemiology, diagnosis and treatment. These concepts are enriched by the addition of definition, synonym, relationship and reference. For the precision diagnosis and treatment, the PCa-associated genes and lifestyles are integrated in the viewpoint of epidemiological aspects of PCa. PCAO2 provides a standardized and systematized semantic framework for studying large amounts of heterogeneous PCa data and knowledge, which can be further, edited and enriched by the scientific community. The PCAO2 is freely available at https://bioportal.bioontology.org/ontologies/PCAO, http://pcaontology.net/ and http://pcaontology.net/mobile/.

PMID:38557678 | DOI:10.1093/bib/bbae136

J Water Health. 2024 Mar;22(3):536-549. doi: 10.2166/wh.2024.290. Epub 2024 Feb 8.

ABSTRACT

Bacterial communities in drinking water provide a gauge to measure quality and confer insights into public health. In contrast to urban systems, water treatment in rural areas is not adequately monitored and could become a health risk. We performed 16S rRNA amplicon sequencing to analyze the microbiome present in the water treatment plants at two rural communities, one city, and the downstream water for human consumption in schools and reservoirs in the Andean highlands of Ecuador. We tested the effect of water treatment on the diversity and composition of bacterial communities. A set of physicochemical variables in the sampled water was evaluated and correlated with the structure of the observed bacterial communities. Predominant bacteria in the analyzed communities belonged to Proteobacteria and Actinobacteria. The Sphingobium genus, a chlorine resistance group, was particularly abundant. Of health concern in drinking water reservoirs were Fusobacteriaceae, Lachnospiraceae, and Ruminococcaceae; these families are associated with human and poultry fecal contamination. We propose the latter families as relevant biomarkers for establishing local standards for the monitoring of potable water systems in highlands of Ecuador. Our assessment of bacterial community composition in water systems in the Ecuadorian highlands provides a technical background to inform management decisions.

PMID:38557569 | DOI:10.2166/wh.2024.290

Circ Res. 2024 Apr 1. doi: 10.1161/CIRCRESAHA.123.323190. Online ahead of print.

ABSTRACT

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown.

METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events.

RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3, which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase.

CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

PMID:38557119 | DOI:10.1161/CIRCRESAHA.123.323190

Gene. 2024 Mar 29:148420. doi: 10.1016/j.gene.2024.148420. Online ahead of print.

ABSTRACT

Sleep disorders have emerged as a widespread public health concern, primarily due to their association with an increased risk of developing cardiovascular diseases. Our previous research indicated a potential direct impact of insufficient sleep duration on cardiac remodeling in children and adolescents. Nevertheless, the underlying mechanisms behind the link between sleep fragmentation (SF) and cardiac abnormalities remain unclear. In this study, we aimed to investigate the effects of SF interventions at various life stages on cardiac structure and function, as well as to identify genes associated with SF-induced cardiac dysfunction. To achieve this, we established mouse models of chronic SF and two-week sleep recovery (SR).Our results revealed that chronic SF significantly compromised left ventricular contractile function across different life stages, leading to alterations in cardiac structure and ventricular remodeling, particularly during early life stages. Moreover, microarray analysis of mouse heart tissue identified two significant modules and nine hub genes (Ddx60, Irf9, Oasl2, Rnf213, Cmpk2, Stat2, Parp14, Gbp3, and Herc6) through protein-protein interaction analysis. Notably, the interactome predominantly involved innate immune responses. Importantly, all hub genes lost significance following SR. The second module primarily consisted of circadian clock genes, and real-time PCR validation demonstrated significant upregulation of Arntl, Dbp, and Cry1 after SF, while subsequent SR restored normal Arntl expression. Furthermore, the expression levels of four hub genes (Ddx60, Irf9, Oasl2, and Cmpk2) and three circadian clock genes (Arntl, Dbp, and Cry1) exhibited correlations with structural and functional echocardiographic parameters.Overall, our findings suggest that SF impairs left ventricular contractile function and ventricular remodeling during early life stages, and this may be mediated by modulation of the innate immune response and circadian rhythm. Importantly, our findings suggest that a short period of SR can alleviate the detrimental effects of SF on the cardiac immune response, while the influence of SF on circadian rhythm appears to be more persistent. These findings underscore the importance of adequate sleep duration for maintaining cardiac health, particularly during early life stages.

PMID:38556117 | DOI:10.1016/j.gene.2024.148420

Cardiovasc Toxicol. 2024 Mar 31. doi: 10.1007/s12012-024-09850-9. Online ahead of print.

ABSTRACT

Cigarette smoking is positively and robustly associated with cardiovascular disease (CVD), including hypertension, atherosclerosis, cardiac arrhythmias, stroke, thromboembolism, myocardial infarctions, and heart failure. However, after more than a decade of ENDS presence in the U.S. marketplace, uncertainty persists regarding the long-term health consequences of ENDS use for CVD. New approach methods (NAMs) in the field of toxicology are being developed to enhance rapid prediction of human health hazards. Recent technical advances can now consider impact of biological factors such as sex and race/ethnicity, permitting application of NAMs findings to health equity and environmental justice issues. This has been the case for hazard assessments of drugs and environmental chemicals in areas such as cardiovascular, respiratory, and developmental toxicity. Despite these advances, a shortage of widely accepted methodologies to predict the impact of ENDS use on human health slows the application of regulatory oversight and the protection of public health. Minimizing the time between the emergence of risk (e.g., ENDS use) and the administration of well-founded regulatory policy requires thoughtful consideration of the currently available sources of data, their applicability to the prediction of health outcomes, and whether these available data streams are enough to support an actionable decision. This challenge forms the basis of this white paper on how best to reveal potential toxicities of ENDS use in the human cardiovascular system-a primary target of conventional tobacco smoking. We identify current approaches used to evaluate the impacts of tobacco on cardiovascular health, in particular emerging techniques that replace, reduce, and refine slower and more costly animal models with NAMs platforms that can be applied to tobacco regulatory science. The limitations of these emerging platforms are addressed, and systems biology approaches to close the knowledge gap between traditional models and NAMs are proposed. It is hoped that these suggestions and their adoption within the greater scientific community will result in fresh data streams that will support and enhance the scientific evaluation and subsequent decision-making of tobacco regulatory agencies worldwide.

PMID:38555547 | DOI:10.1007/s12012-024-09850-9

J Nat Prod. 2024 Mar 31. doi: 10.1021/acs.jnatprod.4c00082. Online ahead of print.

ABSTRACT

Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two threo-derivatives, and two Z-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13R,14S,15R)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV-vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced E/Z double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC50 values in biological assays addressing the inhibition of cellular inflammatory responses.

PMID:38555526 | DOI:10.1021/acs.jnatprod.4c00082

Biophys J. 2024 Mar 29:S0006-3495(24)00242-X. doi: 10.1016/j.bpj.2024.03.040. Online ahead of print.

ABSTRACT

Due to the high concentration of proteins, nucleic acids and other macromolecules, the bacterial cytoplasm is typically described as a crowded environment. However, the extent to which each of these macromolecules individually affects the mobility of macromolecular complexes, and how this depends on growth conditions, is presently unclear. In this study, we sought to quantify the crowding experienced by an exogenous 40 nm fluorescent particle in the cytoplasm of E. coli under different growth conditions. By performing single particle tracking measurements in cells selectively depleted of DNA and/or mRNA, we determined the contribution to crowding of mRNA, DNA and remaining cellular components, i.e., mostly proteins and ribosomes. To estimate this contribution to crowding, we quantified the difference of the particle's diffusion coefficient in conditions with and without those macromolecules. We found that the contributions of the three classes of components were of comparable magnitude, being largest in the case of proteins and ribosomes. We further found that the contributions of mRNA and DNA to crowding were significantly larger than expected based on their volumetric fractions alone. Finally, we found that the crowding contributions change only slightly with the growth conditions. These results reveal how various cellular components partake in crowding of the cytoplasm and the consequences this has for the mobility of large macromolecular complexes.

PMID:38555507 | DOI:10.1016/j.bpj.2024.03.040

Magn Reson Imaging Clin N Am. 2024 May;32(2):375-384. doi: 10.1016/j.mric.2024.01.003. Epub 2024 Feb 6.

ABSTRACT

Neuroinflammation is a key immune response observed in many neurologic diseases. Although an appropriate immune response can be beneficial, aberrant activation of this response recruits excessive proinflammatory cells to cause damage. Because the central nervous system is separated from the periphery by the blood-brain barrier (BBB) that creates an immune-privileged site, it has its own unique immune cells and immune response. Moreover, neuroinflammation can compromise the BBB causing an influx of peripheral immune cells and factors. Recent advances have brought a deeper understanding of neuroinflammation that can be leveraged to develop more potent therapies and improve patient selection.

PMID:38555147 | DOI:10.1016/j.mric.2024.01.003

Peptides. 2024 Mar 28:171200. doi: 10.1016/j.peptides.2024.171200. Online ahead of print.

ABSTRACT

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptide hormones produced by enteroendocrine cells in the small intestine. Despite being produced in the gut, the leveraging of their role in potentiating glucose-stimulated insulin secretion, also known as the incretin effect, has distracted from discernment of direct intestinal signalling circuits. Both preclinical and clinical evidence have highlighted a role for the incretins in inflammation. In this review, we highlight the discoveries of GLP-1 receptor (GLP-1R)+ natural (TCRαβ and TCRγδ) and induced (TCRαβ+CD4+ cells and TCRαβ+CD8αβ+) intraepithelial lymphocytes. Both endogenous signalling and pharmacological activation of GLP-1R impact local and systemic inflammation, the gut microbiota, whole-body metabolism, as well as the control of GLP-1 bioavailability. While GIPR signalling has been documented to impact hematopoiesis, the impact of these bone marrow-derived cells in gut immunology is not well understood. We uncover gaps in the literature of the evaluation of the impact of sex in these GLP-1R and GIP receptor (GIPR) signalling circuits and provide speculations of the maintenance roles these hormones play within the gut in the fasting-refeeding cycles. GLP-1R agonists and GLP-1R/GIPR agonists are widely used as treatments for diabetes and weight loss, respectively; however, their impact on gut homeostasis has not been fully explored. Advancing our understanding of the roles of GLP-1R and GIPR signalling within the gut at homeostasis as well as metabolic and inflammatory diseases may provide targets to improve disease management.

PMID:38555054 | DOI:10.1016/j.peptides.2024.171200

J Hosp Infect. 2024 Mar 28:S0195-6701(24)00103-8. doi: 10.1016/j.jhin.2024.03.009. Online ahead of print.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa (PA) is a common cause of healthcare-associated infections (PA-HAI) in the intensive care unit (ICU). We aimed to describe the epidemiology of PA-HAI in ICUs in Ontario, Canada, and determine whether we could identify episodes of sink-to-patient PA transmission.

METHODS: This was a prospective cohort study of patients in six ICUs from 2018-2019, with retrieval of PA clinical isolates, and PA-screening of antimicrobial resistant organism surveillance rectal swabs, and of sink drain, air, and faucet samples. All PA isolates underwent whole genome sequencing. PA-HAI was defined using US National Healthcare Safety Network criteria. ICU-acquired PA was defined as PA isolated from specimens obtained >48 hours after ICU admission in those with prior negative rectal swabs. Sink-to-patient PA transmission was defined as ICU-acquired PA with close genomic relationship to isolate(s) previously recovered from sinks in a room/bedspace occupied 3-14 days prior to the relevant patient isolate.

RESULTS: Over ten months, 72 PA-HAI occurred among 60/4263 admissions. The rate of PA-HAI was 2.40 per 1000 patient-ICU days; higher in patients who were PA-colonized on admission. PA-HAI was associated with longer stay (median 26 vs 3 days uninfected, p<0.001) and contributed to death in 22/60 cases (36.7%). Fifty-eight admissions with ICU-acquired PA were identified, contributing 35/72 (48.6%) PA-HAI. Four patients with five PA-HAI (6.9%) had closely related isolates previously recovered from their room/bedspace sinks.

CONCLUSIONS: Nearly half of PA causing HAI appeared to be acquired in ICUs, and 7% of PA-HAI were associated with sink-to-patient transmission. Sinks may be an underrecognized reservoir for HAIs.

PMID:38554807 | DOI:10.1016/j.jhin.2024.03.009

Cell Rep Med. 2024 Mar 27:101489. doi: 10.1016/j.xcrm.2024.101489. Online ahead of print.

ABSTRACT

Lung adenocarcinoma is a type of cancer that exhibits a wide range of clinical radiological manifestations, from ground-glass opacity (GGO) to pure solid nodules, which vary greatly in terms of their biological characteristics. Our current understanding of this heterogeneity is limited. To address this gap, we analyze 58 lung adenocarcinoma patients via machine learning, single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing, and we identify six lung multicellular ecotypes (LMEs) correlating with distinct radiological patterns and cancer cell states. Notably, GGO-associated neoantigens in early-stage cancers are recognized by CD8+ T cells, indicating an immune-active environment, while solid nodules feature an immune-suppressive LME with exhausted CD8+ T cells, driven by specific stromal cells such as CTHCR1+ fibroblasts. This study also highlights EGFR(L858R) neoantigens in GGO samples, suggesting potential CD8+ T cell activation. Our findings offer valuable insights into lung adenocarcinoma heterogeneity, suggesting avenues for targeted therapies in early-stage disease.

PMID:38554705 | DOI:10.1016/j.xcrm.2024.101489

Cell Rep Med. 2024 Mar 23:101484. doi: 10.1016/j.xcrm.2024.101484. Online ahead of print.

ABSTRACT

The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib achieves a remarkable clinical response in mantle cell lymphoma (MCL). Acquired drug resistance, however, is significant and affects long-term survival of MCL patients. Here, we demonstrate that DNA methyltransferase 3A (DNMT3A) is involved in ibrutinib resistance. We find that DNMT3A expression is upregulated upon ibrutinib treatment in ibrutinib-resistant MCL cells. Genetic and pharmacological analyses reveal that DNMT3A mediates ibrutinib resistance independent of its DNA-methylation function. Mechanistically, DNMT3A induces the expression of MYC target genes through interaction with the transcription factors MEF2B and MYC, thus mediating metabolic reprogramming to oxidative phosphorylation (OXPHOS). Targeting DNMT3A with low-dose decitabine inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting DNMT3A-mediated metabolic reprogramming to OXPHOS with decitabine provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory MCL.

PMID:38554704 | DOI:10.1016/j.xcrm.2024.101484

Cell Rep Methods. 2024 Mar 27:100742. doi: 10.1016/j.crmeth.2024.100742. Online ahead of print.

ABSTRACT

The pathogenesis of Alzheimer disease (AD) involves complex gene regulatory changes across different cell types. To help decipher this complexity, we introduce single-cell Bayesian biclustering (scBC), a framework for identifying cell-specific gene network biomarkers in scRNA and snRNA-seq data. Through biclustering, scBC enables the analysis of perturbations in functional gene modules at the single-cell level. Applying the scBC framework to AD snRNA-seq data reveals the perturbations within gene modules across distinct cell groups and sheds light on gene-cell correlations during AD progression. Notably, our method helps to overcome common challenges in single-cell data analysis, including batch effects and dropout events. Incorporating prior knowledge further enables the framework to yield more biologically interpretable results. Comparative analyses on simulated and real-world datasets demonstrate the precision and robustness of our approach compared to other state-of-the-art biclustering methods. scBC holds potential for unraveling the mechanisms underlying polygenic diseases characterized by intricate gene coexpression patterns.

PMID:38554701 | DOI:10.1016/j.crmeth.2024.100742

Biosens Bioelectron. 2024 Mar 28;255:116240. doi: 10.1016/j.bios.2024.116240. Online ahead of print.

ABSTRACT

Public health events caused by pathogens have imposed significant economic and societal burdens. However, conventional methods still face challenges including complex operations, the need for trained operators, and sophisticated instruments. Here, we proposed a fully integrated and automated centrifugal microfluidic chip, also termed IACMC, for point-of-care multiplexed molecular diagnostics by harnessing the advantages of active and passive valves. The IACMC incorporates multiple essential components including a pneumatic balance module for sequential release of multiple reagents, a pneumatic centrifugation-assisted module for on-demand solution release, an on-chip silicon membrane module for nucleic acid extraction, a Coriolis force-mediated fluid switching module, and an amplification module. Numerical simulation and visual validation were employed to iterate and optimize the chip's structure. Upon sample loading, the chip automatically executes the entire process of bacterial sample lysis, nucleic acid capture, elution quantification, and isothermal LAMP amplification. By optimizing crucial parameters including centrifugation speed, direction of rotation, and silicone membrane thickness, the chip achieves exceptional sensitivity (twenty-five Salmonella or forty Escherichia coli) and specificity in detecting Escherichia coli and Salmonella within 40 min. The development of IACMC will drive advancements in centrifugal microfluidics for point-of-care testing and holds potential for broader applications in precision medicine including high-throughput biochemical analysis immune diagnostics, and drug susceptibility testing.

PMID:38554576 | DOI:10.1016/j.bios.2024.116240

Nucleic Acids Res. 2024 Mar 30:gkae216. doi: 10.1093/nar/gkae216. Online ahead of print.

ABSTRACT

Large-genome bacteriophages (jumbo phages) of the proposed family Chimalliviridae assemble a nucleus-like compartment bounded by a protein shell that protects the replicating phage genome from host-encoded restriction enzymes and DNA-targeting CRISPR-Cas nucleases. While the nuclear shell provides broad protection against host nucleases, it necessitates transport of mRNA out of the nucleus-like compartment for translation by host ribosomes, and transport of specific proteins into the nucleus-like compartment to support DNA replication and mRNA transcription. Here, we identify a conserved phage nuclear shell-associated protein that we term Chimallin C (ChmC), which adopts a nucleic acid-binding fold, binds RNA with high affinity in vitro, and binds phage mRNAs in infected cells. ChmC also forms phase-separated condensates with RNA in vitro. Targeted knockdown of ChmC using mRNA-targeting dCas13d results in accumulation of phage-encoded mRNAs in the phage nucleus, reduces phage protein production, and compromises virion assembly. Taken together, our data show that the conserved ChmC protein plays crucial roles in the viral life cycle, potentially by facilitating phage mRNA translocation through the nuclear shell to promote protein production and virion development.

PMID:38554115 | DOI:10.1093/nar/gkae216