Curr Med Chem. 2024 Jun 13. doi: 10.2174/0109298673300320240604062533. Online ahead of print.

ABSTRACT

INTRODUCTION: microRNA (miRNA) levels are dysregulated in many cancers, suggesting that miRNA-based therapy may be effective. The molecular pathways of colorectal cancer (CRC) development are unknown.

METHOD: Understanding miRNAs implicated in CRC formation may reveal new diagnostic and therapeutic targets. Angiogenesis is a key mechanism in tumor growth. CRC treatment may involve inhibiting angiogenesis, but existing drugs can cause negative effects. Tranexamic acid, an FDA-approved medication, may reduce the adverse effects of angiogenesis inhibitors. This work examined miRNAs implicated in CRC angiogenesis and how miR-16 and tranexamic acid may synergistically decrease CRC cell migration and angiogenesis. We identified miRNAs targeting CRC angiogenesis genes using bioinformatic databases. Proteins were docked with tranexamic acid utilizing the PyRx software. Quantitative Real-time PCR was used to analyze the effects of overexpressed miRNA and tranexamic acid on the expression of target genes. Scratch, transwell migration, and Chicken Chorioallantoic Membrane (CAM) assays were used to evaluate the effect of selected miRNA and tranexamic acid on the invasion and angiogenesis of CRC cells. in silico studies identified hsa-miR-16-5p, -101-3p, and 34a-5p as possible CRC angiogenesis modulators.

RESULTS: The study found that miR-16 and tranexamic acid influence the expression of VEGFA, ANGPT2, MMP9, and HIF1A. miR-16 and tranexamic acid influenced CRC cell movement in scratch tests and transwell migration assays. Furthermore, the CAM assay results demonstrated that miR-16 and tranexamic acid can alter angiogenesis in CRC.

CONCLUSION: These findings highlight the potential of miR-16 and tranexamic acid as combination therapeutic agents for CRC, with the ability to simultaneously target tumorigenesis and angiogenesis.

PMID:38874036 | DOI:10.2174/0109298673300320240604062533

Autophagy. 2024 Jun 14. doi: 10.1080/15548627.2024.2366748. Online ahead of print.

ABSTRACT

Microglia are specialized macrophages responsible for the clearance of dead neurons and pathogens by phagocytosis and degradation. The degradation requires phagosome maturation and acidification provided by the vesicular- or vacuolar-type H+-translocating adenosine triphosphatase (V-ATPase), which is composed of the cytoplasmic V1 domain and the membrane-embedded Vo domain. The V-ATPase a subunit, an integral part of the Vo domain, has four isoforms in mammals. The functions of different isoforms on phagosome maturation in different cells/species remain controversial. Here we show that mutations of both the V-ATPase Atp6v0a1 and Tcirg1b/Atp6v0a3 subunits lead to the accumulation of phagosomes in zebrafish microglia. However, their mechanisms are different. The V-ATPase Atp6v0a1 subunit is mainly distributed in early and late phagosomes. Defects of this subunit lead to a defective transition from early phagosomes to late phagosomes. In contrast, The V-ATPase Tcirg1b/Atp6v0a3 subunit is primarily located on lysosomes and regulates late phagosome-lysosomal fusion. Defective Tcirg1b/Atp6v0a3, but not Atp6v0a1 subunit leads to reduced acidification and impaired macroautophagy/autophagy in microglia. We further showed that ATP6V0A1/a1 and TCIRG1/a3 subunits in mouse macrophages preferentially located in endosomes and lysosomes, respectively. Blocking these subunits disrupted early-to-late endosome transition and endosome-to-lysosome fusion, respectively. Taken together, our results highlight the essential and conserved roles played by different V-ATPase subunits in multiple steps of phagocytosis and endocytosis across various species.

PMID:38873931 | DOI:10.1080/15548627.2024.2366748

Front Immunol. 2024 May 30;15:1371118. doi: 10.3389/fimmu.2024.1371118. eCollection 2024.

ABSTRACT

BACKGROUND: The respiratory tract microbiome is essential for human health and well-being and is determined by genetic, lifestyle, and environmental factors. Patients with Common Variable Immunodeficiency (CVID) suffer from respiratory and intestinal tract infections, leading to chronic diseases and increased mortality rates. While CVID patients' gut microbiota have been analyzed, data on the respiratory microbiome ecosystem are limited.

OBJECTIVE: This study aims to analyze the bacterial composition of the oropharynx of adults with CVID and its link with clinical and immunological features and risk for respiratory acute infections.

METHODS: Oropharyngeal samples from 72 CVID adults and 26 controls were collected in a 12-month prospective study. The samples were analyzed by metagenomic bacterial 16S ribosomal RNA sequencing and processed using the Quantitative Insights Into Microbial Ecology (QIME) pipeline. Differentially abundant species were identified and used to build a dysbiosis index. A machine learning model trained on microbial abundance data was used to test the power of microbiome alterations to distinguish between healthy individuals and CVID patients.

RESULTS: Compared to controls, the oropharyngeal microbiome of CVID patients showed lower alpha- and beta-diversity, with a relatively increased abundance of the order Lactobacillales, including the family Streptococcaceae. Intra-CVID analysis identified age >45 years, COPD, lack of IgA, and low residual IgM as associated with a reduced alpha diversity. Expansion of Haemophilus and Streptococcus genera was observed in patients with undetectable IgA and COPD, independent from recent antibiotic use. Patients receiving azithromycin as antibiotic prophylaxis had a higher dysbiosis score. Expansion of Haemophilus and Anoxybacillus was associated with acute respiratory infections within six months.

CONCLUSIONS: CVID patients showed a perturbed oropharynx microbiota enriched with potentially pathogenic bacteria and decreased protective species. Low residual levels of IgA/IgM, chronic lung damage, anti antibiotic prophylaxis contributed to respiratory dysbiosis.

PMID:38873612 | PMC:PMC11169596 | DOI:10.3389/fimmu.2024.1371118

Chem Sci. 2024 Apr 11;15(23):8800-8812. doi: 10.1039/d3sc06880c. eCollection 2024 Jun 12.

ABSTRACT

The Critical Assessment of Computational Hit-Finding Experiments (CACHE) Challenge series is focused on identifying small molecule inhibitors of protein targets using computational methods. Each challenge contains two phases, hit-finding and follow-up optimization, each of which is followed by experimental validation of the computational predictions. For the CACHE Challenge #1, the Leucine-Rich Repeat Kinase 2 (LRRK2) WD40 Repeat (WDR) domain was selected as the target for in silico hit-finding and optimization. Mutations in LRRK2 are the most common genetic cause of the familial form of Parkinson's disease. The LRRK2 WDR domain is an understudied drug target with no known molecular inhibitors. Herein we detail the first phase of our winning submission to the CACHE Challenge #1. We developed a framework for the high-throughput structure-based virtual screening of a chemically diverse small molecule space. Hit identification was performed using the large-scale Deep Docking (DD) protocol followed by absolute binding free energy (ABFE) simulations. ABFEs were computed using an automated molecular dynamics (MD)-based thermodynamic integration (TI) approach. 4.1 billion ligands from Enamine REAL were screened with DD followed by ABFEs computed by MD TI for 793 ligands. 76 ligands were prioritized for experimental validation, with 59 compounds successfully synthesized and 5 compounds identified as hits, yielding a 8.5% hit rate. Our results demonstrate the efficacy of the combined DD and ABFE approaches for hit identification for a target with no previously known hits. This approach is widely applicable for the efficient screening of ultra-large chemical libraries as well as rigorous protein-ligand binding affinity estimation leveraging modern computational resources.

PMID:38873063 | PMC:PMC11168082 | DOI:10.1039/d3sc06880c

BMC Methods. 2024;1(1):5. doi: 10.1186/s44330-024-00005-4. Epub 2024 Jun 7.

ABSTRACT

BACKGROUND: Functional evaluation of molecules that are predicted to promote stem cell mediated endogenous repair often requires in vivo transplant studies that are low throughput and hinder the rate of discovery. To offer greater throughput for functional validation studies, we miniaturized, simplified and expanded the functionality of a previously developed muscle endogenous repair (MEndR) in vitro assay that was shown to capture significant events of in vivo muscle endogenous repair.

METHODS: The mini-MEndR assay consists of miniaturized cellulose scaffolds designed to fit in 96-well plates, the pores of which are infiltrated with human myoblasts encapsulated in a fibrin-based hydrogel to form engineered skeletal muscle tissues. Pre-adsorbing thrombin to the cellulose scaffolds facilitates in situ tissue polymerization, a critical modification that enables new users to rapidly acquire assay expertise. Following the generation of the 3D myotube template, muscle stem cells (MuSCs), enriched from digested mouse skeletal muscle tissue using an improved magnetic-activated cell sorting protocol, are engrafted within the engineered template. Murine MuSCs are fluorescently labeled, enabling co-evaluation of human and mouse Pax7+ cell responses to drug treatments. A regenerative milieu is introduced by injuring the muscle tissue with a myotoxin to initiate endogenous repair "in a dish". Phenotypic data is collected at endpoints with a high-content imaging system and is analyzed using ImageJ-based image analysis pipelines.

RESULTS: The miniaturized format and modified manufacturing protocol cuts reagent costs in half and hands-on seeding time ~ threefold, while the image analysis pipelines save 40 h of labour. By evaluating multiple commercially available human primary myoblast lines in 2D and 3D culture, we establish quality assurance metrics for cell line selection that standardizes myotube template quality. In vivo outcomes (enhanced muscle production and Pax7+ cell expansion) to a known modulator of MuSC mediated repair (p38/β MAPK inhibition) are recapitulated in the miniaturized culture assay, but only in the presence of stem cells and the regenerative milieu.

DISCUSSION: The miniaturized predictive assay offers a simple, scaled platform to co-investigate human and mouse skeletal muscle endogenous repair molecular modulators, and thus is a promising strategy to accelerate the muscle endogenous repair discovery pipeline.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44330-024-00005-4.

PMID:38872952 | PMC:PMC11173370 | DOI:10.1186/s44330-024-00005-4

Sci Prog. 2024 Apr-Jun;107(2):368504241261833. doi: 10.1177/00368504241261833.

ABSTRACT

Our memories help us plan for the future. In some cases, we use memories to repeat the choices that led to preferable outcomes in the past. The success of these memory-guided decisions depends on close interactions between the hippocampus and medial prefrontal cortex. In other cases, we need to use our memories to deduce hidden connections between the present and past situations to decide the best choice of action based on the expected outcome. Our recent study investigated neural underpinnings of such inferential decisions by monitoring neural activity in the medial prefrontal cortex and hippocampus in rats. We identified several neural activity patterns indicating awake memory trace reactivation and restructuring of functional connectivity among multiple neurons. We also found that these patterns occurred concurrently with the ongoing hippocampal activity when rats recalled past events but not when they planned new adaptive actions. Here, we discussed how these computational properties might contribute to success in inferential decision-making and propose a working model on how the medial prefrontal cortex changes its interaction with the hippocampus depending on whether it reflects on the past or looks into the future.

PMID:38872470 | DOI:10.1177/00368504241261833

J Exp Bot. 2024 Jun 14:erae270. doi: 10.1093/jxb/erae270. Online ahead of print.

ABSTRACT

Post-translational modifications (PTMs) greatly increase protein diversity and functionality. To help the plant research community interpret the ever-increasing number of reported PTMs, The Plant PTM Viewer (https://www.psb.ugent.be/PlantPTMViewer) provides an intuitive overview and tools to assess plant protein PTMs. This update includes 62 novel PTM profiling studies, adding a total of 112,000 modified peptides reporting plant PTMs, including 14 additional PTM types and three species (moss, tomato and soybean). Furthermore, an open modification re-analysis of a large-scale Arabidopsis thaliana mass spectrometry tissue atlas identified previously uncharted landscapes of lysine acylations predominant in seed and flower tissues and 3-phosphoglycerylation on glycolytic enzymes in plants. An extra 'protein list analysis' tool was developed for retrieval and assessing the enrichment of PTMs a protein list of interest. We conducted a protein list analysis on nuclear proteins, revealing a substantial number of redox modifications in the nucleus, confirming previous assumptions regarding the redox regulation of transcription. We encourage the plant research community to use PTM Viewer 2.0 for hypothesis testing and new target discovery and also to submit new data to expand the coverage of conditions, plant species, and PTM types, thereby enriching our understanding of plant biology.

PMID:38872385 | DOI:10.1093/jxb/erae270

J Med Chem. 2024 Jun 13. doi: 10.1021/acs.jmedchem.4c00534. Online ahead of print.

ABSTRACT

Papain-like protease (PLpro) is a promising therapeutic target for its pivotal role in the life cycle of SARS-CoV-2. A series of 1,2,4-oxadiazole derivatives was designed and synthesized via a ring formation strategy based on SARS-CoV-2 PLpro-GRL0617 complex structure. Systematic structure-activity relationship studies revealed that introducing oxadiazole and aryl carboxylic acid moieties to GRL0617 enhanced the enzymatic inhibition activity, affinity, and deubiquitination capacity toward PLpro. 1,2,4-Oxadiazole compounds 13f and 26r, which had PLpro inhibition activity (IC50 = 1.8 and 1.0 μM) and antiviral activity against SARS-CoV-2 (EC50 = 5.4 and 4.3 μM), exhibited good metabolic stability (t1/2 > 93.2 min) and higher plasma exposure (AUC0-t = 17,380.08 and 24,289.76 ng·h/mL) in mice. Especially, compound 26r with moderate oral bioavailability of 39.1% and potent antiviral activity is worthy of further studies in vivo. Our findings provide a new insight for the discovery of antiviral agents targeting PLpro.

PMID:38871484 | DOI:10.1021/acs.jmedchem.4c00534

Metabolism. 2024 Jun 11:155941. doi: 10.1016/j.metabol.2024.155941. Online ahead of print.

ABSTRACT

BACKGROUND: An altered gut microbiome characterized by reduced abundance of butyrate producing bacteria and reduced gene richness is associated with type 2 diabetes (T2D). An important complication of T2D is increased risk of cognitive impairment and dementia. The biguanide metformin is a commonly prescribed medication for the control of T2D and metformin treatment has been associated with a significant reduction in the risk of dementia and improved cognition, particularly in people with T2D.

AIM: To investigate the associations of metformin use with cognition exploring potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively.

METHODS: We explored two independent cohorts: an observational study (Aging Imageomics) and a phase IV, randomized, double-blind, parallel-group, randomized pilot study (MEIFLO). From the two studies, we analyzed four study groups: (1) individuals with no documented medical history or medical treatment (n = 172); (2) people with long-term T2D on metformin monotherapy (n = 134); (3) people with long-term T2D treated with oral hypoglycemic agents other than metformin (n = 45); (4) a newly diagnosed T2D subjects on metformin monotherapy (n = 22). Analyses were also performed stratifying by sex.

RESULTS: Several bacterial species belonging to the Proteobacteria (Escherichia coli) and Verrucomicrobia (Akkermansia muciniphila) phyla were positively associated with metformin treatment, while bacterial species belonging to the Firmicutes phylum (Romboutsia timonensis, Romboutsia ilealis) were negatively associated. Due to the consistent increase in A. muciniphila and decrease in R.ilealis in people with T2D subjects treated with metformin, we investigated the association between this ratio and cognition. In the entire cohort of metformin-treated T2D subjects, the A.muciniphila/R.ilealis ratio was not significantly associated with cognitive test scores. However, after stratifying by sex, the A.muciniphila/R. ilealis ratio was significantly and positively associated with higher memory scores and improved memory in men. Metformin treatment was associated with an enrichment of microbial pathways involved in the TCA cycle, and butanoate, arginine, and proline metabolism in both cohorts. The bacterial genes involved inarginine metabolism, especially in production of glutamate (astA, astB, astC, astD, astE, putA), were enriched following metformin intake. In agreement, in the metabolomics analysis, metformin treatment was strongly associated with the amino acid proline, a metabolite involved in the metabolism of glutamate.

CONCLUSIONS: The beneficial effects of metformin may be mediated by changes in the composition of the gut microbiota and microbial-host-derived co-metabolites.

PMID:38871078 | DOI:10.1016/j.metabol.2024.155941

N Biotechnol. 2024 Jun 11:S1871-6784(24)00023-2. doi: 10.1016/j.nbt.2024.06.002. Online ahead of print.

ABSTRACT

Microbes able to convert gaseous one-carbon (C1) waste feedstocks are increasingly important to transition to the sustainable production of renewable chemicals and fuels. Acetogens are interesting biocatalysts since gas fermentation using Clostridium autoethanogenum has been commercialised. However, most acetogen strains need complex nutrients, display slow growth, and are not robust for bioreactor fermentations. In this work, we used three different and independent adaptive laboratory evolution (ALE) strategies to evolve the wild-type C. autoethanogenum to grow faster, without yeast extract and to be robust in operating continuous bioreactor cultures. Multiple evolved strains with improved phenotypes were isolated on minimal media with one strain, named "LAbrini", exhibiting superior performance regarding the maximum specific growth rate, product profile, and robustness in continuous cultures. Whole-genome sequencing of the evolved strains identified 25 mutations. Of particular interest are two genes that acquired seven different mutations across the three ALE strategies, potentially as a result of convergent evolution. Reverse genetic engineering of mutations in potentially sporulation-related genes CLAU_3129 (spo0A) and CLAU_1957 recovered all three superior features of our ALE strains through triggering significant proteomic rearrangements. This work provides a robust C. autoethanogenum strain "LAbrini" to accelerate phenotyping and genetic engineering and to better understand acetogen metabolism.

PMID:38871051 | DOI:10.1016/j.nbt.2024.06.002

Genome Biol. 2024 Jun 13;25(1):154. doi: 10.1186/s13059-024-03296-6.

ABSTRACT

Genomic data holds huge potential for medical progress but requires strict safety measures due to its sensitive nature to comply with data protection laws. This conflict is especially pronounced in genome-wide association studies (GWAS) which rely on vast amounts of genomic data to improve medical diagnoses. To ensure both their benefits and sufficient data security, we propose a federated approach in combination with privacy-enhancing technologies utilising the findings from a systematic review on federated learning and legal regulations in general and applying these to GWAS.

PMID:38872191 | DOI:10.1186/s13059-024-03296-6

Nat Food. 2024 Jun 13. doi: 10.1038/s43016-024-00996-x. Online ahead of print.

ABSTRACT

Human milk oligosaccharides (HMOs) are a diverse class of carbohydrates which support the health and development of infants. The vast health benefits of HMOs have made them a commercial target for microbial production; however, producing the approximately 200 structurally diverse HMOs at scale has proved difficult. Here we produce a diversity of HMOs by leveraging the robust carbohydrate anabolism of plants. This diversity includes high-value and complex HMOs, such as lacto-N-fucopentaose I. HMOs produced in transgenic plants provided strong bifidogenic properties, indicating their ability to serve as a prebiotic supplement with potential applications in adult and infant health. Technoeconomic analyses demonstrate that producing HMOs in plants provides a path to the large-scale production of specific HMOs at lower prices than microbial production platforms. Our work demonstrates the promise in leveraging plants for the low-cost and sustainable production of HMOs.

PMID:38872016 | DOI:10.1038/s43016-024-00996-x

Nat Methods. 2024 Jun 13. doi: 10.1038/s41592-024-02303-9. Online ahead of print.

ABSTRACT

Single-cell RNA sequencing allows us to model cellular state dynamics and fate decisions using expression similarity or RNA velocity to reconstruct state-change trajectories; however, trajectory inference does not incorporate valuable time point information or utilize additional modalities, whereas methods that address these different data views cannot be combined or do not scale. Here we present CellRank 2, a versatile and scalable framework to study cellular fate using multiview single-cell data of up to millions of cells in a unified fashion. CellRank 2 consistently recovers terminal states and fate probabilities across data modalities in human hematopoiesis and endodermal development. Our framework also allows combining transitions within and across experimental time points, a feature we use to recover genes promoting medullary thymic epithelial cell formation during pharyngeal endoderm development. Moreover, we enable estimating cell-specific transcription and degradation rates from metabolic-labeling data, which we apply to an intestinal organoid system to delineate differentiation trajectories and pinpoint regulatory strategies.

PMID:38871986 | DOI:10.1038/s41592-024-02303-9

Nat Methods. 2024 Jun 13. doi: 10.1038/s41592-024-02307-5. Online ahead of print.

NO ABSTRACT

PMID:38871985 | DOI:10.1038/s41592-024-02307-5

NPJ Syst Biol Appl. 2024 Jun 13;10(1):67. doi: 10.1038/s41540-024-00392-y.

ABSTRACT

Biological networks, such as gene regulatory networks, possess desirable properties. They are more robust and controllable than random networks. This motivates the search for structural and dynamical features that evolution has incorporated into biological networks. A recent meta-analysis of published, expert-curated Boolean biological network models has revealed several such features, often referred to as design principles. Among others, the biological networks are enriched for certain recurring network motifs, the dynamic update rules are more redundant, more biased, and more canalizing than expected, and the dynamics of biological networks are better approximable by linear and lower-order approximations than those of comparable random networks. Since most of these features are interrelated, it is paramount to disentangle cause and effect, that is, to understand which features evolution actively selects for, and thus truly constitute evolutionary design principles. Here, we compare published Boolean biological network models with different ensembles of null models and show that the abundance of canalization in biological networks can almost completely explain their recently postulated high approximability. Moreover, an analysis of random N-K Kauffman models reveals a strong dependence of approximability on the dynamical robustness of a network.

PMID:38871768 | DOI:10.1038/s41540-024-00392-y

Oncogenesis. 2024 Jun 13;13(1):22. doi: 10.1038/s41389-024-00521-6.

ABSTRACT

Breast cancer (BC) is a leading cause of cancer-related death worldwide. The diverse nature and heterogeneous biology of BC pose challenges for survival prediction, as patients with similar diagnoses often respond differently to treatment. Clinically relevant BC intrinsic subtypes have been established through gene expression profiling and are implemented in the clinic. While these intrinsic subtypes show a significant association with clinical outcomes, their long-term survival prediction beyond 5 years often deviates from expected clinical outcomes. This study aimed to identify naturally occurring long-term prognostic subgroups of BC based on an integrated multi-omics analysis. This study incorporates a clinical cohort of 335 untreated BC patients from the Oslo2 study with long-term follow-up (>12 years). Multi-Omics Factor Analysis (MOFA+) was employed to integrate transcriptomic, proteomic, and metabolomic data obtained from the tumor tissues. Our analysis revealed three prominent multi-omics clusters of BC patients with significantly different long-term prognoses (p = 0.005). The multi-omics clusters were validated in two independent large cohorts, METABRIC and TCGA. Importantly, a lack of prognostic association to long-term follow-up above 12 years in the previously established intrinsic subtypes was shown for these cohorts. Through a systems-biology approach, we identified varying enrichment levels of cell-cycle and immune-related pathways among the prognostic clusters. Integrated multi-omics analysis of BC revealed three distinct clusters with unique clinical and biological characteristics. Notably, these multi-omics clusters displayed robust associations with long-term survival, outperforming the established intrinsic subtypes.

PMID:38871719 | DOI:10.1038/s41389-024-00521-6

Nat Commun. 2024 Jun 13;15(1):5057. doi: 10.1038/s41467-024-49171-7.

ABSTRACT

Spatially resolved transcriptomics (SRT) has enabled precise dissection of tumor-microenvironment (TME) by analyzing its intracellular molecular networks and intercellular cell-cell communication (CCC). However, lacking computational exploration of complicated relations between cells, genes, and histological regions, severely limits the ability to interpret the complex structure of TME. Here, we introduce stKeep, a heterogeneous graph (HG) learning method that integrates multimodality and gene-gene interactions, in unraveling TME from SRT data. stKeep leverages HG to learn both cell-modules and gene-modules by incorporating features of diverse nodes including genes, cells, and histological regions, allows for identifying finer cell-states within TME and cell-state-specific gene-gene relations, respectively. Furthermore, stKeep employs HG to infer CCC for each cell, while ensuring that learned CCC patterns are comparable across different cell-states through contrastive learning. In various cancer samples, stKeep outperforms other tools in dissecting TME such as detecting bi-potent basal populations, neoplastic myoepithelial cells, and metastatic cells distributed within the tumor or leading-edge regions. Notably, stKeep identifies key transcription factors, ligands, and receptors relevant to disease progression, which are further validated by the functional and survival analysis of independent clinical data, thereby highlighting its clinical prognostic and immunotherapy applications.

PMID:38871687 | DOI:10.1038/s41467-024-49171-7

Science. 2024 Jun 14;384(6701):eado0713. doi: 10.1126/science.ado0713. Epub 2024 Jun 14.

ABSTRACT

Bacteria can repurpose their own bacteriophage viruses (phage) to kill competing bacteria. Phage-derived elements are frequently strain specific in their killing activity, although there is limited evidence that this specificity drives bacterial population dynamics. Here, we identified intact phage and their derived elements in a metapopulation of wild plant-associated Pseudomonas genomes. We discovered that the most abundant viral cluster encodes a phage remnant resembling a phage tail called a tailocin, which bacteria have co-opted to kill bacterial competitors. Each pathogenic Pseudomonas strain carries one of a few distinct tailocin variants that target the variable polysaccharides in the outer membrane of co-occurring pathogenic Pseudomonas strains. Analysis of herbarium samples from the past 170 years revealed that the same tailocin and bacterial receptor variants have persisted in Pseudomonas populations. These results suggest that tailocin genetic diversity can be mined to develop targeted "tailocin cocktails" for microbial control.

PMID:38870284 | DOI:10.1126/science.ado0713

J Exp Med. 2024 Jul 1;221(7):e20221721. doi: 10.1084/jem.20221721. Epub 2024 Jun 13.

ABSTRACT

While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

PMID:38869480 | DOI:10.1084/jem.20221721

Epigenomics. 2024 May 21:1-9. doi: 10.1080/17501911.2024.2343274. Online ahead of print.

ABSTRACT

Aim: This study addresses the challenge of predicting the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy. Methods: Using DNA methylation cytometry, we analyzed the immune profiles of six HNSCC patients who showed a positive response to immunotherapy over a year without disease progression. Results: There was an initial increase in CD8 T memory cells and natural killer cells during the first four cycles of immunotherapy, which then returned to baseline levels after a year. Baseline CD8 T cell levels were lower in HNSCC immunotherapy responders but became similar to those in healthy subjects after immunotherapy. Conclusion: These findings suggest that monitoring fluctuations in immune profiles could potentially identify biomarkers for immunotherapy response in HNSCC patients.

PMID:38869472 | DOI:10.1080/17501911.2024.2343274