Microb Biotechnol. 2023 Mar 30. doi: 10.1111/1751-7915.14246. Online ahead of print.

ABSTRACT

A better understanding of the genetic regulation of the biosynthesis of microbial compounds could accelerate the discovery of new biologically active molecules and facilitate their production. To this end, we have investigated the time course of genome-wide transcription in the myxobacterium Sorangium sp. So ce836 in relation to its production of natural compounds. Time-resolved RNA sequencing revealed that core biosynthesis genes from 48 biosynthetic gene clusters (BGCs; 92% of all BGCs encoded in the genome) were actively transcribed at specific time points in a batch culture. The majority (80%) of polyketide synthase and non-ribosomal peptide synthetase genes displayed distinct peaks of transcription during exponential bacterial growth. Strikingly, these bursts in BGC transcriptional activity were associated with surges in the net production rates of known natural compounds, indicating that their biosynthesis was critically regulated at the transcriptional level. In contrast, BGC read counts from single time points had limited predictive value about biosynthetic activity, since transcription levels varied >100-fold among BGCs with detected natural products. Taken together, our time-course data provide unique insights into the dynamics of natural compound biosynthesis and its regulation in a wild-type myxobacterium, challenging the commonly cited notion of preferential BGC expression under nutrient-limited conditions. The close association observed between BGC transcription and compound production warrants additional efforts to develop genetic engineering tools for boosting compound yields from myxobacterial producer strains.

PMID:36998231 | DOI:10.1111/1751-7915.14246

iScience. 2023 Mar 30;26(4):106511. doi: 10.1016/j.isci.2023.106511. eCollection 2023 Apr 21.

ABSTRACT

In their latest article, Seki and colleagues investigate the potential role of cold as a therapeutical option to treat various cancer types, including even clinically untreatable cancers such as pancreatic cancers. The authors suggest that cold exposure may have a tumor-suppressive effect mediated by the activation of brown adipose tissue (BAT), in charge of dissipating heat through non-shivering thermogenesis. In this regard, circulating blood glucose is decreased, restricting the tumor glucose uptake, which is redistributed, favoring BAT uptake to fuel thermogenesis.1.

PMID:37091251 | PMC:PMC10119757 | DOI:10.1016/j.isci.2023.106511

Environ Microbiome. 2023 Mar 30;18(1):26. doi: 10.1186/s40793-023-00479-9.

ABSTRACT

BACKGROUND: For a sustainable production of food, research on agricultural soil microbial communities is inevitable. Due to its immense complexity, soil is still some kind of black box. Soil study designs for identifying microbiome members of relevance have various scopes and focus on particular environmental factors. To identify common features of soil microbiomes, data from multiple studies should be compiled and processed. Taxonomic compositions and functional capabilities of microbial communities associated with soils and plants have been identified and characterized in the past few decades. From a fertile Loess-Chernozem-type soil located in Germany, metagenomically assembled genomes (MAGs) classified as members of the phylum Thaumarchaeota/Thermoproteota were obtained. These possibly represent keystone agricultural soil community members encoding functions of relevance for soil fertility and plant health. Their importance for the analyzed microbiomes is corroborated by the fact that they were predicted to contribute to the cycling of nitrogen, feature the genetic potential to fix carbon dioxide and possess genes with predicted functions in plant-growth-promotion (PGP). To expand the knowledge on soil community members belonging to the phylum Thaumarchaeota, we conducted a meta-analysis integrating primary studies on European agricultural soil microbiomes.

RESULTS: Taxonomic classification of the selected soil metagenomes revealed the shared agricultural soil core microbiome of European soils from 19 locations. Metadata reporting was heterogeneous between the different studies. According to the available metadata, we separated the data into 68 treatments. The phylum Thaumarchaeota is part of the core microbiome and represents a major constituent of the archaeal subcommunities in all European agricultural soils. At a higher taxonomic resolution, 2074 genera constituted the core microbiome. We observed that viral genera strongly contribute to variation in taxonomic profiles. By binning of metagenomically assembled contigs, Thaumarchaeota MAGs could be recovered from several European soil metagenomes. Notably, many of them were classified as members of the family Nitrososphaeraceae, highlighting the importance of this family for agricultural soils. The specific Loess-Chernozem Thaumarchaeota MAGs were most abundant in their original soil, but also seem to be of importance in other agricultural soil microbial communities. Metabolic reconstruction of Switzerland_1_MAG_2 revealed its genetic potential i.a. regarding carbon dioxide (CO[Formula: see text]) fixation, ammonia oxidation, exopolysaccharide production and a beneficial effect on plant growth. Similar genetic features were also present in other reconstructed MAGs. Three Nitrososphaeraceae MAGs are all most likely members of a so far unknown genus.

CONCLUSIONS: On a broad view, European agricultural soil microbiomes are similarly structured. Differences in community structure were observable, although analysis was complicated by heterogeneity in metadata recording. Our study highlights the need for standardized metadata reporting and the benefits of networking open data. Future soil sequencing studies should also consider high sequencing depths in order to enable reconstruction of genome bins. Intriguingly, the family Nitrososphaeraceae commonly seems to be of importance in agricultural microbiomes.

PMID:36998097 | DOI:10.1186/s40793-023-00479-9

Nat Plants. 2023 Mar 30. doi: 10.1038/s41477-023-01378-0. Online ahead of print.

ABSTRACT

A diploid genome in the Saccharum complex facilitates our understanding of evolution in the highly polyploid Saccharum genus. Here we have generated a complete, gap-free genome assembly of Erianthus rufipilus, a diploid species within the Saccharum complex. The complete assembly revealed that centromere satellite homogenization was accompanied by the insertions of Gypsy retrotransposons, which drove centromere diversification. An overall low rate of gene transcription was observed in the palaeo-duplicated chromosome EruChr05 similar to other grasses, which might be regulated by methylation patterns mediated by homologous 24 nt small RNAs, and potentially mediating the functions of many nucleotide-binding site genes. Sequencing data for 211 accessions in the Saccharum complex indicated that Saccharum probably originated in the trans-Himalayan region from a diploid ancestor (x = 10) around 1.9-2.5 million years ago. Our study provides new insights into the origin and evolution of Saccharum and accelerates translational research in cereal genetics and genomics.

PMID:36997685 | DOI:10.1038/s41477-023-01378-0

Nat Commun. 2023 Mar 30;14(1):1790. doi: 10.1038/s41467-023-37449-1.

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Mutations in the PKD1 gene, which encodes polycystin-1 (PC1), account for approximately 78% of cases. PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We show that transgenic expression of a protein corresponding to the final 200 amino acid (aa) residues of PC1 in two Pkd1-KO orthologous murine models of ADPKD suppresses cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase (NNT). This interaction modulates tubular/cyst cell proliferation, the metabolic profile, mitochondrial function, and the redox state. Together, these results suggest that a short fragment of PC1 is sufficient to suppress cystic phenotype and open the door to the exploration of gene therapy strategies for ADPKD.

PMID:36997516 | DOI:10.1038/s41467-023-37449-1

Gut. 2023 Mar 30:gutjnl-2022-329313. doi: 10.1136/gutjnl-2022-329313. Online ahead of print.

ABSTRACT

Recent advances in single-cell RNA sequencing and bioinformatics have drastically increased our ability to interrogate the cellular composition of traditionally difficult to study organs, such as the pancreas. With the advent of these technologies and approaches, the field has grown, in just a few years, from profiling pancreas disease states to identifying molecular mechanisms of therapy resistance in pancreatic ductal adenocarcinoma, a particularly deadly cancer. Single-cell transcriptomics and related spatial approaches have identified previously undescribed epithelial and stromal cell types and states, how these populations change with disease progression, and potential mechanisms of action which will serve as the basis for designing new therapeutic strategies. Here, we review the recent literature on how single-cell transcriptomic approaches have changed our understanding of pancreas biology and disease progression.

PMID:36997301 | DOI:10.1136/gutjnl-2022-329313

Mol Cell. 2023 Mar 22:S1097-2765(23)00166-1. doi: 10.1016/j.molcel.2023.03.009. Online ahead of print.

ABSTRACT

Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.

PMID:36996812 | DOI:10.1016/j.molcel.2023.03.009

Bioconjug Chem. 2023 Mar 30. doi: 10.1021/acs.bioconjchem.3c00019. Online ahead of print.

ABSTRACT

Targeted delivery of nucleic acid therapeutics to the lungs could transform treatment options for pulmonary disease. We have previously developed oligomeric charge-altering releasable transporters (CARTs) for in vivo mRNA transfection and demonstrated their efficacy for use in mRNA-based cancer vaccination and local immunomodulatory therapies against murine tumors. While our previously reported glycine-based CART-mRNA complexes (G-CARTs/mRNA) show selective protein expression in the spleen (mouse, >99%), here, we report a new lysine-derived CART-mRNA complex (K-CART/mRNA) that, without additives or targeting ligands, shows selective protein expression in the lungs (mouse, >90%) following systemic IV administration. We further show that by delivering siRNA using the K-CART, we can significantly decrease expression of a lung-localized reporter protein. Blood chemistry and organ pathology studies demonstrate that K-CARTs are safe and well-tolerated. We report on the new step economical, organocatalytic synthesis (two steps) of functionalized polyesters and oligo-carbonate-co-α-aminoester K-CARTs from simple amino acid and lipid-based monomers. The ability to direct protein expression selectively in the spleen or lungs by simple, modular changes to the CART structure opens fundamentally new opportunities in research and gene therapy.

PMID:36996808 | DOI:10.1021/acs.bioconjchem.3c00019

J Autoimmun. 2023 Mar 28;136:103025. doi: 10.1016/j.jaut.2023.103025. Online ahead of print.

ABSTRACT

OBJECTIVES: We aimed at investigating the whole-blood transcriptome, expression quantitative trait loci (eQTLs), and levels of selected serological markers in patients with SLE versus healthy controls (HC) to gain insight into pathogenesis and identify drug targets.

METHODS: We analyzed differentially expressed genes (DEGs) and dysregulated gene modules in a cohort of 350 SLE patients and 497 HC from the European PRECISESADS project (NTC02890121), split into a discovery (60%) and a replication (40%) set. Replicated DEGs qualified for eQTL, pathway enrichment, regulatory network, and druggability analysis. For validation purposes, a separate gene module analysis was performed in an independent cohort (GSE88887).

RESULTS: Analysis of 521 replicated DEGs identified multiple enriched interferon signaling pathways through Reactome. Gene module analysis yielded 18 replicated gene modules in SLE patients, including 11 gene modules that were validated in GSE88887. Three distinct gene module clusters were defined i.e., "interferon/plasma cells", "inflammation", and "lymphocyte signaling". Predominant downregulation of the lymphocyte signaling cluster denoted renal activity. By contrast, upregulation of interferon-related genes indicated hematological activity and vasculitis. Druggability analysis revealed several potential drugs interfering with dysregulated genes within the "interferon" and "PLK1 signaling events" modules. STAT1 was identified as the chief regulator in the most enriched signaling molecule network. Drugs annotated to 15 DEGs associated with cis-eQTLs included bortezomib for its ability to modulate CTSL activity. Belimumab was annotated to TNFSF13B (BAFF) and daratumumab was annotated to CD38 among the remaining replicated DEGs.

CONCLUSIONS: Modulation of interferon, STAT1, PLK1, B and plasma cell signatures showed promise as viable approaches to treat SLE, pointing to their importance in SLE pathogenesis.

PMID:36996699 | DOI:10.1016/j.jaut.2023.103025

Anal Chem. 2023 Mar 30. doi: 10.1021/acs.analchem.3c00557. Online ahead of print.

ABSTRACT

Low-cost, rapid, and accurate acquisition of minimum inhibitory concentrations (MICs) is key to limiting the development of antimicrobial resistance (AMR). Until now, conventional antibiotic susceptibility testing (AST) methods are typically time-consuming, high-cost, and labor-intensive, making them difficult to accomplish this task. Herein, an electricity-free, portable, and robust handyfuge microfluidic chip was developed for on-site AST, termed handyfuge-AST. With simply handheld centrifugation, the bacterial-antibiotic mixtures with accurate antibiotic concentration gradients could be generated in less than 5 min. The accurate MIC values of single antibiotics (including ampicillin, kanamycin, and chloramphenicol) or their combinations against Escherichia coli could be obtained within 5 h. To further meet the growing demands of point-of-care testing, we upgraded our handyfuge-AST with a pH-based colorimetric strategy, enabling naked eye recognition or intelligent recognition with a homemade mobile app. Through a comparative study of 60 clinical data (10 clinical samples corresponding to six commonly used antibiotics), the accurate MICs by handyfuge-AST with 100% categorical agreements were achieved compared to clinical standard methods (area under curves, AUCs = 1.00). The handyfuge-AST could be used as a low-cost, portable, and robust point-of-care device to rapidly obtain accurate MIC values, which significantly limit the progress of AMR.

PMID:36996249 | DOI:10.1021/acs.analchem.3c00557

Science. 2023 Mar 31;379(6639):eadf4721. doi: 10.1126/science.adf4721. Epub 2023 Mar 31.

ABSTRACT

Brassinosteroids are plant steroid hormones that regulate diverse processes, such as cell division and cell elongation, through gene regulatory networks that vary in space and time. By using time series single-cell RNA sequencing to profile brassinosteroid-responsive gene expression specific to different cell types and developmental stages of the Arabidopsis root, we identified the elongating cortex as a site where brassinosteroids trigger a shift from proliferation to elongation associated with increased expression of cell wall-related genes. Our analysis revealed HOMEOBOX FROM ARABIDOPSIS THALIANA 7 (HAT7) and GT-2-LIKE 1 (GTL1) as brassinosteroid-responsive transcription factors that regulate cortex cell elongation. These results establish the cortex as a site of brassinosteroid-mediated growth and unveil a brassinosteroid signaling network regulating the transition from proliferation to elongation, which illuminates aspects of spatiotemporal hormone responses.

PMID:36996230 | DOI:10.1126/science.adf4721

Science. 2023 Mar 30:eadg6518. doi: 10.1126/science.adg6518. Online ahead of print.

ABSTRACT

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, arises from SMN protein insufficiency following SMN1 loss. Approved therapies circumvent endogenous SMN regulation and require repeated dosing or may wane. We describe genome editing of SMN2, an insufficient copy of SMN1 harboring a C6>T mutation, to permanently restore SMN protein levels and rescue SMA phenotypes. We used nucleases or base editors to modify five SMN2 regulatory regions. Base editing converted SMN2 T6>C, restoring SMN protein levels to wild-type. AAV9-mediated base editor delivery in Δ7SMA mice yielded 87% average T6>C conversion, improved motor function, and extended average lifespan, which was enhanced by one-time base editor+nusinersen co-administration (111 versus 17 days untreated). These findings demonstrate the potential of a one-time base editing treatment for SMA.

PMID:36996170 | DOI:10.1126/science.adg6518

PLoS One. 2023 Mar 30;18(3):e0283727. doi: 10.1371/journal.pone.0283727. eCollection 2023.

ABSTRACT

There is a controversy over what causes the low robustness of some programs for predicting protein stability change upon mutation. Some researchers suggested that low-quality data and insufficiently informative features are the primary reasons, while others attributed the problem largely to a bias caused by data imbalance as there are more destabilizing mutations than stabilizing ones. In this study, a simple approach was developed to construct a balanced dataset that was then conjugated with a leave-one-protein-out approach to illustrate that the bias may not be the primary reason for poor performance. A balanced dataset with some seemly good conventional n-fold CV results should not be used as a proof that a model for predicting protein stability change upon mutations is robust. Thus, some of the existing algorithms need to be re-examined before any practical applications. Also, more emphasis should be put on obtaining high quality and quantity of data and features in future research.

PMID:36996153 | DOI:10.1371/journal.pone.0283727

J Med Internet Res. 2023 Mar 30;25:e41588. doi: 10.2196/41588.

ABSTRACT

BACKGROUND: The collection, storage, and analysis of large data sets are relevant in many sectors. Especially in the medical field, the processing of patient data promises great progress in personalized health care. However, it is strictly regulated, such as by the General Data Protection Regulation (GDPR). These regulations mandate strict data security and data protection and, thus, create major challenges for collecting and using large data sets. Technologies such as federated learning (FL), especially paired with differential privacy (DP) and secure multiparty computation (SMPC), aim to solve these challenges.

OBJECTIVE: This scoping review aimed to summarize the current discussion on the legal questions and concerns related to FL systems in medical research. We were particularly interested in whether and to what extent FL applications and training processes are compliant with the GDPR data protection law and whether the use of the aforementioned privacy-enhancing technologies (DP and SMPC) affects this legal compliance. We placed special emphasis on the consequences for medical research and development.

METHODS: We performed a scoping review according to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). We reviewed articles on Beck-Online, SSRN, ScienceDirect, arXiv, and Google Scholar published in German or English between 2016 and 2022. We examined 4 questions: whether local and global models are "personal data" as per the GDPR; what the "roles" as defined by the GDPR of various parties in FL are; who controls the data at various stages of the training process; and how, if at all, the use of privacy-enhancing technologies affects these findings.

RESULTS: We identified and summarized the findings of 56 relevant publications on FL. Local and likely also global models constitute personal data according to the GDPR. FL strengthens data protection but is still vulnerable to a number of attacks and the possibility of data leakage. These concerns can be successfully addressed through the privacy-enhancing technologies SMPC and DP.

CONCLUSIONS: Combining FL with SMPC and DP is necessary to fulfill the legal data protection requirements (GDPR) in medical research dealing with personal data. Even though some technical and legal challenges remain, for example, the possibility of successful attacks on the system, combining FL with SMPC and DP creates enough security to satisfy the legal requirements of the GDPR. This combination thereby provides an attractive technical solution for health institutions willing to collaborate without exposing their data to risk. From a legal perspective, the combination provides enough built-in security measures to satisfy data protection requirements, and from a technical perspective, the combination provides secure systems with comparable performance with centralized machine learning applications.

PMID:36995759 | DOI:10.2196/41588

Adv Mater. 2023 Mar 30:e2302335. doi: 10.1002/adma.202302335. Online ahead of print.

ABSTRACT

High-entropy alloys nanoparticles (HEANPs) are receiving extensive attention due to their broad compositional tunability and unlimited potential in bioapplication. However, developing new methods to prepare ultra-small high-entropy alloy nanoparticles (US-HEANPs) faces severe challenges owing to their intrinsic thermodynamic instability. Furthermore, there are few reports on studying the effect of HEANPs in tumor therapy. Herein, the fabricated PtPdRuRhIr US-HEANPs act as bifunctional nanoplatforms for the highly efficient treatment of tumors. The US-HEANPs are engineered by the universal metal-ligand cross-linking strategy. This simple and scalable strategy is based on the aldol condensation of organometallics to form the target US-HEANPs. The synthesized US-HEANPs exhibit excellent peroxidase-like (POD-like) activity and can spanking catalyze the endogenous hydrogen peroxide to produce highly toxic hydroxyl radicals. Furthermore, the US-HEANPs possess a high photothermal conversion effect for converting 808 nm near-infrared light into heat energy. In vivo and in vitro experiments demonstrated that under the synergistic effect of POD-like activity and photothermal action, the US-HEANPs nanoplatform can effectively ablate cancer cells and treat tumors. We believe that this work not only provides a new perspective for the fabrication of HEANPs, but also opens the high-entropy nanozymes research direction and their biomedical application. This article is protected by copyright. All rights reserved.

PMID:36995655 | DOI:10.1002/adma.202302335

Microbiol Spectr. 2023 Mar 30:e0434022. doi: 10.1128/spectrum.04340-22. Online ahead of print.

ABSTRACT

Lactiplantibacillus plantarum (previously known as Lactobacillus plantarum) is increasingly used as a probiotic to treat human diseases, but its phages in the human gut remain unexplored. Here, we report its first gut phage, Gut-P1, which we systematically screened using metagenomic sequencing, virus-like particle (VLP) sequencing, and enrichment culture from 35 fecal samples. Gut-P1 is virulent, belongs to the Douglaswolinvirus genus, and is highly prevalent in the gut (~11% prevalence); it has a genome of 79,928 bp consisting of 125 protein coding genes and displaying low sequence similarities to public L. plantarum phages. Physiochemical characterization shows that it has a short latent period and adapts to broad ranges of temperatures and pHs. Furthermore, Gut-P1 strongly inhibits the growth of L. plantarum strains at a multiplicity of infection (MOI) of 1e-6. Together, these results indicate that Gut-P1 can greatly impede the application of L. plantarum in humans. Strikingly, Gut-P1 was identified only in the enrichment culture, not in our metagenomic or VLP sequencing data nor in any public human phage databases, indicating the inefficiency of bulk sequencing in recovering low-abundance but highly prevalent phages and pointing to the unexplored hidden diversity of the human gut virome despite recent large-scale sequencing and bioinformatics efforts. IMPORTANCE As Lactiplantibacillus plantarum (previously known as Lactobacillus plantarum) is increasingly used as a probiotic to treat human gut-related diseases, its bacteriophages may pose a certain threat to their further application and should be identified and characterized more often from the human intestine. Here, we isolated and identified the first gut L. plantarum phage that is prevalent in a Chinese population. This phage, Gut-P1, is virulent and can strongly inhibit the growth of multiple L. plantarum strains at low MOIs. Our results also show that bulk sequencing is inefficient at recovering low-abundance but highly prevalent phages such as Gut-P1, suggesting that the hidden diversity of human enteroviruses has not yet been explored. Our results call for innovative approaches to isolate and identify intestinal phages from the human gut and to rethink our current understanding of the enterovirus, particularly its underestimated diversity and overestimated individual specificity.

PMID:36995238 | DOI:10.1128/spectrum.04340-22

Front Oncol. 2023 Mar 13;13:1132811. doi: 10.3389/fonc.2023.1132811. eCollection 2023.

ABSTRACT

INTRODUCTION: Lung cancer is one of the major causes of cancer-related mortality worldwide. High-throughput RNA sequencing (RNA-seq) of surgically removed tumors has been used to identify new biomarkers of lung cancer; however, contamination by non-tumor cells in the tumor microenvironment significantly interferes with the search for novel biomarkers. Tumor organoids, as a pre-clinical cancer model, exhibit similar molecular characteristics with tumor samples while minimizing the interference from other cells.

METHODS AND RESULTS: Here we analyzed six RNA-seq datasets collected from different organoid models, in which cells with oncogenic mutations were reprogrammed to mimic lung adenocarcinoma (LUAD) tumorigenesis. We uncovered 9 LUAD-specific biomarker genes by integrating transcriptomic data from multiple sources, and identified IRAK1BP1 as a novel predictor of LUAD disease outcome. Validation with RNA-seq and microarray data collected from multiple patient cohorts, as well as patient-derived xenograft (PDX) and lung cancer cell line models confirmed that IRAK1BP1 expression was significantly lower in tumor cells, and had no correlation with known markers oflung cancer prognosis. In addition, loss of IRAK1BP1 correlated with the group of LUAD patients with worse survival; and gene-set enrichment analysis using tumor and cell line data implicated that high IRAK1BP1 expression was associated with suppression of oncogenic pathways.

DISCUSSION: In conclusion, we demonstrate that IRAK1BP1 is a promising biomarker of LUAD prognosis.

PMID:36994215 | PMC:PMC10040777 | DOI:10.3389/fonc.2023.1132811

iScience. 2023 Mar 3;26(3):106246. doi: 10.1016/j.isci.2023.106246. eCollection 2023 Mar 17.

ABSTRACT

Peritoneal recurrence is the most frequent and lethal recurrence pattern in gastric cancer (GC) with serosal invasion after radical surgery. However, current evaluation methods are not adequate for predicting peritoneal recurrence in GC with serosal invasion. Emerging evidence shows that pathomics analyses could be advantageous for risk stratification and outcome prediction. Herein, we propose a pathomics signature composed of multiple pathomics features extracted from digital hematoxylin and eosin-stained images. We found that the pathomics signature was significantly associated with peritoneal recurrence. A competing-risk pathomics nomogram including carbohydrate antigen 19-9 level, depth of invasion, lymph node metastasis, and pathomics signature was developed for predicting peritoneal recurrence. The pathomics nomogram had favorable discrimination and calibration. Thus, the pathomics signature is a predictive indicator of peritoneal recurrence, and the pathomics nomogram may provide a helpful reference for predicting an individual's risk in peritoneal recurrence of GC with serosal invasion.

PMID:36994190 | PMC:PMC10040964 | DOI:10.1016/j.isci.2023.106246

Front Immunol. 2023 Mar 13;14:1080853. doi: 10.3389/fimmu.2023.1080853. eCollection 2023.

ABSTRACT

A variety of B cell clones seed the germinal centers, where a selection stringency expands the fitter clones to generate higher affinity antibodies. However, recent experiments suggest that germinal centers often retain a diverse set of B cell clones with a range of affinities and concurrently carry out affinity maturation. Amid a tendency to flourish germinal centers with fitter clones, how several B cell clones with differing affinities can be concurrently selected remains poorly understood. Such a permissive selection may allow non-immunodominant clones, which are often rare and of low-affinity, to somatically hypermutate and result in a broad and diverse B cell response. How the constituent elements of germinal centers, their quantity and kinetics may modulate diversity of B cells, has not been addressed well. By implementing a state-of-the-art agent-based model of germinal center, here, we study how these factors impact temporal evolution of B cell clonal diversity and its underlying balance with affinity maturation. While we find that the extent of selection stringency dictates clonal dominance, limited antigen availability on follicular dendritic cells is shown to expedite the loss of diversity of B cells as germinal centers mature. Intriguingly, the emergence of a diverse set of germinal center B cells depends on high affinity founder cells. Our analysis also reveals a substantial number of T follicular helper cells to be essential in balancing affinity maturation with clonal diversity, as a low number of T follicular helper cells impedes affinity maturation and also contracts the scope for a diverse B cell response. Our results have implications for eliciting antibody responses to non-immunodominant specificities of the pathogens by controlling the regulators of the germinal center reaction, thereby pivoting a way for vaccine development to generate broadly protective antibodies.

PMID:36993964 | PMC:PMC10042134 | DOI:10.3389/fimmu.2023.1080853

Nat Aging. 2023 Mar;3(3):346-365. doi: 10.1038/s43587-023-00363-8. Epub 2023 Feb 9.

ABSTRACT

The commonalities and differences in cell-type-specific pathways that lead to Alzheimer disease (AD) and Parkinson disease (PD) remain unknown. Here, we performed a single-nucleus transcriptome comparison of control, AD and PD striata. We describe three astrocyte subpopulations shared across different brain regions and evolutionarily conserved between humans and mice. We reveal common features between AD and PD astrocytes and regional differences that contribute toward amyloid pathology and neurodegeneration. In contrast, we found that transcriptomic changes in microglia are largely unique to each disorder. Our analysis identified a population of activated microglia that shared molecular signatures with murine disease-associated microglia (DAM) as well as disease-associated and regional differences in microglia transcriptomic changes linking microglia to disease-specific amyloid pathology, tauopathy and neuronal death. Finally, we delineate undescribed subpopulations of medium spiny neurons (MSNs) in the striatum and provide neuronal transcriptomic profiles suggesting disease-specific changes and selective neuronal vulnerability.

PMID:36993867 | PMC:PMC10046522 | DOI:10.1038/s43587-023-00363-8