Sci Data. 2023 Apr 7;10(1):193. doi: 10.1038/s41597-023-02108-z.

ABSTRACT

Defining cellular and subcellular structures in images, referred to as cell segmentation, is an outstanding obstacle to scalable single-cell analysis of multiplex imaging data. While advances in machine learning-based segmentation have led to potentially robust solutions, such algorithms typically rely on large amounts of example annotations, known as training data. Datasets consisting of annotations which are thoroughly assessed for quality are rarely released to the public. As a result, there is a lack of widely available, annotated data suitable for benchmarking and algorithm development. To address this unmet need, we release 105,774 primarily oncological cellular annotations concentrating on tumor and immune cells using over 40 antibody markers spanning three fluorescent imaging platforms, over a dozen tissue types and across various cellular morphologies. We use readily available annotation techniques to provide a modifiable community data set with the goal of advancing cellular segmentation for the greater imaging community.

PMID:37029126 | DOI:10.1038/s41597-023-02108-z

Food Chem Toxicol. 2023 Apr 5:113760. doi: 10.1016/j.fct.2023.113760. Online ahead of print.

ABSTRACT

Food-grade titanium dioxide (TiO2-FG) is a widespread metal oxide used in the food industries. Recently, the European Food Safety Authority concluded that TiO2-FG cannot be considered safe for consumption due to its genotoxicity; however, its effect on the gut microbiota has not yet been completely unraveled. We studied the effects of TiO2-FG (0.125 mg/mL) on Lactobacillus rhamnosus GG (LGG) and Enterococcus faecium NCIMB10415 (Ent), in particular some physiological and phenotypic traits (growth kinetics, bile salts, and ampicillin resistance) and their interactions with the host (auto-aggregation, biofilm formation, and adhesion on Caco-2/TC7 monolayers) and other gut microorganisms (antimicrobial activity towards pathogens). The results obtained revealed that TiO2-FG alters both LGG and Ent growth and lowers bile resistance (62 and 34.5%, respectively) and adhesion on Caco-2/TC7 monolayers (34.8 and 14.16%, respectively). The other outcomes were strictly species-specific: Ent showed a lower ampicillin sensitivity (14.48%) and auto-aggregation (38.1%), while LGG showed a reduced biofilm formation (37%) and antimicrobial activity towards Staphylococcus aureus (35.73%). Overall, these results suggest an adverse effect of TiO2-FG on both the endogenous and exogenously administered probiotics, contributing to the argument against using TiO2-FG as a food additive.

PMID:37028743 | DOI:10.1016/j.fct.2023.113760

Am J Med. 2023 Apr 5:S0002-9343(23)00208-5. doi: 10.1016/j.amjmed.2023.03.004. Online ahead of print.

NO ABSTRACT

PMID:37028693 | DOI:10.1016/j.amjmed.2023.03.004

Curr Opin Immunol. 2023 Apr 5;82:102323. doi: 10.1016/j.coi.2023.102323. Online ahead of print.

ABSTRACT

Single-cell technologies have revealed the extensive heterogeneity and complexity of the immune system. Systems biology approaches in immunology have taken advantage of the high-parameter, high-throughput data and analyzed immune cell types in a 'bottom-up' data-driven method. This approach has discovered previously unrecognized cell types and functions. Especially for human immunology, in which experimental manipulations are challenging, systems approach has become a successful means to investigate physiologically relevant contexts. This review focuses on the recent findings in lymphocyte biology, from their development, differentiation into subsets, and heterogeneity in their functions, enabled by these systems approaches. Furthermore, we review examples of the application of findings from systems approach studies and discuss how now to leave the rich dataset in the curse of high dimensionality.

PMID:37028221 | DOI:10.1016/j.coi.2023.102323

Neural Netw. 2023 Apr 5;163:64. doi: 10.1016/j.neunet.2023.03.027. Online ahead of print.

NO ABSTRACT

PMID:37028155 | DOI:10.1016/j.neunet.2023.03.027

Sci Immunol. 2023 Apr 14;8(82):eabg2200. doi: 10.1126/sciimmunol.abg2200. Epub 2023 Apr 7.

ABSTRACT

Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen identification and prioritization relies on correctly predicting whether the presenting peptide sequence can successfully induce an immune response. Because most somatic mutations are single-nucleotide variants, changes between wild-type and mutated peptides are typically subtle and require cautious interpretation. A potentially underappreciated variable in neoantigen prediction pipelines is the mutation position within the peptide relative to its anchor positions for the patient's specific MHC molecules. Whereas a subset of peptide positions are presented to the T cell receptor for recognition, others are responsible for anchoring to the MHC, making these positional considerations critical for predicting T cell responses. We computationally predicted anchor positions for different peptide lengths for 328 common HLA alleles and identified unique anchoring patterns among them. Analysis of 923 tumor samples shows that 6 to 38% of neoantigen candidates are potentially misclassified and can be rescued using allele-specific knowledge of anchor positions. A subset of anchor results were orthogonally validated using protein crystallography structures. Representative anchor trends were experimentally validated using peptide-MHC stability assays and competition binding assays. By incorporating our anchor prediction results into neoantigen prediction pipelines, we hope to formalize, streamline, and improve the identification process for relevant clinical studies.

PMID:37027480 | DOI:10.1126/sciimmunol.abg2200

Chin Med J (Engl). 2023 Apr 7. doi: 10.1097/CM9.0000000000002250. Online ahead of print.

NO ABSTRACT

PMID:37026872 | DOI:10.1097/CM9.0000000000002250

Adv Sci (Weinh). 2023 Apr 7:e2204514. doi: 10.1002/advs.202204514. Online ahead of print.

ABSTRACT

As a type of immunogenic cell death, ferroptosis participates in the creation of immunoactive tumor microenvironments. However, knowledge of spatial location of tumor cells with ferroptosis signature in tumor environments and the role of ferroptotic stress in inducing the expression of immune-related molecules in cancer cells is limited. Here the spatial association of the transcriptomic signatures is demonstrated for ferroptosis and inflammation/immune activation located in the invasive front of head and neck squamous cell carcinoma (HNSCC). The association between ferroptosis signature and inflammation/immune activation is more prominent in HPV-negative HNSCC compared to HPV-positive ones. Ferroptotic stress induces PD-L1 expression through reactive oxygen species (ROS)-elicited NF-κB signaling pathway and calcium influx. Priming murine HNSCC with the ferroptosis inducer sensitizes tumors to anti-PD-L1 antibody treatment. A positive correlation between the ferroptosis signature and the active immune cell profile is shown in the HNSCC samples. This study reveals a subgroup of ferroptotic HNSCC with immune-active signatures and indicates the potential of priming HNSCC with ferroptosis inducers to increase the antitumor efficacy of immune checkpoint inhibitors.

PMID:37026630 | DOI:10.1002/advs.202204514

Front Public Health. 2023 Mar 21;11:1069906. doi: 10.3389/fpubh.2023.1069906. eCollection 2023.

ABSTRACT

INTRODUCTION: The metabolomic changes caused by airborne fine particulate matter (PM2.5) exposure in patients with chronic obstructive pulmonary disease (COPD) remain unclear. The aim of this study was to determine whether it is possible to predict PM2.5-induced acute exacerbation of COPD (AECOPD) using metabolic markers.

METHODS: Thirty-eight patients with COPD diagnosed by the 2018 Global Initiative for Obstructive Lung Disease were selected and divided into high exposure and low exposure groups. Questionnaire data, clinical data, and peripheral blood data were collected from the patients. Targeted metabolomics using liquid chromatography-tandem mass spectrometry was performed on the plasma samples to investigate the metabolic differences between the two groups and its correlation with the risk of acute exacerbation.

RESULTS: Metabolomic analysis identified 311 metabolites in the plasma of patients with COPD, among which 21 metabolites showed significant changes between the two groups, involving seven pathways, including glycerophospholipid, alanine, aspartate, and glutamate metabolism. Among the 21 metabolites, arginine and glycochenodeoxycholic acid were positively associated with AECOPD during the three months of follow-up, with an area under the curve of 72.50% and 67.14%, respectively.

DISCUSSION: PM2.5 exposure can lead to changes in multiple metabolic pathways that contribute to the development of AECOPD, and arginine is a bridge between PM2.5 exposure and AECOPD.

PMID:37026137 | PMC:PMC10070744 | DOI:10.3389/fpubh.2023.1069906

Front Immunol. 2023 Mar 21;14:1183969. doi: 10.3389/fimmu.2023.1183969. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fimmu.2023.1122409.].

PMID:37026016 | PMC:PMC10071529 | DOI:10.3389/fimmu.2023.1183969

Tanaffos. 2022 Mar;21(3):336-347.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) as one of the health-threatening problems imposes many economic costs on health systems. Today, there is a greater tendency to use complementary and alternative therapies in the treatment of diseases. This study aimed to evaluate the efficacy of a Persian herbal formulation in patients with COPD.

MATERIALS AND METHODS: This randomized clinical trial was conducted on 76 patients with mild-severe COPD assigned to 2 groups (in each group n=38) for 8 weeks. The interventional group received Compound Honey Syrup (CHS), consisting of combination of honey and extracts of five medicinal plants (i.e., ginger, cinnamon, saffron, cardamom, and galangal) and the control group received a placebo. The COPD Assessment Test (CAT), St George's Respiratory Questionnaire (SGRQ), and lung function test were used before and after.

RESULTS: Seventy-six patients, 88.6% male and 55.7% under 60 years of age, completed the course of treatment. At the end of the study, the overall score of the CAT questionnaire was significantly different between the first and fourth week (P=0.029). Meanwhile the findings of SGRQ questionnaire were significantly different between the interventional and control groups at other times (P=0.001). FEV1 and FEV1/FVC were found to be significantly different between two groups in weeks 4 and 8 (P <0.05). At the end of the study, no side effects of CHS were reported.

CONCLUSION: Based on the data presented herein, CHS could be effective as a complementary and safe drug in increasing the quality of life of with COPD.

PMID:37025308 | PMC:PMC10073945

Front Cell Dev Biol. 2023 Mar 21;11:1124874. doi: 10.3389/fcell.2023.1124874. eCollection 2023.

ABSTRACT

All cells employ signal transduction pathways to respond to physiologically relevant extracellular cytokines, stressors, nutrient levels, hormones, morphogens, and other stimuli that vary in concentration and rate in healthy and diseased states. A central unsolved fundamental question in cell signaling is whether and how cells sense and integrate information conveyed by changes in the rate of extracellular stimuli concentrations, in addition to the absolute difference in concentration. We propose that different environmental changes over time influence cell behavior in addition to different signaling molecules or different genetic backgrounds. However, most current biomedical research focuses on acute environmental changes and does not consider how cells respond to environments that change slowly over time. As an example of such environmental change, we review cell sensitivity to environmental rate changes, including the novel mechanism of rate threshold. A rate threshold is defined as a threshold in the rate of change in the environment in which a rate value below the threshold does not activate signaling and a rate value above the threshold leads to signal activation. We reviewed p38/Hog1 osmotic stress signaling in yeast, chemotaxis and stress response in bacteria, cyclic adenosine monophosphate signaling in Amoebae, growth factors signaling in mammalian cells, morphogen dynamics during development, temporal dynamics of glucose and insulin signaling, and spatio-temproral stressors in the kidney. These reviewed examples from the literature indicate that rate thresholds are widespread and an underappreciated fundamental property of cell signaling. Finally, by studying cells in non-linear environments, we outline future directions to understand cell physiology better in normal and pathophysiological conditions.

PMID:37025183 | PMC:PMC10072286 | DOI:10.3389/fcell.2023.1124874

Front Plant Sci. 2023 Mar 21;14:1139106. doi: 10.3389/fpls.2023.1139106. eCollection 2023.

ABSTRACT

Holliday junction (HJ) is a four-way structured DNA intermediate in homologous recombination. In bacteria, the HJ-specific binding protein RuvA and the motor protein RuvB together form the RuvAB complex to catalyze HJ branch migration. Pseudomonas aeruginosa (P. aeruginosa, Pa) is a ubiquitous opportunistic bacterial pathogen that can cause serious infection in a variety of host species, including vertebrate animals, insects and plants. Here, we describe the cryo-Electron Microscopy (cryo-EM) structure of the RuvAB-HJ intermediate complex from P. aeruginosa. The structure shows that two RuvA tetramers sandwich HJ at the junction center and disrupt base pairs at the branch points of RuvB-free HJ arms. Eight RuvB subunits are recruited by the RuvA octameric core and form two open-rings to encircle two opposite HJ arms. Each RuvB subunit individually binds a RuvA domain III. The four RuvB subunits within the ring display distinct subdomain conformations, and two of them engage the central DNA duplex at both strands with their C-terminal β-hairpins. Together with the biochemical analyses, our structure implicates a potential mechanism of RuvB motor assembly onto HJ DNA.

PMID:37025142 | PMC:PMC10071043 | DOI:10.3389/fpls.2023.1139106

Front Plant Sci. 2023 Mar 21;14:1158933. doi: 10.3389/fpls.2023.1158933. eCollection 2023.

ABSTRACT

Plants play a crucial role in supplying food globally. Various environmental factors lead to plant diseases which results in significant production losses. However, manual detection of plant diseases is a time-consuming and error-prone process. It can be an unreliable method of identifying and preventing the spread of plant diseases. Adopting advanced technologies such as Machine Learning (ML) and Deep Learning (DL) can help to overcome these challenges by enabling early identification of plant diseases. In this paper, the recent advancements in the use of ML and DL techniques for the identification of plant diseases are explored. The research focuses on publications between 2015 and 2022, and the experiments discussed in this study demonstrate the effectiveness of using these techniques in improving the accuracy and efficiency of plant disease detection. This study also addresses the challenges and limitations associated with using ML and DL for plant disease identification, such as issues with data availability, imaging quality, and the differentiation between healthy and diseased plants. The research provides valuable insights for plant disease detection researchers, practitioners, and industry professionals by offering solutions to these challenges and limitations, providing a comprehensive understanding of the current state of research in this field, highlighting the benefits and limitations of these methods, and proposing potential solutions to overcome the challenges of their implementation.

PMID:37025141 | PMC:PMC10070872 | DOI:10.3389/fpls.2023.1158933

Front Genet. 2023 Apr 6;14:1029758. doi: 10.3389/fgene.2023.1029758. eCollection 2023.

ABSTRACT

Single-cell sequencing has become one of the most used techniques across the wide field of biology. It has enabled researchers to investigate the whole transcriptome at the cellular level across tissues, which unlocks numerous potentials for basic and applied studies in future diagnosis and therapy. Here, we review the impact of single-cell RNA sequencing, as the prominent single-cell technique, in pancreatic biology and cancer. We discuss the most recent findings about pancreatic physiology and pathophysiology owing to this technological advancement in the past few years. Using single-cell RNA sequencing, researchers have been able to discover cellular heterogeneity across healthy cell types, as well as cancer tissues of the pancreas. We will discuss the new immunological targets and new molecular mechanisms of progression in the microenvironment of pancreatic cancer studied using single-cell RNA sequencing. The scope is not limited to cancer tissues, and we cover novel developmental, evolutionary, physiological, and heterogenic insights that have also been achieved recently for pancreatic tissues. We cover all biological insights derived from the single-cell RNA sequencing data, discuss the corresponding pros and cons, and finally, conclude how future research can move better by utilizing single-cell analysis for pancreatic biology.

PMID:37091793 | PMC:PMC10115972 | DOI:10.3389/fgene.2023.1029758

Nat Cell Biol. 2023 Apr 6. doi: 10.1038/s41556-023-01114-y. Online ahead of print.

ABSTRACT

DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape's molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation.

PMID:37024684 | DOI:10.1038/s41556-023-01114-y

Nat Methods. 2023 Apr 6. doi: 10.1038/s41592-023-01831-0. Online ahead of print.

ABSTRACT

The discovery of biomolecular condensates transformed our understanding of intracellular compartmentalization of molecules. To integrate interdisciplinary scientific knowledge about the function and composition of biomolecular condensates, we developed the crowdsourcing condensate database and encyclopedia ( cd-code.org ). CD-CODE is a community-editable platform, which includes a database of biomolecular condensates based on the literature, an encyclopedia of relevant scientific terms and a crowdsourcing web application. Our platform will accelerate the discovery and validation of biomolecular condensates, and facilitate efforts to understand their role in disease and as therapeutic targets.

PMID:37024650 | DOI:10.1038/s41592-023-01831-0

Nat Methods. 2023 Apr 6. doi: 10.1038/s41592-023-01832-z. Online ahead of print.

ABSTRACT

Major computational challenges exist in relation to the collection, curation, processing and analysis of large genomic and imaging datasets, as well as the simulation of larger and more realistic models in systems biology. Here we discuss how a relative newcomer among programming languages-Julia-is poised to meet the current and emerging demands in the computational biosciences and beyond. Speed, flexibility, a thriving package ecosystem and readability are major factors that make high-performance computing and data analysis available to an unprecedented degree. We highlight how Julia's design is already enabling new ways of analyzing biological data and systems, and we provide a list of resources that can facilitate the transition into Julian computing.

PMID:37024649 | DOI:10.1038/s41592-023-01832-z

Nat Genet. 2023 Apr 6. doi: 10.1038/s41588-023-01366-2. Online ahead of print.

ABSTRACT

Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.

PMID:37024583 | DOI:10.1038/s41588-023-01366-2

Nat Genet. 2023 Apr 6. doi: 10.1038/s41588-023-01355-5. Online ahead of print.

ABSTRACT

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.

PMID:37024582 | DOI:10.1038/s41588-023-01355-5