Eur J Hum Genet. 2024 Mar 4. doi: 10.1038/s41431-024-01566-2. Online ahead of print.

NO ABSTRACT

PMID:38433264 | DOI:10.1038/s41431-024-01566-2

Inflamm Res. 2024 Mar 3. doi: 10.1007/s00011-024-01857-w. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) were vulnerable to venous thromboembolism (VTE), which further increases the risk of unfavorable outcomes. However, neither genetic correlations nor shared genes underlying COVID-19 and VTE are well understood.

OBJECTIVE: This study aimed to characterize genetic correlations and common pathogenic mechanisms between COVID-19 and VTE.

METHODS: We used linkage disequilibrium score (LDSC) regression and Mendelian Randomization (MR) analysis to investigate the genetic associations and causal effects between COVID-19 and VTE, respectively. Then, the COVID-19 and VTE-related datasets were obtained from the Gene Expression Omnibus (GEO) database and analyzed by bioinformatics and systems biology approaches with R software, including weighted gene co-expression network analysis (WGCNA), enrichment analysis, and single-cell transcriptome sequencing analysis. The miRNA-genes and transcription factor (TF)-genes interaction networks were conducted by NetworkAnalyst. We performed the secondary analysis of the ATAC-seq and Chip-seq datasets to address the epigenetic-regulating relationship of the shared genes.

RESULTS: This study demonstrated positive correlations between VTE and COVID-19 by LDSC and bidirectional MR analysis. A total of 26 potential shared genes were discovered from the COVID-19 dataset (GSE196822) and the VTE dataset (GSE19151), with 19 genes showing positive associations and 7 genes exhibiting negative associations with these diseases. After incorporating two additional datasets, GSE164805 (COVID-19) and GSE48000 (VTE), two hub genes TP53I3 and SLPI were identified and showed up-regulation and diagnostic capabilities in both illnesses. Furthermore, this study illustrated the landscapes of immune processes in COVID-19 and VTE, revealing the downregulation in effector memory CD8+ T cells and activated B cells. The single-cell sequencing analysis suggested that the hub genes were predominantly expressed in the monocytes of COVID-19 patients at high levels. Additionally, we identified common regulators of hub genes, including five miRNAs (miR-1-3p, miR-203a-3p, miR-210-3p, miR-603, and miR-124-3p) and one transcription factor (RELA).

CONCLUSIONS: Collectively, our results highlighted the significant correlations between COVID-19 and VTE and pinpointed TP53I3 and SLPI as hub genes that potentially link the severity of both conditions. The hub genes and their common regulators might present an opportunity for the simultaneous treatment of these two diseases.

PMID:38433131 | DOI:10.1007/s00011-024-01857-w

J Toxicol Sci. 2024;49(3):105-115. doi: 10.2131/jts.49.105.

ABSTRACT

With the advancement of large-scale omics technologies, particularly transcriptomics data sets on drug and treatment response repositories available in public domain, toxicogenomics has emerged as a key field in safety pharmacology and chemical risk assessment. Traditional statistics-based bioinformatics analysis poses challenges in its application across multidimensional toxicogenomic data, including administration time, dosage, and gene expression levels. Motivated by the visual inspection workflow of field experts to augment their efficiency of screening significant genes to derive meaningful insights, together with the ability of deep neural architectures to learn the image signals, we developed DTox, a deep neural network-based in visio approach. Using the Percellome toxicogenomics database, instead of utilizing the numerical gene expression values of the transcripts (gene probes of the microarray) for dose-time combinations, DTox learned the image representation of 3D surface plots of distinct time and dosage data points to train the classifier on the experts' labels of gene probe significance. DTox outperformed statistical threshold-based bioinformatics and machine learning approaches based on numerical expression values. This result shows the ability of image-driven neural networks to overcome the limitations of classical numeric value-based approaches. Further, by augmenting the model with explainability modules, our study showed the potential to reveal the visual analysis process of human experts in toxicogenomics through the model weights. While the current work demonstrates the application of the DTox model in toxicogenomic studies, it can be further generalized as an in visio approach for multi-dimensional numeric data with applications in various fields in medical data sciences.

PMID:38432953 | DOI:10.2131/jts.49.105

Food Chem. 2024 Mar 1;446:138884. doi: 10.1016/j.foodchem.2024.138884. Online ahead of print.

ABSTRACT

Arabica coffee contains the bitter-tasting diterpene glycoside mozambioside, which degrades during coffee roasting, leading to yet unknown structurally related degradation products with possibly similar bitter-receptor-activating properties. The study aimed at the generation, isolation, and structure elucidation of individual pyrolysis products of mozambioside and characterization of bitter receptor activation by in vitro analysis in HEK 293T-Gα16gust44 cells. The new compounds 17-O-β-d-glucosyl-11-hydroxycafestol-2-on, 11-O-β-d-glucosyl-16-desoxycafestol-2-on, 11-O-β-d-glucosyl-(S)-16-desoxy-17-oxocafestol-2-on, 11-O-β-d-glucosyl-15,16-dehydrocafestol-2-on, and 11-O-β-d-glucosyl-(R)-16-desoxy-17-oxocafestol-2-on were isolated from pyrolyzed mozambioside by HPLC and identified by NMR and UHPLC-ToF-MS. Roasting products 11-O-β-d-glucosyl-(S)-16-desoxy-17-oxocafestol-2-on, 11-O-β-d-glucosyl-15,16-dehydrocafestol-2-on, and 11-O-β-d-glucosyl-(R)-16-desoxy-17-oxocafestol-2-on had lower bitter receptor activation thresholds compared to mozambioside. Molecular docking simulations revealed the binding modes of the compounds 11-O-β-d-glucosyl-15,16-dehydrocafestol-2-on and 11-O-β-d-glucosyl-(R)-16-desoxy-17-oxocafestol-2-on and their aglycone 11-hydroxycafestol-2-on in the two cognate receptors TAS2R43 and TAS2R46. The newly discovered roasting products 17-O-β-d-glucosyl-11-hydroxycafestol-2-on, 11-O-β-d-glucosyl-(S)-16-desoxy-17-oxocafestol-2-on, 11-O-β-d-glucosyl-15,16-dehydrocafestol-2-on, and 11-O-β-d-glucosyl-(R)-16-desoxy-17-oxocafestol-2-on were detected in authentic roast coffee brew by UHPLC-ToF-MS and could contribute to coffee's bitter taste impression.

PMID:38432139 | DOI:10.1016/j.foodchem.2024.138884

NPJ Syst Biol Appl. 2024 Mar 2;10(1):23. doi: 10.1038/s41540-024-00349-1.

ABSTRACT

Skin cancer and other skin-related inflammatory pathologies are rising due to heightened exposure to environmental pollutants and carcinogens. In this context, natural products and repurposed compounds hold promise as novel therapeutic and preventive agents. Strengthening the skin's antioxidant defense mechanisms is pivotal in neutralizing reactive oxygen species (ROS) and mitigating oxidative stress. Sunset Yellow (SY) exhibits immunomodulatory characteristics, evidenced by its capacity to partially inhibit the secretion of proinflammatory cytokines, regulate immune cell populations, and modulate the activation of lymphocytes. This study aimed to investigate the antioxidant and anti-genotoxic properties of SY using in-silico, in vitro, and physiochemical test systems, and to further explore its potential role in 7,12-dimethylbenz(a) anthracene (DMBA)/ 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis. In vitro experiments showed that pre-treatment of SY significantly enhanced the cell viability of HaCaT cells when exposed to tertiary-Butyl Hydrogen Peroxide (tBHP). This increase was accompanied by reduced ROS levels, restoration of mitochondrial membrane potential, and notable reduction in DNA damage in (SY + tBHP) treated cells. Mechanistic investigations using DPPH chemical antioxidant activity test and potentiometric titrations confirmed SY's antioxidant properties, with a standard reduction potential ( E o ) of 0.211 V. Remarkably, evaluating the effect of topical application of SY in DMBA/TPA-induced two-step skin carcinogenesis model revealed dose-dependent decreases in tumor latency, incidence, yield, and burden over 21-weeks. Furthermore, computational analysis and experimental validations identified GSK3β, KEAP1 and EGFR as putative molecular targets of SY. Collectively, our findings reveal that SY enhances cellular antioxidant defenses, exhibits anti-genotoxic effects, and functions as a promising chemopreventive agent.

PMID:38431714 | DOI:10.1038/s41540-024-00349-1

Chest. 2024 Feb 29:S0012-3692(24)00282-4. doi: 10.1016/j.chest.2024.02.044. Online ahead of print.

ABSTRACT

BACKGROUND: Corticosteroids have demonstrated their beneficial effects in improving outcomes in hospitalized patients with severe COVID-19 by suppressing excessive immune responses. However, the effect of corticosteroids on the humoral and T cell responses of COVID-19 survivors one year after infection remains uncertain, as it relates to the extent of immediate, antigen-specific defense provided by protective memory.

RESEARCH QUESTION: What's the effect of corticosteroids on long-term humoral and T cell immune responses?

STUDY DESIGN AND METHODS: In this retrospective cohort study conducted at a single center, we analyzed data from a post-COVID cohort to compare the one-year seropositivity and titers change of neutralizing antibodies (NAbs) and SARS-CoV-2 specific antibodies. Additionally, we evaluated the magnitude and rate of SARS-CoV-2 specific T cell response in individuals who had received corticosteroids during hospitalization and those who did not.

RESULTS: Our findings indicate that corticosteroids do not statistically influence the kinetics or seropositive rate of NAbs against the Wuhan strain from half year to one year. However, subgroup analysis reveals a numerical increase of absolute NAbs titres, from 20.0 to 28.2, in categories where long-term (>15 days) and high dosage (>560 mg) corticosteroids are administered. Similarly, corticosteroids show no significant effect on N and RBD-IgG at one year, except for S-IgG (β 0.08, 95% CI 0.04-0.12), which demonstrate a delayed decline of titres. Regarding T cell immunity, corticosteroids do not significantly affect the rate and magnitude of T cell responses either. However, functional assessment of memory T cells reveals higher interferon-γ (IFNγ) responses in CD4 (β 0.61, 95% CI 0.10-1.12) and CD8 (β 0.63, 95% CI 0.11-1.15) memory T cells in the corticosteroids group at one year.

INTERPRETATION: Based on our findings, short-term and low-dose corticosteroid therapy during hospitalization does not have a significant effect on long-term humoral kinetics, as well as the magnitude and rate of memory T cell responses to SARS-CoV-2 antigens. However, the potential harmful effects of long-term and high-dose corticosteroid usage on memory immune responses require further investigation.

PMID:38431050 | DOI:10.1016/j.chest.2024.02.044

Biosystems. 2024 Feb 29:105165. doi: 10.1016/j.biosystems.2024.105165. Online ahead of print.

ABSTRACT

Abiotic stresses are predominant and main causes of the losses in the crop yield. A complexity of systems biology and involvement of numerous genes in the response to abiotic factors have challenged efforts to create tolerant cultivars with sustainable production. The root is the main organ of the plant and determines a plant tolerance under stressful conditions. In this study, we carried out a meta-analysis of expression datasets from wheat root to identify differentially expressed genes, followed by the weighted gene co-expression network analysis (WGCNA) to construct the weighted gene co-expression network. The aim was to identify consensus differentially expressed genes with regulatory functions, gene networks, and biological pathways involved in response of wheat root to a set of abiotic stresses. The meta-analysis using Fisher method (FDR<0.05) identified consensus 526 DEGs from 55,367 probe sets. Although the annotated expression data are limited for wheat, the functional analysis based on the data from model plants could identify the up-regulated seven regulatory genes involved in chromosome organization and response to oxygen-containing compounds. WGCNA identified four gene modules that were mostly associated with the ribosome biogenesis and polypeptide synthesis. This study's findings enhance our understanding of key players and gene networks related to wheat root response to multiple abiotic stresses.

PMID:38430956 | DOI:10.1016/j.biosystems.2024.105165

Structure. 2024 Feb 28:S0969-2126(24)00042-X. doi: 10.1016/j.str.2024.02.003. Online ahead of print.

ABSTRACT

Dyneins are an AAA+ motor responsible for motility and force generation toward the minus end of microtubules. Dynein motility is powered by nucleotide-dependent transitions of its linker domain, which transitions between straight (post-powerstroke) and bent (pre-powerstroke) conformations. To understand the dynamics and energetics of the linker, we performed all-atom molecular dynamics simulations of human dynein-2 primed for its power stroke. Simulations revealed that the linker can adopt either a bent conformation or a semi-bent conformation, separated by a 5.7 kT energy barrier. The linker cannot switch back to its straight conformation in the pre-powerstroke state due to a steric clash with the AAA+ ring. Simulations also showed that an isolated linker has a free energy minimum near the semi-bent conformation in the absence of the AAA+ ring, indicating that the linker stores energy as it bends and releases this energy during the powerstroke.

PMID:38430911 | DOI:10.1016/j.str.2024.02.003

Theor Appl Genet. 2024 Mar 2;137(3):65. doi: 10.1007/s00122-024-04569-1.

ABSTRACT

Using associative transcriptomics, our study identifies genes conferring resistance to four diverse fungal pathogens in crops, emphasizing key genetic determinants of multi-pathogen resistance. Crops are affected by several pathogens, but these are rarely studied in parallel to identify common and unique genetic factors controlling diseases. Broad-spectrum quantitative disease resistance (QDR) is desirable for crop breeding as it confers resistance to several pathogen species. Here, we use associative transcriptomics (AT) to identify candidate gene loci associated with Brassica napus constitutive QDR to four contrasting fungal pathogens: Alternaria brassicicola, Botrytis cinerea, Pyrenopeziza brassicae, and Verticillium longisporum. We did not identify any shared loci associated with broad-spectrum QDR to fungal pathogens with contrasting lifestyles. Instead, we observed QDR dependent on the lifestyle of the pathogen-hemibiotrophic and necrotrophic pathogens had distinct QDR responses and associated loci, including some loci associated with early immunity. Furthermore, we identify a genomic deletion associated with resistance to V. longisporum and potentially broad-spectrum QDR. This is the first time AT has been used for several pathosystems simultaneously to identify host genetic loci involved in broad-spectrum QDR. We highlight constitutive expressed candidate loci for broad-spectrum QDR with no antagonistic effects on susceptibility to the other pathogens studies as candidates for crop breeding. In conclusion, this study represents an advancement in our understanding of broad-spectrum QDR in B. napus and is a significant resource for the scientific community.

PMID:38430276 | DOI:10.1007/s00122-024-04569-1

Bioinformatics. 2024 Mar 1:btae123. doi: 10.1093/bioinformatics/btae123. Online ahead of print.

ABSTRACT

MOTIVATION: Promoters with desirable properties are crucial in biotechnological applications. Generative AI (GenAI) has demonstrated potential in creating novel synthetic promoters with significantly enhanced functionality. However, these methods' reliance on various programming frameworks and specific task-oriented contexts limits their flexibilities. Overcoming these limitations is essential for researchers to fully leverage the power of GenAI to design promoters for their tasks.

RESULTS: Here, we introduce GPro (Generative AI-empowered toolkit for promoter design), a user-friendly toolkit that integrates a collection of cutting-edge GenAI-empowered approaches for promoter design. This toolkit provides a standardized pipeline covering essential promoter design processes, including training, optimization, and evaluation. Several detailed demos are provided to reproduce state-of-the-art promoter design pipelines. GPro's user-friendly interface makes it accessible to a wide range of users including non-AI experts. It also offers a variety of optional algorithms for each design process, and gives users the flexibility to compare methods and create customized pipelines.

AVAILABILITY: GPro is released as an open-source software under the MIT license. The source code for GPro is available on GitHub for Linux, macOS, and Windows: https://github.com/WangLabTHU/GPro, and is available for download via Zenodo repository at https://zenodo.org/doi/10.5281/zenodo.10681733.

PMID:38429953 | DOI:10.1093/bioinformatics/btae123

Chin Med. 2024 Mar 1;19(1):36. doi: 10.1186/s13020-024-00896-z.

ABSTRACT

BACKGROUND: Liver cirrhosis is a chronic liver disease with hepatocyte necrosis and lesion. As one of the TCM formulas Wuling Powder (WLP) is widely used in the treatment of liver cirrhosis. However, it's key functional components and action mechanism still remain unclear. We attempted to explore the Key Group of Effective Components (KGEC) of WLP in the treatment of Liver cirrhosis through integrative pharmacology combined with experiments.

METHODS: The components and potential target genes of WLP were extracted from published databases. A novel node importance calculation model considering both node control force and node bridging force is designed to construct the Function Response Space (FRS) and obtain key effector proteins. The genetic knapsack algorithm was employed to select KGEC. The effectiveness and reliability of KGEC were evaluated at the functional level by using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the effectiveness and potential mechanism of KGEC were confirmed by CCK-8, qPCR and Western blot.

RESULTS: 940 effective proteins were obtained in FRS. KEGG pathways and GO terms enrichments analysis suggested that effective proteins well reflect liver cirrhosis characteristics at the functional level. 29 components of WLP were defined as KGEC, which covered 100% of the targets of the effective proteins. Additionally, the pathways enriched for the KGEC targets accounted for 83.33% of the shared genes between the targets and the pathogenic genes enrichment pathways. Three components scopoletin, caryophyllene oxide, and hydroxyzinamic acid from KGEC were selected for in vivo verification. The qPCR results demonstrated that all three components significantly reduced the mRNA levels of COL1A1 in TGF-β1-induced liver cirrhosis model. Furthermore, the Western blot assay indicated that these components acted synergistically to target the NF-κB, AMPK/p38, cAMP, and PI3K/AKT pathways, thus inhibiting the progression of liver cirrhosis.

CONCLUSION: In summary, we have developed a new model that reveals the key components and potential mechanisms of WLP for the treatment of liver cirrhosis. This model provides a reference for the secondary development of WLP and offers a methodological strategy for studying TCM formulas.

PMID:38429802 | DOI:10.1186/s13020-024-00896-z

Nutr J. 2024 Mar 2;23(1):28. doi: 10.1186/s12937-024-00928-2.

ABSTRACT

BACKGROUND: The relationship between circulating bile acids (BAs) and kidney function among patients with type 2 diabetes is unclear. We aimed to investigate the associations of circulating concentrations of BAs, particularly individual BA subtypes, with chronic kidney disease (CKD) in patients of newly diagnosed type 2 diabetes.

METHODS: In this cross-sectional study, we included 1234 newly diagnosed type 2 diabetes who participated in an ongoing prospective study, the Dongfeng-Tongji cohort. Circulating primary and secondary unconjugated BAs and their taurine- or glycine-conjugates were measured using ultraperformance liquid chromatography-tandem mass spectrometry. CKD was defined as eGFR < 60 ml/min per 1.73 m2. Logistic regression model was used to compute odds ratio (OR) and 95% confidence interval (CI).

RESULTS: After adjusting for multiple testing, higher levels of total primary BAs (OR per standard deviation [SD] increment: 0.78; 95% CI: 0.65-0.92), cholate (OR per SD: 0.78; 95% CI: 0.66-0.92), chenodeoxycholate (OR per SD: 0.81; 95% CI: 0.69-0.96), glycocholate (OR per SD: 0.81; 95% CI: 0.68-0.96), and glycochenodeoxycholate (OR per SD: 0.82; 95% CI: 0.69-0.97) were associated with a lower likelihood of having CKD in patients with newly diagnosed type 2 diabetes. No significant relationships between secondary BAs and odds of CKD were observed.

CONCLUSIONS: Our findings showed that higher concentrations of circulating unconjugated primary BAs and their glycine-conjugates, but not taurine-conjugates or secondary BAs, were associated with lower odds of having CKD in patients with type 2 diabetes.

PMID:38429722 | DOI:10.1186/s12937-024-00928-2

Nat Commun. 2024 Mar 1;15(1):1897. doi: 10.1038/s41467-024-46273-0.

ABSTRACT

Kidney filtration is ensured by the interaction of podocytes, endothelial and mesangial cells. Immunoglobulin accumulation at the filtration barrier is pathognomonic for glomerular injury. The mechanisms that regulate filter permeability are unknown. Here, we identify a pivotal role for the proteasome in a specific cell type. Combining genetic and inhibitor-based human, pig, mouse, and Drosophila models we demonstrate that the proteasome maintains filtration barrier integrity, with podocytes requiring the constitutive and glomerular endothelial cells the immunoproteasomal activity. Endothelial immunoproteasome deficiency as well as proteasome inhibition disrupt the filtration barrier in mice, resulting in pathologic immunoglobulin deposition. Mechanistically, we observe reduced endocytic activity, which leads to altered membrane recycling and endocytic receptor turnover. This work expands the concept of the (immuno)proteasome as a control protease orchestrating protein degradation and antigen presentation and endocytosis, providing new therapeutic targets to treat disease-associated glomerular protein accumulations.

PMID:38429282 | DOI:10.1038/s41467-024-46273-0

Cell. 2024 Feb 29;187(5):1206-1222.e16. doi: 10.1016/j.cell.2024.01.039.

ABSTRACT

Plasmids are extrachromosomal genetic elements that often encode fitness-enhancing features. However, many bacteria carry "cryptic" plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes and is 14 times as numerous as crAssphage, currently established as the most abundant extrachromosomal genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one's mother. pBI143 can transfer between Bacteroidales, and although it does not appear to impact bacterial host fitness in vivo, it can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an alternative approach to track human colonic inflammatory states.

PMID:38428395 | DOI:10.1016/j.cell.2024.01.039

Food Chem. 2024 Feb 28;446:138852. doi: 10.1016/j.foodchem.2024.138852. Online ahead of print.

ABSTRACT

Foodomics has become a popular methodology in food science studies. Mass spectrometry (MS) based metabolomics and proteomics analysis played indispensable roles in foodomics research. So far, several methodologies have been developed to detect the metabolites and proteins in diets and consumers, including sample preparation, MS data acquisition, annotation and interpretation. Moreover, multiomics analysis integrated metabolomics and proteomics have received considerable attentions in the field of food safety and nutrition, because of more comprehensive and deeply. In this context, we intended to review the emerging strategies and their applications in MS-based foodomics, as well as future challenges and trends. The principle and application of multiomics were also discussed, such as the optimization of data acquisition, development of analysis algorithm and exploration of systems biology.

PMID:38428078 | DOI:10.1016/j.foodchem.2024.138852

Phys Rev Lett. 2024 Feb 16;132(7):078401. doi: 10.1103/PhysRevLett.132.078401.

ABSTRACT

Coordinated cellular movements are key processes in tissue morphogenesis. Using a cell-based modeling approach we study the dynamics of epithelial layers lining surfaces with constant and varying curvature. We demonstrate that extrinsic curvature effects can explain the alignment of cell elongation with the principal directions of curvature. Together with specific self-propulsion mechanisms and cell-cell interactions this effect gets enhanced and can explain observed large-scale, persistent, and circumferential rotation on cylindrical surfaces. On toroidal surfaces the resulting curvature coupling is an interplay of intrinsic and extrinsic curvature effects. These findings unveil the role of curvature and postulate its importance for tissue morphogenesis.

PMID:38427891 | DOI:10.1103/PhysRevLett.132.078401

Proc Natl Acad Sci U S A. 2024 Mar 5;121(10):e2319491121. doi: 10.1073/pnas.2319491121. Epub 2024 Mar 1.

ABSTRACT

Translocation of cytoplasmic molecules to the plasma membrane is commonplace in cell signaling. Membrane localization has been hypothesized to increase intermolecular association rates; however, it has also been argued that association should be faster in the cytosol because membrane diffusion is slow. Here, we directly compare an identical association reaction, the binding of complementary DNA strands, in solution and on supported membranes. The measured rate constants show that for a 10-µm-radius spherical cell, association is 22- to 33-fold faster at the membrane than in the cytoplasm. The kinetic advantage depends on cell size and is essentially negligible for typical ~1 µm prokaryotic cells. The rate enhancement is attributable to a combination of higher encounter rates in two dimensions and a higher reaction probability per encounter.

PMID:38427601 | DOI:10.1073/pnas.2319491121

Blood. 2024 Mar 1:blood.2023022343. doi: 10.1182/blood.2023022343. Online ahead of print.

ABSTRACT

Allogeneic stem cell transplantation (alloSCT) is a curative treatment for hematological malignancies. After HLA-matched alloSCT, anti-tumor immunity is caused by donor T cells recognizing polymorphic peptides, designated minor histocompatibility antigens (MiHAs), that are presented by HLA on malignant patient cells. However, T cells often target MiHAs on healthy non-hematopoietic tissues of patients, thereby inducing side effects known as Graft-versus-Host Disease. Here, we aimed to identify the dominant repertoire of HLA-I-restricted MiHAs to enable strategies to predict, monitor or modulate immune responses after alloSCT. To systematically identify novel MiHAs by genome-wide association screening, T-cell clones were isolated from 39 transplanted patients and tested for reactivity against 191 EBV-B cell lines of the 1000 Genomes Project. By discovering 81 new MiHAs, we more than doubled the antigen repertoire to 159 MiHAs and demonstrated that, despite many genetic differences between patients and donors, often the same MiHAs are targeted in multiple patients. Furthermore, we showed that one quarter of the antigens are cryptic, i.e. translated from unconventional open reading frames, for example long non-coding RNAs, showing that these antigen types are relevant targets in natural immune responses. Finally, using single cell RNA-seq data, we analyzed tissue expression of MiHA-encoding genes to explore their potential role in clinical outcome, and characterized 11 new hematopoietic-restricted MiHAs as potential targets for immunotherapy. In conclusion, we expanded the repertoire of HLA-I-restricted MiHAs and identified recurrent, cryptic and hematopoietic-restricted antigens, which are fundamental to predict, follow or manipulate immune responses to improve clinical outcome after alloSCT.

PMID:38427583 | DOI:10.1182/blood.2023022343

STAR Protoc. 2024 Feb 29;5(1):102912. doi: 10.1016/j.xpro.2024.102912. Online ahead of print.

ABSTRACT

Seasonality in laboratory healthcare data is associated with possible under- and overdiagnoses of patients in the clinic. Here, we present a protocol to analyze electronic health record data for seasonality patterns and adjust existing reference intervals for these changes using R software. We describe steps for preprocessing population-wide patient laboratory data into a single dataset. We then detail steps for defining strata, normalizing to median, and fitting data to selected functions. For complete details on the use and execution of this protocol, please refer to Muse et al. (2023).1.

PMID:38427569 | DOI:10.1016/j.xpro.2024.102912

Cell Rep. 2024 Feb 29;43(3):113872. doi: 10.1016/j.celrep.2024.113872. Online ahead of print.

ABSTRACT

Infection, autoimmunity, and cancer are principal human health challenges of the 21st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (TRM) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation and increased humoral immunity and that they resemble TRM cells. Our results suggest NKG2A+ biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer.

PMID:38427562 | DOI:10.1016/j.celrep.2024.113872