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At least 613 records · Page 34Linked to original sources
PubMed2020

Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274.

BACKGROUND: Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA. METHODS: Untargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes. RESULTS: Elevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were DGKA, MBOAT2, PLPP1, and LPL. The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p. CONCLUSIONS: A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.

Chromosomes, Human, Pair 9↗
PubMed2026

Evaluation of the clinical and mechanistic role of MCM2 expression in the prediction of meningioma recurrence after radiotherapy.

OBJECTIVE: Postoperative radiotherapy is an effective treatment for meningiomas; however, treatment response varies among patients. In addition, practical methods for predicting tumor recurrence after radiotherapy have not been well established. Minichromosome maintenance protein 2 (MCM2), a key regulator of DNA replication licensing, was recently implicated in highly proliferative molecular subtypes of meningioma. In this study, the authors evaluated whether MCM2 immunohistochemical expression predicts response to radiotherapy in patients with meningiomas. METHODS: The authors retrospectively analyzed the records of patients with WHO grade 1-3 meningiomas treated with resection followed by radiotherapy at a single institution between July 2003 and November 2023. The MCM2 labeling index was assessed immunohistochemically, and patients were stratified into MCM2-high and -low groups using a cutoff of 35%. Progression-free survival (PFS) was defined as the interval from the completion of radiation therapy to postoperative radiological tumor recurrence or regrowth. Patients who showed no progression were censored at their last follow-up. PFS was estimated using Kaplan-Meier analysis and subsequently evaluated with Cox proportional hazards models. To further investigate the biological mechanisms associated with MCM2 expression, comprehensive transcriptomic analyses, including gene set enrichment analysis, was performed to elucidate the molecular processes that occur within MCM2-high tumors. RESULTS: The study population included 15 men (42%) and 21 women (58%), with a mean age of 63 years. Ten tumors (28%) were classified as MCM2-high meningiomas and 26 (72%) as MCM2-low meningiomas. High MCM2 expression was significantly associated with WHO grades 2-3 histology and higher Ki-67 labeling indices. During a median follow-up of 2.52 years, tumor progression after radiotherapy occurred in 47% of the patients. High MCM2 expression (HR 8.34, p = 0.03) was significantly associated with shorter PFS and remained an independent predictor of recurrence after adjustment for WHO grade, tumor size, and Ki-67 labeling index. Transcriptomic analyses of MCM2-high tumors revealed upregulation of cell proliferation-related pathways, accompanied by increased signaling through the E2F8-CHEK1 axis associated with radiation resistance and suppression of the TNF-α signaling pathway implicated in radiosensitivity. CONCLUSIONS: In meningiomas, high MCM2 expression is associated with early recurrence following radiotherapy. The study findings suggest that this association is driven by diverse biological mechanisms related to cell cycle regulation and radioresistance. Immunohistochemical assessment of MCM2 expression may serve as a practical and accessible biomarker for risk stratification and may support the future development of individualized postoperative radiotherapy strategies.

Humans↗
PubMed2026

PLK1/FOXM1-associated tumor-cell state and macrophage-related immune features in endometrial cancer.

BACKGROUND: Polo-like kinase 1 (PLK1) and forkhead box M1 (FOXM1) have been widely studied in various cancers; however, their expression characteristics in endometrial cancer (EC) and their potential association with tumor microenvironment remodeling remain insufficiently characterized. METHODS: This study integrated The Cancer Genome Atlas uterine corpus endometrial carcinoma cohort, Gene Expression Omnibus, pan-cancer transcriptomic data, Human Protein Atlas/Clinical Proteomic Tumor Analysis Consortium, and local immunohistochemistry data to evaluate PLK1 expression and clinicopathological relevance across transcriptomic, proteomic, and histopathological data. Differential expression, survival, gene-set enrichment, transcription-factor enrichment, and immune-infiltration analyses characterized PLK1-associated features. In vitro experiments combined EC cell lines AN3CA and HEC-1A with co-immunoprecipitation, Western blotting, Transwell assays, and a THP-1 conditioned-medium model. Drug-response prediction and structure-based analysis prioritized candidate therapeutic hypotheses. RESULTS: PLK1 was consistently upregulated at both mRNA and protein levels in EC and was associated with higher tumor grade and International Federation of Gynecology and Obstetrics (FIGO) stage. In survival analysis, higher PLK1 expression was associated with poorer overall survival in univariable models but not after adjustment for age, tumor grade, and FIGO stage. Functional enrichment analysis showed that PLK1-associated genes were mainly involved in cell-cycle and mitotic processes. FOXM1 was identified as a potential candidate component of the PLK1-associated transcriptional program and was positively correlated with PLK1 expression and cell-cycle-related features. In vitro experiments supported an interaction between PLK1 and FOXM1 and suggested that FOXM1 Thr600 phosphorylation-related alterations were associated with migration and invasion phenotypes. Furthermore, the PLK1/FOXM1-associated tumor-cell state was linked to macrophage-related immune features and changes in the M2-like marker profile of THP-1-derived macrophage-like cells. Drug response analyses suggested differential predicted sensitivity patterns in PLK1-high tumors, providing candidate therapeutic hypotheses for further validation. CONCLUSION: The PLK1/FOXM1-associated tumor-cell state may represent a distinct molecular feature associated with proliferative activity, invasive phenotypes, and macrophage-related immune features in EC. This study provides preliminary evidence supporting the biological relevance of this molecular feature and highlights potential therapeutic directions for future investigation.

FoxM1↗
PubMed2025

Microbiology Galaxy Lab: The first community-driven gateway for reproducible and FAIR analysis of microbial data.

The explosion of microbial omics data has outpaced the ability of many researchers to analyze it, with complex tools and limited computational resources creating barriers to discovery. To address this gap, we present the Microbiology Galaxy Lab: a free, globally accessible, community-supported platform that combines state-of-the-art analytical power with user-friendly accessibility. Supported by the Galaxy and global microbiology communities, this platform integrates over 315 tool suites and 115 curated workflows, enabling comprehensive metabarcoding, (meta)genomic, (meta)transcriptomic, and (meta)proteomic data analysis within a FAIR-aligned environment. It also supports research in the health and infectious disease sectors, as well as in environmental microbiology. The platform's utility is exemplified through various use cases, including antimicrobial resistance tracking, biomarker prediction, microbiome classification, and functional annotation of key microbes. Built on reproducibility and community engagement, it supports creation, sharing, and updating of best-practice workflows. Over 35 tutorials and learning paths empower scientists, fostering an ecosystem that keeps resources at the forefront of microbial science. The Microbiology Galaxy Lab enables collective analysis, democratising research, thereby accelerating discovery across the global microbiology community (microbiology.usegalaxy.org, .eu, .org.au, .fr).

Journal Article↗
PubMed2026

A GWAS-derived histone H4 variant linked to ear row number reveals functional insights into the maize ZmHistone gene family.

Ear row number (ERN) is a major yield determinant in maize and a key target for breeding of high-yielding varieties. This study utilized a multi-parent population (MPP) of 780 recombinant inbred lines (RILs) derived from seven inbred lines across three environments. Genotyping-by-sequencing (GBS) of the MPP yielded 638,646 high-quality SNPs. Using genome-wide association study (GWAS), we detected 80 significant SNPs including S2-15316355 and S4-224453431, which were consistently detected in all environments and best linear unbiased prediction (BLUP) analysis. A linkage disequilibrium-defined ±20 kb window around these two lead SNPs contained three positional candidate genes: Zm00001eb072840, Zm00001eb072850 and Zm00001eb202890. Zm00001eb072850 (ZmHistone12), a histone H4 variant, was prioritized for hypothesis-driven follow-up because the lead SNP lies within its coding sequence and the gene is expressed in ear-related tissues. Additionally, we identified 91 ZmHistone genes in the maize genome and described their phylogeny, promoter motif and expression patterns. Public transcriptome and qRT-PCR analysis in seven parental lines provide descriptive evidence of Histone variant genes in maize ear development. These results suggest a potential involvement of chromatin-associated regulation of ERN in maize and provide a foundation for future functional validation.

Ear development↗
PubMed2026

Genome-wide epigenomic atlas and multi-omics responses of Eriocheir sinensis to natural extreme heat.

BACKGROUND: Global climate warming has led to increasingly frequent and prolonged extreme summer heat events, posing severe environmental challenges to aquaculture systems. Extreme summer heat can disrupt the performance of pond-cultured ectotherms. The Chinese mitten crab (Eriocheir sinensis) is an economically important freshwater crustacean, but coordinated molecular differences following contrasting natural summers remain incompletely characterized. RESULTS: We performed a comprehensive multi-omics analysis integrating meteorological monitoring, mRNA/lncRNA transcriptomics, small-RNA profiling of miRNAs, DNA methylomics, and LC-MS metabolomics in E. sinensis populations collected from Yancheng, China, between 2020 and 2024. Across the ten farms, survival was significantly lower in 2024, whereas yield and the proportion of large individuals showed nonsignificant downward trends. Gene-set analyses showed negative enrichment of cellular heat-response, protein-folding, oxidative-phosphorylation, and mitochondrial ATP-production terms in the 2024 cohort at the time of sampling. The integrated transcript annotation contained 72,240 lncRNAs and 63,833 mRNAs, and CpG was the predominant methylation context. Differential methylation analysis identified 73 regions and 185 cytosines, with hypomethylated events predominating within the significant subset. Metabolomic profiles differed between annual cohorts and mapped to carbohydrate, lipid, and amino-acid pathways. Cross-omics integration prioritized eight candidate genes-ADCY9, UNC79, UBN1, IFT52, ACO2, LOC126986070, LOC127001126, and LOC126997895-and qPCR reproduced the reported directions of expression for selected RNAs. CONCLUSION: This study provides the first integrative multi-omics framework for understanding chronic heat adaptation in E. sinensis. By linking transcriptomic, epigenomic, and metabolic remodeling, we elucidate the molecular mechanisms underlying energy imbalance, epigenetic reprogramming, and immune dysregulation during prolonged thermal stress. These findings offer valuable insights and genomic resources for breeding heat-tolerant crab strains and improving aquaculture resilience under ongoing climate change.

DNA methylation↗
PubMed2026

Genus-Wide Pan-Genome Analysis of Populus bZIP Transcription Factors with Reanalysis of Public Salt-Stress Transcriptomes.

Basic leucine zipper (bZIP) transcription factors regulate plant development and stress responses, but their genus-wide diversity in Populus remains unclear. We analyzed 19 Populus genomes and retained 1764 bZIP proteins, including 21 independent new loci and four annotation corrections. Of these, 1762 were assigned to 79 orthologous gene groups (OGGs), comprising 43 core, 20 soft-core, 15 shell and one cloud OGG, of which 59 showed copy-number variation. Phylogenetic analysis assigned 74 representative pangenes to 13 subfamilies, with five remaining unclassified and motif patterns differing among subfamilies. Whole-genome duplication (WGD)/segmental duplication accounted for 81.0% of OGG-assigned proteins and contributed predominantly to the conserved component. Although 72.2% of bZIP proteins overlapped a transposable element within the gene body or 2-kb flanks, this proportion was modestly lower than in matched non-bZIP genes, and copy-number-variable OGGs showed no greater TE coverage than invariant OGGs. Among retained homologous comparisons, 97.6% had Ka/Ks ≤ 1, supporting predominant purifying selection. Across the heterogeneous public salt-stress RNA-seq datasets analyzed, no OGG showed a significant, directionally concordant response in at least two Populus taxa. These results reveal a conserved bZIP framework shaped mainly by ancient duplication alongside variable genomic contexts and transcriptional responses.

Populus↗
PubMed2025

LungGENIE: the lung gene-expression and network imputation engine.

BACKGROUND: Few cohorts have study populations large enough to conduct molecular analysis of ex vivo lung tissue for genomic analyses. Transcriptome imputation is a non-invasive alternative with many potential applications. We present a novel transcriptome-imputation method called the Lung Gene Expression and Network Imputation Engine (LungGENIE) that uses principal components from blood gene-expression levels in a linear regression model to predict lung tissue-specific gene-expression. METHODS: We use paired blood and lung RNA sequencing data from the Genotype-Tissue Expression (GTEx) project to train LungGENIE models. We replicate model performance in a unique dataset, where we generated RNA sequencing data from paired lung and blood samples available through the SUNY Upstate Biorepository (SUBR). We further demonstrate proof-of-concept application of LungGENIE models in an independent blood RNA sequencing data from the Genetic Epidemiology of COPD (COPDGene) study. RESULTS: We show that LungGENIE prediction accuracies have higher correlation to measured lung tissue expression compared to existing cis-expression quantitative trait loci-based methods (median Pearson's r = 0.25, IQR 0.19-0.32), with close to half of the reliably predicted transcripts being replicated in the testing dataset. Finally, we demonstrate significant correlation of differential expression results in chronic obstructive pulmonary disease (COPD) from imputed lung tissue gene-expression and differential expression results experimentally determined from lung tissue. CONCLUSION: Our results demonstrate that LungGENIE provides complementary results to existing expression quantitative trait loci-based methods and outperforms direct blood to lung results across internal cross-validation, external replication, and proof-of-concept in an independent dataset. Taken together, we establish LungGENIE as a tool with many potential applications in the study of lung diseases.

Humans↗
PubMed2003

Can transcriptome size be estimated from SAGE catalogs?

MOTIVATION: SAGE (Serial Analysis of Gene Expression) can be used to estimate the number of unique transcripts in a transcriptome. A simple estimator that corrects for sequencing and sampling errors was applied to a SAGE library (137 832 tags) obtained from mouse embryonic stem cells, and also to Monte Carlo simulated libraries generated using assumed distributions of 'true' expression levels consistent with the data. RESULTS: When the corrected data themselves were taken as the underlying model of 'ground truth', the estimator converged to the 'true' value (53 535) only after counting 300 000 simulated tags, more than twice the number in the experiment. The SAGE data could also be well fit by a Monte Carlo model based on a truncated inverse-square distribution of expression levels, with 130 000 'true' transcripts and 10(6) samples needed for convergence. We conclude that the size of a transcriptome is ill-determined from SAGE libraries of even moderately large size. In order to obtain a valid estimate, one must sample a number of tags inversely proportional to the lowest abundance level, which is not known a priori. This constrains the design of SAGE experiments intended to determine biological complexity. AVAILABILITY: The 'homemade' software used for this analysis was not designed for general or 'production' use, but the authors will be happy to share Fortran sourcecode with interested parties. CONTACT: sternm@grc.nia.nih.gov

Algorithms↗
PubMed2002

Temperature-regulated transcription in the pathogenic fungus Cryptococcus neoformans.

The basidiomycete fungus Cryptococcus neoformans is an opportunistic pathogen of worldwide importance that causes meningitis, leading to death in immunocompromised individuals. Unlike many basidiomycete fungi, C. neoformans is thermotolerant, and its ability to grow at 37 degrees C is considered to be a virulence factor. We used serial analysis of gene expression (SAGE) to characterize the transcriptomes of C. neoformans strains that represent two varieties with different polysaccharide capsule serotypes. These include a serotype D strain of the C. neoformans variety neoformans and a serotype A strain of variety grubii. In this report, we describe the construction and characterization of SAGE libraries from each strain grown at 25 degrees C and 37 degrees C. The SAGE data reveal transcriptome differences between the two strains, even at this early stage of analysis, and identify sets of genes with higher transcript levels at 25 degrees C or 37 degrees C. Notably, growth at the lower temperature increased transcript levels for histone genes, indicating a general influence of temperature on chromatin structure. At 37 degrees C, we noted elevated transcript levels for several genes encoding heat shock proteins and translation machinery. Some of these genes may play a role in temperature-regulated phenotypes in C. neoformans, such as the adaptation of the fungus to growth in the host and the dimorphic transition between budding and filamentous growth. Overall, this work provides the most comprehensive gene expression data available for C. neoformans; this information will be a critical resource both for gene discovery and genome annotation in this pathogen.

Blotting, Northern↗
PubMed2026

Advances in the diagnosis and classification of B-ALL: comparative insights from updated guidelines.

Accurate molecular classification is essential for diagnosis, risk stratification, and treatment selection in B-cell lymphoblastic leukemia (B-ALL). In this study, we performed a comprehensive, real-world reclassification of 1015 consecutively diagnosed B-ALL patients using the fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) and the International Consensus Classification (ICC). An integrative genomic strategy that combined whole transcriptome sequencing, fusion detection, mutational analysis, and cytogenetics enabled reclassification according to both the WHO-HAEM5 and ICC frameworks, thereby substantially reducing the proportion of unclassifiable B-ALL from 41.9% (2016 WHO revision [WHO-HAEM4R]) to 15.9% (WHO-HAEM5) and 11.9% (ICC). Distinct clinical and prognostic features were identified across newly defined subtypes. Multivariable analysis confirmed that this genomic classification is a robust, independent predictor of survival after adjusting for age, minimal residual disease status, and transplant intervention. Specifically, HLF-rearranged and MEF2D-rearranged B-ALL conferred a persistently poor prognosis across all age groups despite allogeneic hematopoietic stem cell transplantation, highlighting an urgent need for novel therapeutic strategies. Gene expression profiling resolved cryptic subtypes, including ETV6::RUNX1-like, ZNF384-rearranged-like, and BCR::ABL1-like B-ALL, and uncovered diagnostic ambiguity in patients with concurrent lesions. In addition, we report emerging high-risk groups, including IDH1/2- and ZEB2 Q1072-mutated B-ALL, that may warrant recognition as distinct molecular entities. Our findings demonstrate the clinical use of integrative transcriptomic profiling in refining B-ALL taxonomy in guiding risk-adapted therapies and informing future revisions of diagnostic standards. This study supports the incorporation of high-throughput molecular diagnostics into routine leukemia classification and precision treatment planning.

Humans↗
PubMed2002

Gene array analysis and the liver.

Functional genomics methods promise a previously unparalleled high-throughput examination of intrahepatic gene expression. Profiling transcriptomes as well as examining the coordinate expression of many genes in diverse pathobiologic pathways is now possible with techniques such as gene array analysis. However, the nature of the hepatic transcriptome, limitations of the functional genomics methodologies used, and analysis of the data generated are often poorly understood. Further, the use of replicates during analysis and the downstream confirmation of results using a supplemental methodology are important but frequently neglected aspects of experimental design. This review presents an overview of functional genomics methodologies in the organ-specific context of studying intrahepatic gene expression. The focus of the review is the most widely used functional genomic methodology, gene array analysis. The nature of the hepatic transcriptome is discussed, together with a summary of gene array analysis methodologies. Analysis of data generated by gene array analysis, determination of intrahepatic cellular origin of transcript expression, and studies of intrahepatic gene expression using gene array analysis are also reviewed. Finally, the importance of a coordinate experimental approach examining both liver protein and mRNA expression is presented.

Humans↗
PubMed2026

Pathogenesis of psoriasis and psoriatic arthritis: Insights from animal models and single-cell and spatial transcriptomic analyses of skin, synovium and entheses.

Psoriasis (PsO) and psoriatic arthritis (PsA) are immune-mediated diseases characterized by chronic systemic inflammation, including inflammation of the skin and joints. Recent advances in animal models, single-cell transcriptomics, spatial transcriptomics, and proteomics have greatly enhanced our understanding of disease pathogenesis. Mouse models exhibit key features of skin and joint inflammation, facilitating analysis of molecular pathways, and identification of therapeutic targets. Single-cell and spatial transcriptomic analyses have revealed cell-type-specific contributions to inflammation, highlighting interactions between keratinocytes, T cells, fibroblasts, and dendritic cells that drive psoriatic pathology. In psoriatic synovium, type 17 tissue-resident memory T cells, monocytes, and fibroblasts contribute to local inflammation and joint damage, whereas the roles of B cells and plasma cells are less clear. Proteomic and metabolomic profiling in patients with PsA has identified circulating protein signatures and metabolites associated with disease progression, sex-specific differences, and response to therapy. The integration of these multiomic approaches provides a detailed map of immune-stromal-epithelial crosstalk across skin, synovium, and entheses, uncovering mechanisms that were previously inaccessible. These insights have implications for predicting disease progression, identifying novel therapeutic targets, and optimizing treatment strategies. Collectively, advances in animal models and multiomic profiling are reshaping our understanding of PsO and PsA, providing a framework for future research, disease monitoring, and therapeutic development.

Animals↗
PubMed2003

Zinc suppresses the iron-accumulation phenotype of Saccharomyces cerevisiae lacking the yeast frataxin homologue (Yfh1).

Analysis of Saccharomyces cerevisiae cell transcriptome revealed that iron deprivation/supplementation affects genes other than those of the iron regulon (controlled by Aft proteins). Several genes regulated by zinc (induced by zinc deprivation) were induced by iron. Cells lacking the yeast frataxin homologue Yfh1 accumulate large amounts of iron in their mitochondria. We have shown that the zinc metabolism of these cells is also impaired: zinc uptake and zinc accumulation were both much lower in Delta yfh1 cells than in wild-type cells. Excess zinc in the growth medium also influenced the phenotypes of Delta yfh1 cells. It prevented the accumulation of iron in the mitochondria of Delta yfh1 cells and increased the growth rate of these cells and their resistance to oxidative stress. However, zinc did not restore the deficiency of Fe-S and haem proteins of Delta yfh1 cells. Zinc inhibited mitochondrial respiration and protected Yah1p, the mitochondrial ferredoxin. These results suggest that zinc nutrition may be important in the aetiology of Friedreich's ataxia.

Cell Division↗
PubMed2026

Spatially guided in vivo single-cell functional genomics of postnatal heart.

Understanding how spatial organization and cell-cell interactions shape gene regulatory programs is central to decoding tissue development and function. The transition at birth, marked by increased circulatory demands and rapid tissue growth, requires precise spatiotemporal coordination of cardiac maturation. In this study, we generated a high-resolution spatial and temporal atlas of the postnatal mouse heart by integrating single-nucleus RNA sequencing with image-based spatial transcriptomics. This framework revealed dynamic cellular interactions, niche-specific signaling and transcriptional programs guiding cardiomyocyte maturation. To functionally test prioritized regulators in vivo and at scale, we developed PIP-seq (probe-based indel-detectable Perturb-seq), a high-throughput platform that detects single guide RNA identity, infers gene editing and profiles transcription from fixed nuclei. Applying PIP-seq to the developing postnatal heart, we identified 21 previously uncharacterized regulators of cardiomyocyte maturation, including genes essential for sarcomere assembly, metabolic reprogramming and electrophysiological transitions. Together, our findings define how microenvironmental signals and intrinsic gene programs cooperate to guide heart maturation and establish a broadly applicable framework for functional genomics in complex tissues.

Animals↗
PubMed2002

Differential display analysis of gene expression in yeast.

RNA differential display (DD) is a powerful and straightforward method that employs random reverse-transcription polymerase chain reaction amplification of mRNA species with electrophoresis for comparative analysis of two or more transcriptomes. The small yeast genome represents a convenient model for studying basic functions of the eukaryotic genome and simultaneously provides valuable information towards further refinement of this technique. Several examples discussed below illustrate how DD coupled with classical yeast genetic approaches may be used for studying transcriptionally regulated genetic systems.

Blotting, Northern↗
PubMed2026

Intratumoral PD-1+LAG-3+CD8+ T cells are associated with improved prognosis in gastric cancer.

PURPOSE: PD-1 and LAG-3 are frequently used as markers of T cell exhaustion, yet the prognostic relevance and phenotypic characteristics of PD-1+LAG-3+CD8+ T cells in gastric cancer (GC) remain poorly defined. This study aimed to investigate their association with clinical outcomes and characterize their immune characteristics across independent GC cohorts. METHODS: Four independent GC cohorts were analyzed: the Zhongshan Hospital cohort (ZSGC, n = 298), The Cancer Genome Atlas cohort (TCGA, n = 371), an Immune Checkpoint Blockade cohort (ICB, n = 45), and the Yonsei cohort (n = 433). Intratumoral PD-1+LAG-3+CD8+ T cell infiltration was quantified by immunofluorescence staining and transcriptomic gene signature scoring. Survival analysis was performed using Kaplan-Meier estimation and multivariate Cox regression. Functional characterization was performed by flow cytometry on resected GC tissue. The immune microenvironment composition was evaluated using computational analyses. RESULTS: PD-1+LAG-3+CD8+ T cells were enriched within tumors compared to adjacent normal mucosa, and their infiltration correlated with advanced tumor stage, poor differentiation, microsatellite instability, and Epstein-Barr virus (EBV)-positive molecular subtypes. High intratumoral infiltration was significantly associated with improved overall survival in both the ZSGC and TCGA cohorts, whereas single-positive PD-1+CD8+ or LAG-3+CD8+ T cells showed no such association. In the ICB cohort, higher infiltration was associated with a higher response rate to pembrolizumab. Intratumoral PD-1+LAG-3+CD8+ T cells exhibit an activated phenotype characterized by increased expression of CD137, IFN-γ, perforin, and CXCL13, along with elevated TCF7 and lower PD-1 levels, suggesting a tumor-reactive, pre-exhausted state. High infiltration was further associated with an immune-active tumor microenvironment. CONCLUSIONS: High intratumoral infiltration of PD-1+LAG-3+CD8+ T cells is associated with favorable prognosis and an immune-active microenvironment in GC. These cells display phenotypic features consistent with a pre-exhausted state and may serve as independent prognostic biomarkers and candidate predictive biomarkers for immunotherapy stratification.

Humans↗
PubMed2025

Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy.

PURPOSE: Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease. METHODS: To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants' blood and heterologous cell system. RESULTS: We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling. CONCLUSION: Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.

Humans↗