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At least 397 records · Page 22Linked to original sources
PubMed2005

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome.

The postnatal maturation of the gut, partially modulated by bacterial colonization, ends up in the establishment of an efficient barrier to luminal antigens and bacteria. The use of broad-spectrum antibiotics in pediatric practices alters the gut bacterial colonization and, consequently, may impair the maturation of the gut barrier function. To test this hypothesis, suckling Sprague-Dawley rats received a daily intragastric gavage of antibiotic (Clamoxyl; an amoxicillin-based commercial preparation) or saline solution from postnatal day 7 (d7) until d17 or d21. Luminal microbiota composition and global gene expression profile were analyzed on samples from small intestine and colon of each group. The treatment with Clamoxyl resulted in the almost-complete eradication of Lactobacillus in the whole intestine and in a drastic reduction of colonic total aerobic and anaerobic bacteria, in particular Enterobacteriacae and Enterococcus. The global gene expression analysis revealed that Clamoxyl affects the maturation process of 249 and 149 Affymetrix probe sets in the proximal and distal small intestine, respectively, and 163 probe sets in the colon. The expression of genes coding for Paneth cell products (defensins, matrilysin, and phospholipase A2) was significantly downregulated by the Clamoxyl treatment. A significant downregulation of major histocompatibility complex (MHC) class Ib and II genes, involved in antigen presentation, was also observed. Conversely, mast cell proteases expression was upregulated. These results suggest that early treatment with a large-spectrum antibiotic deeply affects the gut barrier function at the suckling-weaning interface, a period during which the gut is challenged by an array of novel food-borne antigens.

Aging↗
PubMed2024

Genomic landscape of hepatocellular carcinoma in Egyptian patients by whole exome sequencing.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. METHODS: Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. RESULTS: Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. CONCLUSION: Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients.

Humans↗
PubMed2005

Plant peroxisomes.

Peroxisomes, one of single membrane-bound organelles, are present ubiquitously in eukaryotic cells. They were originally identified as organelles for production of hydrogen peroxide, the degradation of its hydrogen peroxide, and metabolism of fatty acids, which are functions common to almost all the organisms. Meanwhile, photorespiration and assimilation of symbiotically induced nitrogen are plant-specific functions. Recent postgenetic approaches such as transcriptome and proteome showed that plant peroxisomes are differentiated in various tissues, and revealed that peroxisomes have more important roles in various metabolic processes including biosynthesis of plant hormones than we speculated. All peroxisomal proteins, including metabolic enzymes in the matrix, membrane proteins, and factors responsible for peroxisome biogenesis, are nuclear encoded, and are provided from the outside of peroxisomes. Peroxisome biogenesis, such as protein transport, division, and enlargement, requires various complicated steps and is one of the most intriguing topics. Analyses using peroxisome biogenesis mutants and the whole-scale sequencing projects among several organisms revealed the existence of essential factors responsible for peroxisome biogenesis such as peroxins. This review addresses a comprehensive issue relating to function and biogenesis of plant peroxisomes and Arabidopsis mutants that have been accelerating our understanding of peroxisomes in planta.

Peroxisomes↗
PubMed2006

Capillary electrophoresis at the omics level: towards systems biology.

Emerging systems biology aims at integrating the enormous amount of existing omics data in order to better understand their functional relationships at a whole systems level. These huge datasets can be obtained through advances in high-throughput, sensitive, precise, and accurate analytical instrumentation and technological innovation. Separation sciences play an important role in revealing biological processes at various omic levels. From the perspective of systems biology, CE is a strong candidate for high-throughput, sensitive data generation which is capable of tackling the challenges in acquiring qualitative and quantitative knowledge through a system-level study. This review focuses on the applicability of CE to systems-based analytical data at the genomic, transcriptomic, proteomic, and metabolomic levels.

Animals↗
PubMed2026

Shared genetic architecture of smoking dependence and Crohn's disease: A cross-trait analysis of GWAS summary statistics.

INTRODUCTION: Smoking dependence (SD) and Crohn's disease (CD) are epidemiologically associated, but whether this relationship reflects shared genetic susceptibility remains unclear. METHODS: We conducted a cross-trait genetic analysis of SD and CD using publicly available genome-wide association study (GWAS) summary statistics from European-ancestry populations. Genome-wide genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Pleiotropic variants were identified using PLACO and mapped to genomic loci using FUMA. Regional signal sharing was assessed by Bayesian colocalization. Functional analyses included stratified LDSC, Multi-marker Analysis of GenoMic Annotation (MAGMA), GTEx tissue analysis, and Metascape. Expression-linked candidate genes were prioritized using expression quantitative trait locus (eQTL)-based summary-data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) testing. Genetically informed spatial mapping of cells for complex traits (gsMap) was used for spatial mapping. RESULTS: SD and CD showed positive genetic correlation by LDSC (rg=0.2090, p=0.0008) and HDL (rg=0.3817, p=0.00106). PLACO identified 81 genome-wide significant pleiotropic SNPs, which were mapped by FUMA to three loci at 1p31.3, 5p13.1, and 12q12, represented by rs11209031, rs1395152, and rs17467116, respectively. MAGMA identified 22 FDR-significant genes, four of which remained Bonferroni significant: LRRK2, TNFRSF6B, ZGPAT, and RP4-583P15.15. Cross-trait tissue analysis showed significant enrichment of the shared genetic signal in whole blood and small intestine, while gene-set analysis highlighted inflammatory response (pbon=1.86×10-5) and T-helper 17 cell differentiation (pbon=7.37×10-4). SMR/HEIDI analysis further prioritized RPS6KB1 as a shared expression-linked candidate. Spatial mapping revealed a prominent signal in the embryonic gastrointestinal tract and gene-specific regional patterns involving LRRK2 and SLC2A13 in the adult mouse brain. CONCLUSIONS: SD and CD showed measurable shared genetic susceptibility, with convergent evidence from pleiotropic loci, immune-inflammatory pathway enrichment, tissue-level associations, and spatial transcriptomic mapping.

Crohn's disease↗
PubMed2026

Impaired leptin A signaling disrupts hepatic lipid metabolism and growth in female medaka (Oryzias latipes).

Leptin is a central regulator of appetite and energy metabolism in vertebrates, and its deficiency in mammals typically results in hyperphagia and severe obesity. In fish, however, the physiological roles of leptin remain less clearly defined, partly due to the whole genome duplication (WGD) and divergent expression patterns. In this study, we generated a leptin A (lepa) loss-of-function mutant in medaka (Oryzias latipes) using CRISPR/Cas9 to investigate the function of leptin signaling. Phenotypic analysis revealed that female homozygous mutants exhibited significantly reduced body length and body weight compared with wild-type females, indicating growth impairment. Unexpectedly, despite their lean phenotype, the female mutants developed pronounced hepatic steatosis accompanied by the formation of spongiosis hepatis structures, while no obvious fibrosis was detected. To explore the molecular mechanisms underlying these abnormalities, transcriptomic profiling of mutant livers was performed. Differentially expressed genes were significantly enriched in pathways related to lipid metabolism, including Fatty acid metabolism and PPAR signaling pathway, suggesting a potential reduction in hepatic fatty acid β-oxidation capacity. In addition, genes involved in endoplasmic reticulum stress, autophagy, and apoptosis were altered, indicating transcriptional changes in cellular stress-response pathways under leptin A deficiency. Together, these findings suggest that leptin A may play an important role in coordinating growth and hepatic lipid metabolism in medaka and highlight potential differences in leptin-mediated metabolic regulation between fish and mammals.

Animals↗
PubMed2026

Biocontrol effect of a solid-state fermentation-derived extract mixture of Trichoderma asperellum on sunflower Sclerotinia rot and associated host defense responses.

Sclerotinia disease is a destructive fungal disease of sunflowers, soybeans, and other economically important crops, causing substantial yield loss and quality deterioration. Long-term reliance on dose-dependent broad-spectrum fungicides is constrained by resistance risks and potential environmental burdens, creating tension with the sustainability goal of "reducing pesticide use while improving efficacy." Here, we explore a Trichoderma spp.-based microbial disease management strategy. Whole-genome sequencing of Trichoderma asperellum TCS007 isolated from Antarctic marine sediments, coupled with genome mining, predicted diverse biosynthetic gene clusters putatively associated with siderophores, polyketides, nonribosomal peptides, and terpenoids; the corresponding metabolites are not chemically confirmed and require further validation. Using a solid-state fermentation workflow, we prepared a fermentation-derived extract mixture (TCS007-SSF-Ex). In vitro assays showed dose-dependent inhibition of Sclerotinia sclerotiorum by TCS007-SSF-Ex (EC50 = 1.252 mg/L), and microscopy revealed cellular damage-consistent changes, including organelle disruption and plasmolysis. Pathogen transcriptomic and metabolism-related analyses indicated broad perturbations in organelle biogenesis and metabolic processes, with significant alterations in pathways associated with succinate, D-glucose, and phenylacetate; these results are consistent with growth inhibition and reduced pathogenicity, but specific molecular targets and causal links remain to be validated. In vivo, under certain application conditions, triple applications increased APX activity (+492.5%) and β-1,3-glucanase activity (+419.6%). Collectively, this work supports a "pathogen suppression-host defense induction" framework and facilitates subsequent identification of active components and mechanistic validation.IMPORTANCESclerotinia diseases cause recurrent and economically important losses in oilseed crops, while long-term fungicide use is constrained by resistance risks and environmental burdens. Trichoderma-based biocontrol is a promising complementary strategy, yet evidence supporting metabolite-containing Trichoderma-derived preparations as immune elicitors remains less consolidated than that for living inoculants, and scalable production routes are still needed. Here, we examine an Antarctic marine sediment-derived strain, Trichoderma asperellum TCS007, and a solid-state fermentation (SSF)-derived extract mixture (TCS007-SSF-Ex) produced via solid-state fermentation. We combine in vitro antifungal assays, pathogen ultrastructural observations, and correlative omics analyses with in vivo measurements of sunflower defense enzymes (APX and β-1,3-glucanase) to evaluate a "pathogen suppression-host defense induction" framework. Our findings support the potential of SSF-derived Trichoderma metabolite mixtures for greener management of Sclerotinia disease and provide a foundation for future chemical identification of active components and mechanistic validation.

Ascomycota↗
PubMed2005

The mouse epididymal transcriptome: transcriptional profiling of segmental gene expression in the epididymis.

Maturation of spermatozoa, including the acquisition of motility and the ability to undergo capacitation, occurs during transit through the dynamic environment of the epididymis. The microenvironments created along the length of the epididymal tubule are essential to the molecular modifications of spermatozoa that result in fertile gametes. The secretory and resorptive processes of the epithelial cells that line this tubule generate these microenvironments. In the current study, 10 morphologically distinct segments of the mouse epididymis were identified by microdissection. We hypothesized that the changing environments of the epididymal lumen are established by differential gene expression among these segments. RNA isolated from each of the 10 segments was analyzed by microarray analysis. More than 17,000 genes are expressed in the mouse epididymis, compared with about 12,000 genes identified from whole epididymal samples. Screening a panel of normal mouse tissues identified both epididymal-selective and epididymal-specific transcripts. In addition, this study identified 2168 genes that are up-regulated or down-regulated by greater than 4-fold between at least two different segments. The expression patterns of these genes identify distinct patterns of segmental regulation. Using principal component analysis, we determined that the 10 segments form 6 different transcriptional units. These analyses elucidate the changes in gene expression along the length of the epididymis for 17,000 expressed transcripts and provide a powerful resource for the research community in future studies of the biological factors that mediate epididymal sperm maturation.

Animals↗
PubMed2005

Identification of novel stage-specific genetic requirements through whole genome transcription profiling of Vibrio cholerae biofilm development.

Bacterial biofilm formation has been described as a developmental process. This process may be divided into three stages: the planktonic stage, the monolayer stage and the biofilm stage. Bacteria in the planktonic stage are not attached to each other or to a surface; bacteria in the monolayer stage are attached to surfaces as single cells; and bacteria in the biofilm stage are attached to surfaces as cellular aggregates. In a study limited to the Vibrio cholerae flaA, mshA and vps genes, we previously demonstrated that transcription in monolayer cells is distinct from that in biofilm cells and that the genetic requirements of monolayer formation are distinct from those of biofilm formation. In this work, we sought to identify additional stage-specific genetic requirements through microarray analysis of the V. cholerae transcriptome during biofilm development. These studies demonstrated unique patterns of transcription in the planktonic, monolayer and biofilm stages of biofilm development. Based on our microarray results, we selected cheY-3 as well as two previously uncharacterized genes, bap1 and leuO, for targeted mutation. The DeltacheY-3 mutant displayed a defect in monolayer but not biofilm formation, suggesting that chemotaxis plays a stage-specific role in formation of the V. cholerae monolayer. Mutants carrying deletions in bap1 and leuO formed monolayers that were indistinguishable from those formed by wild-type V. cholerae. In contrast, these mutants displayed greatly decreased biofilm accumulation. Our microarray analyses document modulation of the transcriptome of V. cholerae as it progresses through the stages in biofilm development. These studies demonstrate that microarray analysis of the transcriptome of biofilm development may greatly accelerate the discovery of novel targets for stage-specific inhibition of biofilm development.

Bacterial Proteins↗
PubMed2006

Analysis of ESTs from Lutzomyia longipalpis sand flies and their contribution toward understanding the insect-parasite relationship.

An expressed sequence tag library has been generated from a sand fly vector of visceral leishmaniasis, Lutzomyia longipalpis. A normalized cDNA library was constructed from whole adults and 16,608 clones were sequenced from both ends and assembled into 10,203 contigs and singlets. Of these 58% showed significant similarity to known genes from other organisms, <4% were identical to described sand fly genes, and 42% had no match to any database sequence. Our analyses revealed putative proteins involved in the barrier function of the gut (peritrophins, microvillar proteins, glutamine synthase), digestive physiology (secreted and membrane-anchored hydrolytic enzymes), and the immune response (gram-negative binding proteins, thioester proteins, scavenger receptors, galectins, signaling pathway factors, caspases, serpins, and peroxidases). Sequence analysis of this transcriptome dataset has provided new insights into genes that might be associated with the response of the vector to the development of Leishmania.

Animals↗
PubMed2005

Studies of the distribution of Escherichia coli cAMP-receptor protein and RNA polymerase along the E. coli chromosome.

Chromatin immunoprecipitation and high-density microarrays have been used to monitor the distribution of the global transcription regulator Escherichia coli cAMP-receptor protein (CRP) and RNA polymerase along the E. coli chromosome. Our results identify targets occupied by CRP and genes transcribed by RNA polymerase in vivo. Many of the loci of CRP binding are at known CRP regulated promoters. However, our results show that CRP also interacts with thousands of weaker sites across the whole chromosome and that this "background" binding can be used as a probe for organization within the E. coli folded chromosome. In rapidly growing cells, we show that the major sites of RNA polymerase binding are approximately 90 transcription units that include genes needed for protein synthesis. Upon the addition of rifampicin, RNA polymerase is distributed among >500 functional promoters. We show that the chromatin immunoprecipitation and high-density-microarrays methodology can be used to study the redistribution of RNA polymerase induced by environmental stress, revealing previously uncharacterized aspects of RNA polymerase behavior and providing an alternative to the "transcriptomics" approach for studying global transcription patterns.

Chromosomes, Bacterial↗
PubMed2005

Natterins, a new class of proteins with kininogenase activity characterized from Thalassophryne nattereri fish venom.

A novel family of proteins with kininogenase activity and unique primary structure was characterized using combined pharmacological, proteomic and transcriptomic approaches of Thalassophryne nattereri fish venom. The major venom components were isolated and submitted to bioassays corresponding to its main effects: nociception and edema. These activities were mostly located in one fraction (MS3), which was further fractionated. The isolated protein, named natterin, was able to induce edema, nociception and cleave human kininogen and kininogen-derived synthetic peptides, releasing kallidin (Lys-bradykinin). The enzymatic digestion was inhibited by kallikrein inhibitors as Trasylol and TKI. Natterin N-terminal peptide showed no similarity with already known proteins present in databanks. Primary structure of natterin was obtained by a transcriptomic approach using a representative cDNA library constructed from T. nattereri venom glands. Several expressed sequence tags (ESTs) were obtained and processed by bioinformatics revealing a major group (18%) of related sequences unknown to gene or protein sequence databases. This group included sequences showing the N-terminus of isolated natterin and was named Natterin family. Analysis of this family allowed us to identify five related sequences, which we called natterin 1-4 and P. Natterin 1 and 2 sequences include the N-terminus of the isolated natterin. Furthermore, internal peptides of natterin 1-3 were found in major spots of whole venom submitted to mass spectrometry/2DGE. Similarly to the ESTs, the complete sequences of natterins did not show any significant similarity with already described tissue kallikreins, kininogenases or any proteinase, all being entirely new. These data present a new task for the knowledge of the action of kininogenases and may help in understanding the mechanisms of T. nattereri fish envenoming, which is an important medical problem in North and Northeast of Brazil.

Amino Acid Sequence↗
PubMed2025

Targeting the bile acid receptor TGR5 with Gentiopicroside to activate Nrf2 antioxidant signaling and mitigate Parkinson's disease in an MPTP mouse model.

INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by classical symptoms including bradykinesia, rest tremor and rigidity. Oxidative stress and mitochondrial dysfunction are recognized as pivotal factors in PD progression. Gentiopicroside (GPS), a secoiridoid derived from Gentiana manshurica Kitagawa, exhibits antioxidant and mitophagy induction properties. Nonetheless, the effects and mechanisms by which GPS mitigates neurodegeneration in PD remain to be thoroughly elucidated. OBJECTIVES: The goal of this study was to investigate the neuroprotective effects and mechanisms of GPS in PD models. METHODS: We established the MPTP/MPP+-induced PD models to measure the neuroprotection of GPS. Transcriptomic analysis, oxidative biochemical kits, western blot and cell immunofluorescence were conducted to elucidate the fundamental mechanisms at play. Subsequently, the targeting and activation of the transmembrane G protein-coupled receptor-5 (TGR5) by GPS were measured by molecular docking, cellular thermal shift assay, microscale thermophoresis (MST) and cyclic adenosine monophosphate (cAMP) quantitation. Finally, we verified whether the neuroprotective and antioxidant effects of GPS were dependent on TGR5 by using specific small interfering RNA (siRNA), pharmacological antagonist and knockout mice. RESULTS: GPS significantly attenuated dopaminergic (DAergic) neuron loss and restored motor function in the MPTP-induced PD mouse model. Whole-genome RNA sequencing and subsequent mechanistic investigations revealed that GPS enhanced the expression and facilitated nuclear entry of factor erythroid-related 2-factor 2 (Nrf2), and reduced oxidative stress and mitochondrial dysfunction stimulated by neurotoxin. Additionally, GPS could target TGR5 and prevent its downregulation in PD model. TGR5's silencing or inhibition weakened the neuroprotective effect of GPS and blocked GPS-mediated activation of Nrf2 antioxidant signaling in PD model. Moreover, the therapeutic effect of GPS in mitigating motor deficits and neurodegeneration was also abolished in Tgr5 knockout mice. CONCLUSION: These findings collectively indicated that GPS targeted TGR5 to activate Nrf2 antioxidant signaling and ultimately ameliorated the pathological progression of PD.

Animals↗
PubMed2001

Genetic engineering of neural function in transgenic rodents: towards a comprehensive strategy?

As mammalian genome projects move towards completion, the attention of molecular neuroscientists is currently moving away from gene identification towards both cell-specific gene expression patterns (neuronal transcriptions) and protein expression/interactions (neuronal proteomics). In the long term, attention will increasingly be directed towards experimental interventions which are able to question neuronal function in a sophisticated manner that is cognisant of both transcriptomic and proteomic organization. Central to this effort will be the application of a new generation of transgenic approaches which are now evolving towards an appropriate level of molecular, temporal and spatial resolution. In this review, we summarize recent developments in transgenesis, and show how they have been applied in the principal model species for neuroscience, namely rats and mice. Current concepts of transgene design are also considered together with an overview of new genetically-encoded tools including both cellular indicators such as fluorescent activity reporters, and cellular regulators such as dominant negative signalling factors. Application of these tools in a whole animal context can be used to question both basic concepts of brain function, and also current concepts of underlying dysfuction in neurological diseases.

Animals↗
PubMed2005

Synaptic and genomic responses to JNK and AP-1 signaling in Drosophila neurons.

BACKGROUND: The transcription factor AP-1 positively controls synaptic plasticity at the Drosophila neuromuscular junction. Although in motor neurons, JNK has been shown to activate AP-1, a positive regulator of growth and strength at the larval NMJ, the consequences of JNK activation are poorly studied. In addition, the downstream transcriptional targets of JNK and AP-1 signaling in the Drosophila nervous system have yet to be identified. Here, we further investigated the role of JNK signaling at this model synapse employing an activated form of JNK-kinase; and using Serial Analysis of Gene Expression and oligonucleotide microarrays, searched for candidate early targets of JNK or AP-1 dependent transcription in neurons. RESULTS: Temporally-controlled JNK induction in postembryonic motor neurons triggers synaptic growth at the NMJ indicating a role in developmental plasticity rather than synaptogenesis. An unexpected observation that JNK activation also causes a reduction in transmitter release is inconsistent with JNK functioning solely through AP-1 and suggests an additional, yet-unidentified pathway for JNK signaling in motor neurons. SAGE profiling of mRNA expression helps define the neural transcriptome in Drosophila. Though many putative AP-1 and JNK target genes arose from the genomic screens, few were confirmed in subsequent validation experiments. One potentially important neuronal AP-1 target discovered, CG6044, was previously implicated in olfactory associative memory. In addition, 5 mRNAs regulated by RU486, a steroid used to trigger conditional gene expression were identified. CONCLUSION: This study demonstrates a novel role for JNK signaling at the larval neuromuscular junction and provides a quantitative profile of gene transcription in Drosophila neurons. While identifying potential JNK/AP-1 targets it reveals the limitations of genome-wide analyses using complex tissues like the whole brain.

Animals↗
PubMed2024

Digital pathology and spatial omics in steatohepatitis: Clinical applications and discovery potentials.

Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction-associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.

Humans↗
PubMed2026

Decoding age-stratified clinical and molecular heterogeneity in male breast cancer through multiomic profiling.

OBJECTIVE: Age-associated molecular heterogeneity is well described in female breast cancer but remains insufficiently characterized in male breast cancer (MBC). We profiled age-stratified clinical and molecular differences between younger (&#x2264;55 years) male breast cancer (YMBC) and older (>55 years) male breast cancer (OMBC). METHODS: We retrospectively analyzed 347 patients with MBC diagnosed at Fudan University Shanghai Cancer Center by integrating clinicopathological data, RNA sequencing, and whole-exome sequencing (WES). Survival, differential expression, and mutational signature analyses were performed. Tumor microenvironment features were inferred using xCell and ESTIMATE, and weighted gene co-expression network analysis (WGCNA) was conducted to identify age-associated co-expression modules. Candidate therapeutics were prioritized using the Genomics of Drug Sensitivity in Cancer (GDSC) resource and evaluated using patient-derived organoids (PDOs). RESULTS: Compared with OMBC, YMBC more frequently had human epidermal growth factor receptor 2 (HER2)-positive status (14.91% vs. 4.02%) and triple-negative tumors (4.92% vs. 1.78%), and had worse 5-year recurrence-free survival (hazard ratio=2.19, P=0.018). Transcriptomic analyses indicated enrichment of neural-related programs and reduced immune-related signaling in YMBC, and xCell/ESTIMATE supported lower immune infiltration. Consistently, WGCNA identified age-associated modules linking neural-related programs with reduced immune infiltration. Immunohistochemistry supported increased perineural invasion and lower CD8+ T cell infiltration in YMBC. GDSC-guided prioritization with PDO testing nominated sepantronium bromide (YM155) as a candidate vulnerability in YMBC. WES showed a higher NBPF10 mutation frequency in YMBC (54.5% vs. 14.3%, P<0.05). CONCLUSIONS: Integrated multi-omics profiling revealed age-stratified clinical and molecular heterogeneity in MBC. YMBC patients demonstrated inferior recurrence-free survival, neural signaling enrichment, an immune-cold microenvironment, and enriched NBPF10 mutations. These findings support age as a meaningful stratification variable in MBC risk assessment and treatment planning, and highlight the need for caution when considering treatment de-escalation in younger patients, while nominating YM155 as a candidate agent for prospective evaluation.

Male breast cancer↗
PubMed2000

Pharmacogenomics and therapeutic target validation in cerebral vasospasm.

One of the most important pharmacogenomic technologies is transcriptome analysis. We used this method to study the change of gene expression profiles in animal models of cerebral vasospasm. We found novel drug target candidates in cerebral vasospasm through pharmacogenomics. By using differential display and quantitative reverse transcriptase-polymerase chain reaction, we found that heme oxygenase-1 (HO-1) mRNA was prominently induced in the basilar artery and modestly in brain tissue in a murine vasospasm model. There was a significant correlation between the degree of vasospasm and HO-1 mRNA levels in the basilar arteries exhibiting vasospasm. Antisense HO-1 oligodeoxynucleotides (ODN) inhibited HO-1 induction in the basilar arteries, but not in the whole brain tissue. This phenomenon was not observed in the nontreatment, sense HO-1 ODN and scrambled ODN treatment arteries. We report, for the first time, the protective effects of HO-1 gene induction by endogenous or clinical compounds in cerebral vasospasm after subarachnoid hemorrhage, a finding that should provide a novel therapeutic target for cerebral vasospasm.

Animals↗