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Results for “methylation class”

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At least 19 recordsLinked to original sources

PubMed2026

Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation.

BACKGROUND: Papillary tumors of the pineal region (PTPR) are rare CNS neoplasms with adult and pediatric presentations, but whether age defines distinct molecular biology is unclear. METHODS: We assembled a multicenter retrospective cohort of 86 histologically confirmed PTPR with genome-wide DNA methylation data, comprising 62 adult and 24 pediatric tumors. Molecular subgroup, array platform, sex, and tumor purity were incorporated into multivariable models. Analyses included DNA methylation class assignment, differential methylation, copy-number variation (CNV), epigenetic mitotic-clock scores, methylation-based tumor microenvironment deconvolution, and descriptive survival evaluation. RESULTS: Adult and pediatric tumors mapped within the established PTPR-A and PTPR-B methylation framework rather than forming age-defined methylation classes. Pediatric tumors were enriched for PTPR-B (22 of 24 tumors [91.7%]) compared with adult tumors (39 of 62 [62.9%]). After adjustment for methylation-based subgroup as well as technical and biological covariates, 2,923 CpG probes were associated with age at a false discovery rate (FDR) threshold below 0.05, and 530 also met the prespecified effect-size threshold. Global methylation summaries were similar between age groups. CNV patterns were dominated by molecular subgroup; adjusted genomic CNV load was not independently associated with pediatric age. In contrast, epiTOC2 intrinsic rate score and the methylation signature represented by the first principal component (PC1) showed age-associated effects independent of molecular subgroup. Methylation-based deconvolution suggested a limited microenvironmental signal, with neutrophil fraction showing the most consistent adjusted association. CONCLUSIONS: Adult and pediatric PTPR share the established PTPR-A/PTPR-B framework. Pediatric tumors, particularly within PTPR-B, showed age-associated DNA methylation differences and higher epigenetic mitotic-clock (epiTOC2) scores in this retrospective cohort. These tissue-level associations do not establish clinical risk or treatment implications and require prospective clinical annotation and orthogonal validation.

Humans↗

PubMed2026

Meningioma methylation profiling as a complement to WHO grading: a single-center experience.

OBJECTIVE: The methylation profile of meningiomas is a promising predictive tool that may improve risk stratification beyond WHO grading. This study aimed to evaluate the clinical relevance and real-world applicability of routine epigenetic testing in meningioma management. METHODS: The authors retrospectively analyzed patients who underwent meningioma resection between January 2021 and December 2023. Histopathological grading (WHO 2021) and methylation profiling (methylation class [MC]) with the MethylationEPIC v1.0 (850k) chip were performed by an independent neuropathologist. RESULTS: A total of 106 patients were included; 81 tumors (76%) were classified as WHO grade 1, 20 (19%) as grade 2, and 5 (5%) as grade 3. Epigenetically, 55 tumors (52%) were classified as benign, 18 (17%) as intermediate, and 2 (2%) as malignant; 31 (29%) could not be classified. Discordances between WHO grading and methylation profiling were observed in 18 of 74 cases. Tumor board decisions were made after a median of 8 days postoperatively, guided by WHO grading; however, the epigenetic report was only available after a median of 23 days. During follow-up, 20 patients experienced tumor progression. Progression was significantly associated with the MC (r = -0.4, p < 0.001) and tumor volume (r = 0.4, p = 0.0005), but not with WHO grading (r = 0.17, p = 0.084). However, the relatively high rate of unclassified tumors and delayed result availability limited the direct impact of MC profiling on immediate clinical decision-making. Interestingly, progression-free survival in MC-unclassified tumors mirrored that of the intermediate group. CONCLUSIONS: Methylation profiling demonstrates superior predictive accuracy for meningioma progression and complements WHO grading, especially in identifying malignant meningiomas. However, its current clinical utility is constrained by technical and logistical limitations. In real-world practice, epigenetic classification should therefore be considered a complementary tool rather than a replacement for established histopathological assessment.

Humans↗

PubMed2025

DNA Methylation-Based Classification of Kidney Neoplasms.

Renal neoplasms are morphologically and molecularly heterogeneous, with their diagnosis often hindered by interobserver variability and overlapping microscopic features. A subset of cases is unclassifiable despite immunohistochemical, mutation, and cytogenetic-based diagnostic workup. Through examination of the genome-wide DNA methylation signatures of over 2000 renal neoplasms, we identified 23 coherent groups that correlate with known neoplasm types and identified novel clinically relevant subtypes of existing neoplasm types. We used machine learning models to develop and validate a classifier trained on DNA methylation profiles of 1284 samples. The classifier was tested on an external data set of 287 renal neoplasms with >90% concordance between expected neoplasm type and high-score DNA methylation-based classification. Discordance between the original histologic label and methylation class led to potential reclassification of some cases. This work demonstrates proof of principle for the feasibility of a DNA methylation classifier as a clinically useful tool to assist in the diagnosis of renal neoplasms.

Humans↗

PubMed2026

Spinal low-grade ependymal tumors harboring telomerase reverse transcriptase promoter mutation and chromosome 7 gain with methylation profile of spinal subependymoma.

Spinal intramedullary tumors comprise a heterogeneous group of entities with diverse histopathological features, making their diagnosis particularly challenging. With the introduction of DNA methylation profiling, the underlying biological diversity of these tumors has been increasingly clarified and systematized; however, owing to the rarity of these tumors, case accumulation remains limited, and significant challenges persist. In this study, we identified two cases of spinal ependymal tumors exhibiting a methylation profile of spinal (SP-) subependymoma (SEPN). Both cases occurred in elderly patients and demonstrated circumscribed growth consistent with low-grade ependymal tumors; however, these tumors did not exhibit the typical histopathological features required for a diagnosis of SEPN in the 2021 WHO classification of central nervous system (CNS) tumors, showing indistinct cluster formation, an astrocytic immunohistochemical profile suggested by Olig2 expression, and relatively elevated Ki-67 labeling indices of 4.5% and 3.1%. At the molecular level, both cases harbored telomerase reverse transcriptase promoter mutations and whole chromosome 7 gain. On two-dimensional t-distributed stochastic neighbor embedding analysis, both clustered within the SP-SEPN methylation class at its periphery, with low classifier calibration scores (0.70 and 0.69). According to the current WHO classification, these cases are designated as low-grade ependymal tumors (CNS WHO grade 2) with methylation profile of SP-SEPN because they do not meet the essential WHO histopathological criteria. Ependymal tumors exhibiting a methylation profile consistent with SEPN, but discordant histopathological features have been increasingly recognized, and the appropriate classification of such tumors remains a subject of ongoing debate. These cases provide important insights into the histopathological diversity of ependymal tumors and contribute to establishing a more comprehensive and systematic classification of ependymal tumors.

Aged↗

PubMed2025

Deciphering Pseudoendocrine Sarcoma: A Clinicopathological, Molecular, and Epigenetic Study Suggesting Biological Links With Solid Pseudopapillary Neoplasm of the Pancreas.

Pseudoendocrine sarcoma (PS) is a recently described neoplasm of uncertain differentiation, characterized by recurrent CTNNB1 mutations, frequent paravertebral location, and a neuroendocrine-like histomorphology. In this study, we report the clinicopathologic, immunohistochemical, transcriptomic, and epigenetic findings of 12 PS cases. The tumors affected 7 men and 5 women with a median age of 66 years and were located in the paraspinal/paravertebral region (n = 11) and the thigh (n = 1). Median tumor size was 82 mm (range, 32-170 mm). Histologically, the tumors comprised sheets and nests of epithelioid-to-ovoid cells with uniform nuclei and speckled chromatin, frequently associated with extracellular hyaline globules and fibrovascular cords/septa. Uncommon findings included microcalcifications, myxoid stroma, pseudopapillary, pseudoglandular, microcystic or corded architecture, and lumen and rosette-like structures. Necrosis was absent, and mitotic activity was low. On immunohistochemistry, the tumors showed aberrant nuclear staining for beta-catenin (8/8) and expression of CD56 (7/7), S100 (8/8), desmin (2/6), and androgen receptor (1/4). Pankeratin (AE1/AE3), progesterone receptor, synaptophysin, chromogranin, and INSM1 were negative. All tested cases harbored CTNNB1 mutations. Using a customized cohort, methylation profiling revealed that PS formed a common cluster with solid pseudopapillary neoplasm of the pancreas (SPNP), distinct from all methylation classes from the Heidelberg sarcoma classifier and a subset of paragangliomas. Transcriptomic analysis showed that PS formed an independent cluster from a control group of tumors (including SPNP). Differential gene expression analysis showed enrichment in genes of the Wnt signaling pathway (HALLMARK gene sets) and biological processes related to sensory perception, among others (gene ontology - biological process [GO-BP]). Additionally, upregulated genes were related to various fetal cell types from the cell type signature data set (MSigDB), particularly of neuronal and epithelial lineage. Immunohistochemical assessment of potential markers identified through gene expression analysis revealed focal-to-diffuse expression of GLUT1 (6/6) and focal/multifocal expression of Brachyury (4/9) and HuD (3/7). Follow-up information, available for 10 cases (median duration of 18 months; range, 7-69 months), showed local recurrences and metastatic spread in 2 patients each. Evidence of response to radiotherapy was documented in one tumor. Altogether, this study expands knowledge on PS and suggests biological links with SPNP, including a potential shared cell of origin.

Humans↗

PubMed2026

A murine model of sepsis induces age- and sex-specific chromatin remodeling in myeloid-derived suppressor cells.

INTRODUCTION: Sepsis survivors frequently develop long-term immune dysfunction, but the epigenetic mechanisms underlying persistent myeloid suppression remain unclear. Myeloid-derived suppressor cells (MDSCs), whose function is shaped by host age and sex, are key contributors to post-sepsis immune dysregulation. METHODS: Here, we present a high-resolution epigenetic map targeting gene promoters of MDSCs after sepsis and daily chronic stress using MAPit-FENGC, a single-molecule assay that simultaneously profiles DNA methylation and chromatin accessibility. In a clinically relevant murine model, including young and older adult male and female mice, splenic MDSCs were isolated for MAPit-FENGC and single-cell RNA sequencing. RESULTS: Unsupervised clustering identified nine promoter classes reflecting chromatin dynamics: age- and sex-dependent sepsis-induced opening (Classes 1-4), persistent closure with varying levels of DNA methylation (Classes 5-7), and constitutive openness post-sepsis (Classes 8, 9). Transcriptomic profiling corroborated these promoter states, linking accessibility with gene expression. CONCLUSIONS: These findings define promoter-level epigenetic classes across a targeted locus panel in splenic CD11b+Gr1+ cells within this murine sepsis model and generate mechanistic hypotheses regarding age- and sex-associated chromatin states.

Animals↗

PubMed2026

DNA hypermethylation of abscisic-acid-related genes helps enhance the cold tolerance of tetraploid rice.

Polyploid plants exhibit enhanced stress resistance and superior adaptability to extreme environments, but the underlying molecular mechanisms remain incompletely understood. Here we confirm that tetraploid rice exhibits stronger cold tolerance than diploid rice. This improved tolerance is mediated by reduced malondialdehyde accumulation, elevated antioxidant enzyme activity, and epigenetic regulation of genes involved in abscisic acid (ABA) biosynthesis and signaling. Under cold stress, tetraploid rice induces stress-responsive genes (especially in the ABA pathway) more rapidly and to higher levels than diploid rice. This enhanced gene expression coincides with increased endogenous ABA accumulation. Furthermore, polyploidization and cold stress synergistically induce high methylation at CG, CHG, and CHH sites in genes and transposons (TEs). Notably, the methylation level of class II TEs in tetraploid rice is significantly higher than in diploid rice under low temperatures. To suppress TE activation in gene promoter regions under cold stress, tetraploid rice enhances the methylation level of ABA pathway-related gene promoters, thereby silencing TEs and maintaining genome stability. Collectively, these results enrich the theoretical understanding of the strong stress tolerance in polyploid plants and provide theoretical support for breeding cold-tolerant polyploid rice varieties.

ABA↗

PubMed2026

Chronic heart failure and GPX3 promoter methylation: A clinical-epigenetic analysis.

BACKGROUND: Selenoprotein GPX3 is linked to Chronic Heart Failure (CHF), but its promoter methylation patterns in CHF remain unclear. OBJECTIVE: To explore CpG methylation in the GPX3 promoter region and its association with clinical parameters in CHF. METHODS: Twenty CHF patients and twenty healthy controls were included. Methylation levels of CpG sites within the GPX3_FA28 promoter region were quantified. Group differences were assessed using appropriate statistical tests. Restricted cubic spline (RCS) models were applied to explore dose-response associations between differentially methylated CpG sites and clinical indicators across multiple physiological systems. RESULTS: Significant locus-specific methylation alterations were identified in CHF patients. CpG_5 showed hypermethylation (P = 0.017), while CpG_9 (P = 0.045) and CpG_19 (P = 0.008) were hypomethylated compared with controls. Patients with NYHA class I/II exhibited higher methylation at CpG_1 (P = 0.028) and CpG_2 (P = 0.040). CpG_5 methylation displayed nonlinear associations (P < 0.05) with total bilirubin (inverted U-shape), carbon dioxide (triphasic), total cholesterol (U-shape), and plateletcrit (wave-like). CpG_9 correlated with activated partial thromboplastin time and hematopoietic markers, while CpG_19 was linked to eosinophil percentage and erythrocyte parameters. CONCLUSIONS: GPX3 promoter methylation displays apparent locus specificity in CHF. Different CpG sites may contribute to CHF pathophysiology through distinct epigenetic mechanisms. These findings highlight the potential of GPX3 methylation as a stratified biomarker in CHF.

Humans↗

PubMed2026

A pragmatic adaptation of the RANO clinical risk score for IDH-Wildtype glioblastoma in the absence of MGMT promoter methylation testing.

BACKGROUND: The novel RANO risk score provides prognostic stratification for patients with IDH-wildtype glioblastoma(GBM) and includes age, Karnofsky Performance Scale(KPS), RANO resection class(RRC), and MGMT promoter methylation(MGMTm). However, MGMTm testing is unavailable in many countries. We aimed to explore the prognostic performance of a RANO-adapted clinical score excluding MGMTm. METHODS: We applied the same scoring system established by original RANO score, excluding MGMTm. Three risk classes were defined as numerical scores derived through tertiles. The primary endpoint was overall survival(OS), and the secondary exploratory endpoint was progression-free survival(PFS). RESULTS: One-hundred twenty patients were included. Three risk classes were identified:low-risk(0-1 points,n:47, 39.2%), intermediate-risk(2-3 points,n:27, 22.5%), and high-risk(≥4 points,n:46, 38.3%). The median OS was 35.5 months(95% CI:21.1-49.9) for the low-risk group, 16 months(95% CI:9.9-22.1) for the intermediate-risk group, and 5 months(95% CI:3.6-6.3) for the high-risk group(p < 0.001). Similarly, the median PFS was 16.3 months(95% CI:12.3-20.3) for the low-risk group, 9.9 months(95% CI:7.2-12.6) for the intermediate-risk group, and 4.1 months(95% CI:3.5-4.7) for the high-risk group(p < 0.001). CONCLUSION: This simplified RANO-adapted score demonstrated promising prognostic stratification using basic clinical parameters. As a pragmatic adaptation study, external validation is required before clinical application, particularly in settings where MGMTm testing is unavailable.

Humans↗

PubMed1978

Decreased activity of peptide-elongation factors after treatment with cholesterol esterase.

1. Peptide-elongation factors were purified from rat liver and treated with cholesterol esterase and phospholipase A2 immobilized on Sepharose 4B. 2. Binding of L-[3H]-phenylalanyl-tRNA to 40S ribosomal subunits was decreased by approx. 70% and to polyribosomes by 30% in the presence of the binding factor incubated with cholesterol esterase. Treatment of this factor with immobilized phospholipase A2 decreased the binding to smaller ribosomal subunits by only about 15%. 3. Poly(U)-dependent phenylalanine polymerization by ribosomal subunits was decreased to approx. 30% of its original value by treatment of both elongation factors with cholesterol esterase. 4. The normal activity of esterase-treated elongation factor in both the binding reaction and peptide-elongation assay was fully recovered by the addition of cholesteryl 14-methyl-hexadecanoate. 5. Different classes of lipids present in peptide-elongation factor 1 have apparently different functions. Whereas phospholipids are required to maintain the strcture of heavy aggregates of this factor, the presence of cholesteryl 14-methylhexadecanoate is obviously necessary for the normal function of peptide-elongation factors.

Animals↗

PubMed2026

DNA methylation biomarkers for early detection of ovarian cancer.

Ovarian cancer (OC) remains difficult to detect at an early stage, and current screening approaches using CA125 and transvaginal ultrasonography have not demonstrated sufficient benefit for population screening. DNA methylation is a promising biomarker class because epigenetic alterations may arise early in tumourigenesis, can be detected in circulating cell-free DNA (cfDNA), and may provide tissue-of-origin information. This review critically evaluates recent evidence on DNA methylation biomarkers for early OC detection. PubMed/MEDLINE, Web of Science, and Scopus were searched for studies published between January 2020 and September 2025, supplemented by selected earlier studies of biological or methodological relevance. Evidence was synthesised across single-gene biomarkers, multi-locus panels, genome-wide signatures, assay platforms, and machine-learning classifiers, with emphasis on early-stage performance, histological representation, comparator populations, analytical methodology, and validation design. Single-gene markers such as BRCA1, RASSF1A, OPCML, HOXA9, and HIC1 show variable performance, while multi-gene and classifier-based approaches generally provide stronger discrimination. However, many studies remain limited by retrospective case-control designs, small FIGO stage I-II subsets, predominance of serous disease, and insufficient prospective validation. Integration with CA125 may improve sensitivity but can reduce specificity, which is critical in low-prevalence screening. Clinical translation will therefore require minimal and reproducible methylation signatures, standardised low-input cfDNA workflows, rigorous external validation, and prospective longitudinal evaluation in intended-use populations.

Humans↗

PubMed1977

DNA-polymerase inhibitors. Rifamycin derivatives.

Ten new derivatives of the antibiotic rifamycin with variable side chains at position 3 were synthesized. The inhibitory activity of these derivatives against DNA-polymerases isolated from avian myeloblastosis virus, E. coli and calf thymus were studied at various conditions. 3-(2,4,6-trinitrophenylhydrazone-(methyl) rifamycin SV is a strong inhibitor for all the polymerases tested and belongs to the C class inhibitors of reverse transcriptase. 3-(monoallylhydrazone-(methyl) rifamycin SV possesses a selective action on polymerases: at 0.1 mg/ml concentration it almost completely inhibits the reverse transcriptase and less than half of the bacterial and eukaryotic enzymes. A drug is found which strongly inhibits the DNA-polymerases from E. coli and calf thymus and weakly the viral enzyme. The inhibitory effect on reverse transcriptase is independent of the choice of template-primer; it could be overcome by the addition of excess enzyme but not of excess template-primer; the inhibition could be completely reversed by dilution of the drug-enzyme mixture. From Lineweaver-Burk analysis, the inhibition is noncompetitive with respect to the template-primer and, thus the drugs bind to the site different from the active site for the template-primer. From protective action of the template-primer and other data it might be suggested that the rifamycin derivatives act at an early step(s) in DNA synthesis catalyzed by reverse transcriptase. The obtained data are in agreement with the results for other derivatives of rifamycin SV described in literature.

Animals↗

PubMed2023

A DUAL MTOR/NAD+ ACTING GEROTHERAPY.

The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it's largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with a novel class of N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, we identified lipid metabolism centering on SIRT3 as a point of intersection of the mTOR/insulin and NAD+ pathways. In vivo testing indicated that BIOIO-1001 reduced high fat, high sugar diet-induced metabolic derangements, inflammation, and fibrosis, each being characteristic of non-alcoholic steatohepatitis (NASH). An unbiased screen of patient datasets suggested a potential link between the anti-inflammatory and anti-fibrotic effects of BIOIO-1001 in NASH models to those in amyotrophic lateral sclerosis (ALS). Directed experiments subsequently determined that BIOIO-1001 was protective in both sporadic and familial ALS models. Both NASH and ALS have no treatments and suffer from a lack of convenient biomarkers to monitor therapeutic efficacy. A potential strength in considering BIOIO-1001 as a therapy is that the blood biomarker that it modulates, namely plasma triglycerides, can be conveniently used to screen patients for responders. More conceptually, to our knowledge BIOIO-1001 is a first therapy that fits the geroscience hypothesis by acting on multiple core aging pathways and that can alleviate multiple conditions after they have set in.

Preprint↗

PubMed1978

Chemical modification of mitochondrial transhydrogenase: evidence for two classes of sulfhydryl groups.

Chemical-modification studies on submitochondrial particle pyridine dinucleotide transhydrogenase (EC 1.6.1.1) demonstrate the presence of one class of sulfhydryl group in the nicotinamide adenine dinucleotide phosphate (NADP) site and another peripheral to the active site. Reaction of the peripheral sulfhydryl group with N-ethylmaleimide, or both classes with 5,5'-dithiobis(2-nitrobenzoic acid), completely inactivated transhydrogenase. NADP+ or NADPH nearly completely protected against 5,5'-dithiobis(2-nitrobenzoic acid) inactivation and modification of both classes of sulfhydryl groups, while NADP+ only partially protected against and NADPH substantially stimulated N-ethylmaleimide inactivation. Methyl methanethiolsulfonate treatment resulted in methanethiolation at both classes of sulfhydryl groups, and either NADP+ or NADPH protected only the NADP site group. S-Methanethio and S-cyano transhydrogenases were active derivatives with pH optima shifted about 1 unit lower than that of the native enzyme. These experiments indicate that neither class of sulfhydryl group is essential for transhydrogenation. Lack of involvement of either sulfhydryl group in energy coupling to transhydrogenation is suggested by the observations that S-methanethio transhydrogenase is functional in (a) energy-linked transhydrogenation promoted by phenazine methosulfate mediated ascorbate oxidation and (b) the generation of a membrane potential during the reduction of NAD+ by reduced nicotinamide adenine dinucleotide phosphate (NADPH).

Animals↗

PubMed2026

High-grade astrocytoma with piloid features: a clinical and genomic analysis of prognostic factors using a large cohort.

BACKGROUND: High-grade astrocytoma with piloid features (HGAP) is a recently defined tumor type that is not well-understood. Prognostic factors of clinical outcomes are not well-established. METHODS: Methylation profiling was performed on tumor samples, many at the National Cancer Institute (NCI) Laboratory of Pathology, and others from publicly available sources. Methylation classifier scores of ≥ 0.90 to the HGAP class on the NCI-Bethesda classifier version 3 were included. Clinical features were collected from the medical record. Survival analyses were performed using the Kaplan-Meier and Cox-proportional hazards methods. RESULTS: The cohort comprised 421 patients. There were high rates of ATRX alteration (62%), CDKN2A/B homozygous loss (78%) and MGMT promoter methylation (53%). MAPK alterations were identified in 74% of evaluable samples. The median age was 46 years, and posterior fossa location was predominant (52%). The median overall survival (OS) was 88 months. Older age (p = 0.01) and the presence of an ATRX alteration (p = 0.04) were found to be negative prognostic factors. The presence of cystic features on magnetic resonance imaging (MRI) was found to be favorably prognostic (p = 0.01). Factors that were not significantly associated with prognosis included histologic high-grade features, CDKN2A/B homozygous deletion, MGMT promoter methylation, extent of resection, and presence of NF1 syndrome. CONCLUSIONS: This large cohort establishes relative frequencies of several important markers. Additionally, older age, the presence of an ATRX alteration, and cystic features on MRI were found to be prognostic. Our work may aid in optimizing treatment regimens for patients with this tumor type.

ATRX alteration↗

PubMed1978

Antidepressant agents. 9. 3,3-Diphenylcyclobutylamines, a new class of central stimulants.

3,3-Diphenylcyclobutylamine (4), N-methyl-3,3-diphenylcyclobutylamine (6), and N,N-dimethyl-3,3-diphenyl-cyclobutylamine (7) have been prepared and tested as potential antidepressant agents. The secondary (6) and tertiary (7) amines strongly decrease the accumulation of NA and 5-HT in brain slices in vitro and in vivo. The cyclobutylamines also cause motor stimulation. The most potent compound in this respect is the tertiary amine 7. The increase in locomotion is not blocked by pretreatment with phenoxybenzamine, methergoline, or alpha-methyltyrosine. Pretreatment with pimozide or reserpine reduces the hyperactivity induced by 7. This hyperstimulation seems to be caused by a mechanism of action which differs from that of amphetamine. 7 may cause increase in locomotion by release of dopamine from granular stores.

5-Hydroxytryptophan↗

PubMed2026

Metab8D: a metabolic regulome network from multiomics and machine learning.

To explore multiomic regulation of the metabolome, we used machine learning to predict metabolomic variation across ~1000 different cancer cell lines with matched omics data from eight biomolecular classes: genomic copy number variation, mutations, DNA methylation, histone post-translational modifications (PTMs), transcriptomics and RNA splice variants, non-coding transcriptomics (miRNA and lncRNA), proteomics, and phosphoproteomics. Overall, the metabolome is tightly associated with the transcriptome, with coding and non-coding RNAs emerging as top predictors. Peripheral metabolites are predictable via levels of corresponding enzymes, while those in central metabolism require combinatorial predictors in signaling and redox pathways, and may not reflect corresponding pathway expression. We reconstruct multiomic interaction subnetworks for highly predictable metabolites, and YAP1 signaling emerged as a top global predictor across four omic layers. We prioritize predictive multiomic features for single-cell and spatial metabolomics assays. Top predictors were enriched for synthetic-lethal interactions and synergistic combination therapies that target compensatory metabolic modulators.

Machine Learning↗

PubMed1978

2-Pyrrolidinylideneureas, a new class of central nervous system agents.

A series of N-aryl-N'-(1-methyl-2-pyrrolidinylidene)ureas was prepared and screened for pharmacological activity. Congeners possessing either phenyl or phenyl substituted with 4-nitro, 3-bromo, 3-chloro, 3-fluoro, and 3-methyl groups were found to demonstrate anxiolytic activity. 2,6-Disubstitution of the phenyl ring with methyl, chloro, and bromo imparted potent muscle-relaxant properties which appear to be centrally mediated. A significant separation of the anxiolytic and muscle-relaxant properties from other CNS activities, e.g., anticonvulsant, sedative, and hypnotic, was achieved.

Animals↗