Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Biologic pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed2004

Retinoid X receptors: X-ploring their (patho)physiological functions.

Retinoid X receptor (RXR) belongs to a family of ligand-activated transcription factors that regulate many aspects of metazoan life. A class of nuclear receptors requires RXR as heterodimerization partner for their function. This places RXR in the crossroad of multiple distinct biological pathways. This and the fact that the debate on the endogenous ligand requirement for RXR is not yet settled make RXR still an enigmatic transcription factor. Here, we review some of the biology of RXR. We place RXR into the evolution of nuclear receptors, review structural details and ligands of the receptor. Then processes regulated by RXR are discussed focusing on the developmental roles deduced from studies on knockout animals and metabolic roles in diseases such as diabetes and atherosclerosis deduced from pharmacological studies. Finally, aspects of RXR's involvement in myeloid differentiation and apoptosis are summarized along with issues on RXR's suitability as a therapeutic target.

Animals↗
PubMed2005

Distinct CpG methylation profiles characterize different clinical groups of neuroblastic tumors.

The hypermethylation of CpG islands within gene promoter regions is an epigenetic phenomenon that is often, but not always, associated with the transcriptional silencing of downstream genes and contributes to carcinogenesis. We have determined the pattern of methylation of several genes involved in distinct biological pathways, including cell proliferation and apoptosis, in neuroblastoma and in the nonmalignant ganglioneuroma. The purpose of this work was to search for epigenetic signatures that could be associated with defined clinical and biological parameters and that, in prospective, could identify specific risk categories among the patients. We have analysed 31 malignant neuroblastoma with or without MYCN amplification and 13 benign ganglioneuroma and we have observed dramatic differences in the methylation pattern of five genes (CASP8, 14.3.3sigma, DeltaN-p73, RASSF1A and DCR2) between these tumors indicating that this phenomenon is not tissue-specific and can be considered as cancer-dependent. Furthermore, the methylation pattern of 14.3.3sigma, RASSF1A and of an intragenic segment of CASP8 was significantly different between MYCN amplified and single copy neuroblastoma suggesting a specific role of epigenetic alterations in aggressive neuroblastoma.

14-3-3 Proteins↗
PubMed2025

Unique signatures of highly constrained genes across publicly available genomic databases.

PURPOSE: Publicly available genomic databases are critical in understanding human genetic variation. They also provide unique insights into patterns of genetic constraints and their relationship with human disease. METHODS: We utilized one of the largest publicly available databases, Genome Aggregate Database, to determine genes that are highly constrained for only loss-of-function, only missense, and both loss-of-function/missense variants. We identified their unique signatures and explored their causal relationship with human diseases. Those genes were also evaluated for chromosomal location, tissue-level expression, Gene Ontology analysis, and gene family categorization using multiple publicly available databases. RESULTS: We identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways for those constrained genes associated with human disease. In addition, we identified genes that are currently not known to cause human disease, which may be excellent gene discovery candidates. CONCLUSION: We elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins. The findings can also advance research in rare diseases.

Humans↗
PubMed2001

Ras-GAP SH3 domain binding protein (G3BP) is a modulator of USP10, a novel human ubiquitin specific protease.

Degradation of cellular proteins through ubiquitination is a fundamental strategy for regulating biological pathways. De-ubiquitination, i.e. the removal of ubiquitin from proteins and peptides to which ubiquitin is attached, is catalyzed by processing proteases known as de-ubiquitinating enzymes. We are studying the biology of a family of de-ubiquitinating enzymes, the mammalian ubiquitin-specific proteases (USPs), some of which appear to play a role in growth control. Given the fact that the modes of regulation of USPs and of their substrate specificity are poorly understood, we decided to attempt the identification of USP interacting proteins. Using the yeast two-hybrid system (2HS), we have isolated a cDNA clone whose product specifically interacts with USP10 but not with other USP baits tested. The isolated clone encodes a protein known to interact with the Ras-GTPase activating protein (G3BP). This interaction was further confirmed by performing a 2HS with G3BP, which led to the isolation of USP10 encoding cDNAs. We validated the interaction between the two proteins by performing in vitro binding assays and immunoprecipitations in human cells. G3BP does not appear to be a substrate of USP10; it rather inhibits the ability of USP10 to disassemble ubiquitin chains. The USP10/G3BP complex appears to co-immunoprecipitate with ubiquitinated species that could be substrates of USP10.

Amino Acid Sequence↗
PubMed2002

Identifying functional links between genes using conserved chromosomal proximity.

Conservation of proximity of a pair of genes across multiple genomes generally indicates that their functions could be linked. Here, we present a systematic evaluation using 42 complete microbial genomes from 25 phylogenetic groups to test the reliability of this observation in predicting function for genes. We find a relationship between the number of phylogenetic groups in which a gene pair is proximate and the probability that the pair belongs to a common pathway. Our method produces 1586 links between ortholog families substantiated by observed proximity in genomes representing at least three phylogenetic groups. Of the pairs annotated in the KEGG database, 80% are in the same biological pathway in KEGG.

Chromosome Mapping↗
PubMed2026

Differential DNA methylation in blood as potential mediator of the association between ambient PM2.5 and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort.

Fine particulate matter (PM2.5) is a known risk factor for Alzheimer's disease (AD), with emerging evidence showing its effects detectable in the pre-clinical stage through cerebrospinal fluid (CSF) biomarkers of AD. While studies have linked PM2.5 exposure and AD to DNA methylation (DNAm) alterations, the role of DNAm as potential mediator in the association between PM2.5 and AD biomarkers in cognitively normal individuals remains largely unexplored, and formal mediation analyses addressing this question are scarce. Genome-wide DNAm profiles (Illumina EPIC BeadChips) in whole blood and CSF Aβ42 concentrations were assessed in 536 cognitively normal individuals from the Emory Healthy Brain Study (EHBS). Residential PM2.5 exposure for the year preceding participants' blood collection was estimated. A multi-stage analytical pipeline, incorporating single-mediator analysis, high-dimensional mediation analysis, and causal mediation analysis, was applied. Nine CpG sites were identified as noteworthy mediators of the relationship between PM2.5 and decreased CSF Aβ42 concentrations. Causal mediation analysis confirmed significant natural indirect effects (NIE) for eight CpGs, with effect estimates ranging from -0.015--0.029 per 1 ug/m3 increase in PM2.5 exposure. The proportion mediated ranging from 14-43%. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. These findings suggest that differential DNAm, particularly in genes related to neuroinflammation, mediates the association between PM2.5 exposure and CSF Aβ42 concentrations, highlighting the utility of blood DNAm in detecting and studying biological pathways underlying PM2.5 toxicity in the pre-clinical stages of AD.

Humans↗
PubMed2025

Comorbidity alters the genetic relationship between anxiety disorders and major depression.

BACKGROUND: Comorbid anxiety disorders (ANX) and major depression (MD) have worse clinical outcomes than either disorder alone. Analysis of genomic data based on comorbidity status may reveal more precise biological pathways and causal relationships with potential clinical implications. We investigated the genetic relationship between ANX and MD with and without mutual comorbidity. METHODS: We leveraged data from UK Biobank to perform disorder-specific genome-wide association studies (GWAS) of ANX-only (n=189,422) and MD-only (n=194,339) and generate polygenic risk scores (PRS). The Norwegian Mother, Father, and Child Cohort (MoBa, n = 130,992) served to test the associations of PRS with diagnoses. MD and ANX GWAS, including comorbidities (MD-comorbid and ANX-comorbid), were used for comparison. Genetic correlations were compared by comorbidity status, and Mendelian randomization was employed to assess causal relationships. RESULTS: The MD-only PRS showed a stronger association with MD-only compared to ANX-only cases (Z=3.74; Padjusted=0.002); however, MD-comorbid PRS did not show a significant difference (Z=2.71; Padjusted=0.08). The genetic correlation between ANX-only and MD-only was 0.53, lower than between ANX-comorbid and MD-comorbid (0.90). ANX-only showed a causal relationship with MD-only (Padjusted=0.015), but not vice versa, and contrasted the bidirectional causal relationship (Padjusted=2.9e-12, and Padjusted=9.3e-06) when comorbidity was included. Gene sets of MD-comorbid, ANX-comorbid, and MD-only, but not of ANX-only, were enriched for immune regulation pathways such as interleukin production. CONCLUSIONS: ANX and MD show more distinct genetics when comorbid cases are excluded, and ANX may be causal for MD. Disorder-specific genetic studies help uncover more relevant biological mechanisms and guide tailored clinical interventions.

Journal Article↗
PubMed2026

CeLLTra: aligning cell names with gene expression via a pathway-informed transformer.

MOTIVATION: Single-cell RNA sequencing (scRNA-Seq) technology enables detailed exploration of gene expression at the individual cell level, crucial for annotating cell types and understanding cellular diversity. Traditional methods for cell type annotation often rely on marker genes and manual labeling, posing challenges due to low data quality and incomplete reference datasets. RESULTS: We developed CeLLTra, a novel contrastive learning framework that leverages a Transformer-based model integrating biological pathway information to group genes into super tokens, effectively capturing comprehensive gene expression from scRNA-Seq data. By combining this pathway-informed Transformer with a pretrained domain-specific language model, CeLLTra accurately aligns cell-type annotations with gene expression profiles. Evaluations on a large-scale human scRNA-Seq dataset showed that CeLLTra significantly outperformed state-of-the-art methods in supervised and zero-shot cell-type prediction. Additionally, CeLLTra generalized well to external datasets, improving clustering performance and enabling better characterization of cancerous cell states in tumor-infiltrating myeloid cells from non-small cell lung cancer patients. AVAILABILITY AND IMPLEMENTATION: CeLLTra is freely available on GitHub (https://github.com/WJZheng-group/CeLLTra) and Zenodo (https://doi.org/10.5281/zenodo.17666735). The datasets underlying this article are the following: GSE201333 and GSE127465. All these datasets are publicly available and can be freely accessed on the Gene Expression Omnibus repository.

Humans↗
PubMed2026

Large language models in bioinformatics: a comprehensive survey.

The emergence of foundation models with trillion-level parameters has redefined the landscape of artificial intelligence. Various fields are developing their own large-scale models, which can solve many problems within the field and improve work efficiency. Biological large-scale models are a cross-disciplinary research field that combines mathematics, computer science, and biology, aiming to simulate and understand the structure, function, and dynamic changes of biological systems through the establishment of complex computational models. This field covers multiple levels such as biological pathways, population dynamics, protein folding, etc., providing us with tools for deep exploration of the mysteries of life and applications in medicine, ecology, and other fields. This article reviews the background and research status of biological large-scale models, and discusses future directions. Large language models (LLMs) and other large-scale foundation models have rapidly advanced in recent years, enabling powerful representation learning and generation across text, sequences, and multimodal data. In bioinformatics and biomedicine, these models are increasingly used to analyze genomic sequences, infer protein properties and structures, support drug discovery, and integrate heterogeneous biomedical evidence. This survey reviews the basic principles of LLMs and summarizes representative applications in (i) gene and genome sequence analysis, (ii) protein structure and function prediction, and (iii) drug design, including virtual screening and personalized medicine. We also discuss emerging multi-model modeling approaches, as well as key challenges such as data quality and privacy, interpretability, generalization to new organisms and tasks, and responsible deployment in health-related settings. Finally, we outline future directions for developing reliable, scalable, and explainable bioinformatics foundation models.

bioinformatics↗
PubMed1994

Psychoneuroimmunology of HIV infection.

The biological pathways exist that could allow psychological factors to alter immune status in HIV-positive individuals. It yet remains to be determined whether such factors can, in fact, act as cofactors in HIV progression. The biology of AIDS is complex, and a multitude of processes may act on HIV progression and complicate studies in this area. The search for modifiable host factors that may alter the progression of HIV infection, however, is an important part of AIDS research and deserves the careful attention of behavioral and biological scientists.

Antigens, CD↗
PubMed2006

Helical flow as fluid dynamic signature for atherogenesis risk in aortocoronary bypass. A numeric study.

The main purpose of the study was to verify if helical flow, widely observed in several vessels, might be a signature of the blood dynamics of vein graft anastomosis. We investigated the existence of a relationship between helical flow structures and vascular wall indexes of atherogenesis in aortocoronary bypass models with different geometric features. In particular, we checked for the existence of a relationship between the degree of helical motion and the magnitude of oscillating shear stress in conventional hand-sewn proximal anastomosis. The study is based on the numerical evaluation of four bypass geometries that are attached to a simplified computer representation of the ascending aorta with different angulations relative to aortic outflow. The finite volume technique was used to simulate realistic graft fluid dynamics, including aortic compliance and proper aortic and graft flow rates. A quantitative method was applied to evaluate the level of helicity in the flow field associated with the four bypass models under investigation. A linear inverse relationship (R = -0.97) was found between the oscillating shear index and the helical flow index for the models under investigation. The results obtained support the hypothesis that an arrangement of the flow field in helical patterns may elicit damping in wall shear stress temporal gradients at the proximal graft. Accordingly, helical flow might play a significant role in preventing plaque deposition or in tuning the mechanotransduction pathways of cells. Therefore, results confirm that helical flow constitutes an important flow signature in vessels, and its strength as a fluid dynamic index (for instance in combination with magnetic resonance imaging flow visualization techniques) for risk stratification, in the activation of both mechanical and biological pathways leading to fibrointimal hyperplasia.

Biomechanical Phenomena↗
PubMed1990

Psychosocial effects on immune function: neuroendocrine pathways.

Psychoneuroimmunology represents the newest interdisciplinary endeavor relevant to psychosomatic medicine. Work in this area is particularly exciting because it promises to reveal a more unified view of the individual and the complex interactions between social, psychological, neural, endocrinological, immunological, and genetic factors that contribute to disease. This article reviews the major biological pathways implicated in the psychosocial modulation of immune function and disease resistance.

Autonomic Nervous System↗
PubMed2004

Gene expression profiling of depression and suicide in human prefrontal cortex.

Mood disorders are a major cause of disability. Etiology includes genetic and environmental factors, but the responsible genes have yet to be identified. Using DNA microarrays, we have conducted a large-scale gene expression analysis, in two regions of the human prefrontal cortex from post-mortem matched groups of subjects with major depression who had died by suicide, and control subjects who died from other causes and were free from psychiatric disorders. Bioinformatic analysis was used to investigate molecular and cellular pathways potentially involved in depression and suicidal behavior. We tested several hypotheses of disease pathology and of their putative molecular impact, including changes in single genes, the existence of subgroups of patients or disease subtypes, or the possibility of common biological pathways being affected in the disease process. Within the analytical limits of this relatively large genomic study, we found no evidence for molecular differences that correlated with depression and suicide, suggesting a pathology that is below the detection level of current genomic approaches, or that is either localized to other brain areas, or more associated with post-transcriptional effects and/or changes in protein levels or functions, rather than altered transcriptome in the prefrontal cortex.

Adult↗
PubMed2006

Gene expression analysis in a canine model of X-linked Alport syndrome.

Chronic kidney disease (CKD) often culminates in renal failure as a consequence of progressive interstitial fibrosis and is an important cause of illness and death in dogs. Identification of disease biomarkers and gene expression changes will yield valuable information regarding the specific biological pathways involved in disease progression. Toward these goals, gene expression changes in the renal cortex of dogs with X-linked Alport syndrome (XLAS) were examined using microarray technology. Extensive changes in inflammatory, metabolic, immune, and extracellular matrix biology were revealed in affected dogs. Statistical analysis showed 133 genes that were robustly induced or repressed in affected animals relative to age-matched littermates. Altered expression of numerous major histocompatibility complex (MHC) molecules suggests that the immune system plays a significant role in XLAS. Increased expression of COL4A1 and TIMP-1 at the end stage of disease supports the suggestion that expression increases in association with progression of fibrosis and confirms an observation of increased COL4A1 protein expression. Clusterin may function as one of the primary defenses of the renal cortex against progressive injury in dogs with XLAS, as demonstrated here by increased CLU gene expression. Cellular mechanisms that function during excess oxidative stress might also act to deter renal damage, as evidenced by alterations in gene expression of SOD1, ACO1, FDXR, and GPX1. This investigation provides a better understanding of interstitial fibrosis pathogenesis, and potential biomarkers for early detection, factors that are essential to discovering more effective treatments thereby reducing clinical illness and death due to CKD.

Animals↗
PubMed2001

Caspase mRNA expression in a rat model of focal cerebral ischemia.

Proteins of the caspase family are involved in the signalling pathway that ultimately leads to programmed cell death (apoptosis), which has been reported to occur in some experimental models of stroke. In a previous paper we used quantitative reverse transcription and polymerase chain reaction (RT-PCR) to characterise changes in the mRNA expression of one member of this family, caspase-3, in a rat model of permanent focal ischemia. Here we have used this technique to study the expression of a further three caspases which are involved in different aspects of caspase signalling. Caspase-8, involved in Fas-mediated apoptosis, was upregulated in the cortex of ischemic rats. Caspase-11, which leads to the synthesis of the functional form of the cytokine interleukin-1 beta, also showed increased expression, but with a different temporal profile from caspase-8. In contrast, caspase-9, which forms part of the pathway signalling through the mitochondria, showed a decrease in expression. The expression of a further four caspases (1, 2, 6 and 7) has also been characterised in a simpler experiment. These caspases all showed distinctive patterns of expression following the induction of ischemia. These data lead us to conclude that caspase expression as a whole is under very strict transcriptional control in this model. Certain elements of caspase signalling, such as the Fas-induced pathway and the events upstream of IL-1 beta processing, are upregulated, while others are not. This may be due to some form of genetic program activated in response to ischemia in the brain and may highlight which biological pathways are modulated.

Animals↗
PubMed2005

Interaction of rapid signal transduction cascades and gene expression in mediating estrogen effects on memory over the life span.

Estrogen treatment during middle-age postpones memory impairments, which depend on the hippocampus. However, estrogen responsiveness diminishes with advanced age. The challenge remains to determine, which processes are important for delaying brain aging and the mechanisms for decreased sensitivity. Estrogen can influence transcription through estrogen receptors (e.g., ERalpha and ERbeta) and membrane effects on rapid signal transduction cascades ultimately influencing the phosphorylation state of transcription factors. In middle-aged animals, the membrane effects involve Ca2+ and G-protein cascades, which rapidly counteract senescent physiology. Moreover, estrogen induces transcription for elements of signal transduction cascades that decline with age. Together, the rapid and genomic influences promote synaptic transmission and cell growth. Thus, interruption of genomic/membrane interactions due to loss of ERs, disruption of the hormone cycle, or uncoupling of the hormone/receptor system associated with extended exposure to estrogen could contribute to a decline in these biological pathways during aging.

Aging↗
PubMed2005

T1DBase, a community web-based resource for type 1 diabetes research.

T1DBase (http://T1DBase.org) is a public website and database that supports the type 1 diabetes (T1D) research community. The site is currently focused on the molecular genetics and biology of T1D susceptibility and pathogenesis. It includes the following datasets: annotated genome sequence for human, rat and mouse; information on genetically identified T1D susceptibility regions in human, rat and mouse, and genetic linkage and association studies pertaining to T1D; descriptions of NOD mouse congenic strains; the Beta Cell Gene Expression Bank, which reports expression levels of genes in beta cells under various conditions, and annotations of gene function in beta cells; data on gene expression in a variety of tissues and organs; and biological pathways from KEGG and BioCarta. Tools on the site include the GBrowse genome browser, site-wide context dependent search, Connect-the-Dots for connecting gene and other identifiers from multiple data sources, Cytoscape for visualizing and analyzing biological networks, and the GESTALT workbench for genome annotation. All data are open access and all software is open source.

Animals↗
PubMed2004

Rational drug design of multifunctional phosphoramidate substituted nucleoside analogs.

This review focuses on our approach to the study of the effect of a series of phosphoramidate substituted nucleoside analogs on model systems for cancer, HIV and fertility. This approach allowed the development of compound WHI-07, an arylphosphoramidate derivative of zidavudine. This compound is a multifunctional agent showing potent activity in the above mentioned model systems. Our rational drug design provided such a powerful derivative with all the necessary characteristic of a drug candidate. Importantly, we have experimental evidence that each of the groups associated with the molecular frame of WHI-07 imparts the multifunctional ability for this agent. In addition, we have also suggested a possible biological pathway for WHI-07 including various products with their therapeutic targets that are formed during the course of its metabolism inside the cell. We also propose which individual moieties in the structure of WHI-07 are responsible for the biological activity from the formation of these metabolites. A detailed structure-activity relationship is presented in the review in connection with various structural modifications of the agent. Application of this active agent in animal models shows the potential usefulness of this agent as a drug candidate. We further plan to utilize gene-chip technology to identify new targets and modes of action using microarrays to measure expression changes in thousands of gene products. In conclusion, we have demonstrated the power of multifunctional drug design to discover drugs to combat various diseases. We believe this is the future direction of the drug discovery process.

Amides↗