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PubMed2026

Epigenetic clues: Predicting maternal depression through DNA methylation.

Perinatal depression (PND) is a prevalent and multifactorial mood disorder affecting approximately 10-20 % of women globally, with higher burdens reported in low- and middle-income countries. Despite the availability of screening tools such as the Edinburgh Postnatal Depression Scale, these approaches primarily identify risk without elucidating underlying biological mechanisms. Emerging evidence highlights the role of epigenetic regulation particularly DNA methylation as a key mediator linking genetic susceptibility and environmental exposures during the perinatal period. This review synthesizes current knowledge on DNA methylation dynamics in maternal depression, emphasizing both candidate gene and epigenome-wide association study (EWAS) approaches. Candidate gene studies have identified differential methylation in stress-related pathways, including HPA axis genes (NR3C1, FKBP5), serotonergic signalling (SLC6A4), and oxytocin pathways (OXTR), though findings remain limited by poor reproducibility and small sample sizes. In contrast, EWAS provides a hypothesis-free framework, identifying novel differentially methylated positions and regions associated with PND, including predictive CpG panels with potential diagnostic utility. The review also highlights the importance of tissue specificity, temporal epigenetic remodeling across pregnancy, and the interplay between maternal and fetal epigenomes. Furthermore, methodological challenges such as heterogeneity in study design, lack of replication, and analytical inconsistencies remain barriers to clinical translation. Integrating genetic, epigenetic, and environmental data through multi-omics approaches may enhance predictive accuracy and improve early intervention strategies. Overall, DNA methylation represents a promising avenue for understanding the biological underpinnings of PND and developing robust biomarkers for risk prediction and personalized care.

Humans↗

PubMed2026

Single-cell and spatial transcriptomic technologies for lung cancer tumor microenvironment analysis.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide; beyond its rising incidence, its marked molecular heterogeneity and complex tumor microenvironment (TME) hinder treatment response and drive resistance, contributing directly to its high mortality rate. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) provide complementary approaches for dissecting these features. scRNA-seq enables high-resolution analysis of cellular diversity and transcriptional states but requires tissue dissociation and therefore loses spatial context. In contrast, ST preserves tissue architecture and provides insights into how gene-expression programs within the TME are organized, although no currently available spatial platform combines whole-transcriptome coverage with true single-cell resolution over large tissue areas. Together, these technologies have enabled detailed mapping of tumor, immune and stromal populations and of their spatial interactions, revealing functionally distinct cellular niches that contribute to immune evasion, metastasis and response to therapy. In this narrative review we organize the primary literature around a single question, how spatially structured cellular ecosystems, rather than individual cell types, determine therapeutic response and resistance in lung cancer - and we explicitly separate observations that are reproducible across independent cohorts and platforms from those that remain confined to single studies. We further summarize the technical, analytical and logistic barriers that currently prevent spatially resolved signatures from entering routine diagnostic pathology. Understanding dysregulated pathways and spatially constrained intercellular communication within the TME helps identify candidate biomarkers and may support the identification of therapeutic approaches directed at tumor-intrinsic programs as well as at microenvironment-driven resistance mechanisms.

Cell-cell communication↗

PubMed2005

Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia.

Phenotypic discordance for schizophrenia in monozygotic twins clearly indicates involvement of environmental factors as key determinants in disease development. Positive findings from genome scans, linkage and association studies apply in only a minority of those affected, while post-mortem brain investigations reveal altered expression of genes and proteins involved in numerous neurodevelopmental, metabolic and neurotransmitter pathways. Such altered expressions could result, on the one hand, from mutations in coding regions or polymorphisms in the promoter and regulatory regions in genes within those areas identified by gene searches or, on the other hand, from inadequate amounts of modulators, transporters and synthesizers of transcription factors necessary for regulation of the putative genes. Hormones and vitamins are such modulators. They could serve as bridges between genes and environment in schizophrenia. Multiple evidence supports the suggestion of retinoids and thyroid hormones as plausible actors in these roles. Both are not only essential for normal development of the central nervous system but also regulate the expression of many neurotransmitters, their synthesizing enzymes and receptors, and other genes in broader signaling transduction cascades affecting pathways that are altered in response to treatment. Functional and positional candidate genes include retinoic acid and thyroid hormone receptors, retinaldehyde dehydrogenases and deiodinases, which synthesize the powerful morphogens, retinoic acid and triiodothyronine, and the enzymes involved in their inactivation. This review highlights selective evidence supporting the retinoid and thyroid hormone hypotheses of schizophrenia.

Animals↗

PubMed2026

Identifying the regulatory network of the key lipid metabolism transcription factor peroxisome proliferator-activated receptor in oysters.

Rising seawater temperatures driven by global warming have led to summer mass mortality events that pose significant challenges for the oyster industry. Peroxisome proliferator-activated receptor (PPAR) serves as a key transcriptional regulator of lipid metabolism and plays an essential role in thermal adaptation. However, the upstream regulatory mechanisms of PPAR remain poorly understood in marine organisms. In this study, we identified two PPAR subtypes (PPARα and PPARβ/δ) in oysters and compared transcriptomic data in different tissues and under various environmental stressors, with PPARα exhibiting higher expression levels and responsiveness to environmental stresses. We observed significantly higher PPARα gene expression levels and promoter activity in the relatively cold-tolerant Crassostrea gigas compared to C. angulata. The low expression of the inhibitory transcription factor CTNNB1 in C. gigas may contribute to higher gene expression of PPARα. Additionally, the expression genome-wide association study (eGWAS) identified 9 significant SNPs and 124 candidate regulatory genes associated with PPARα expression, including ubiquitination, phosphorylation, signaling pathways, lipid metabolism, and glucose metabolism. We provided the first experimental validation of the PPARα ubiquitination-degradation pathway in marine organisms via Co-IP, which was mediated by the E3 ligase RFWD3. The protein kinase SNF1 and signaling-related proteins PIKA and KCNK2 indirectly modulated PPARα downstream pathway activation to varying degrees. This study presents the first systematic investigation of PPARα expression regulation in marine organisms. It identifies key molecular regulators and provides novel insights into lipid metabolic regulation and molecular targets for genetic improvement of heat tolerance in oysters under global warming.

Animals↗

PubMed2004

Development of a same day laminectomy program.

Historically, patients undergoing a lumbar laminectomy for discectomy (LLD) have been admitted to the hospital for 1 to 3 days. Because a patient undergoing a surgical procedure is not necessarily medically ill, many surgical procedures are now performed on an outpatient basis. A multidisciplinary nursing team proposed that some patients scheduled to undergo an LLD would be able to have this surgery as an outpatient. A 6-month research project was developed to study outcomes of patients undergoing LLD who were discharged after 4 to 6 hours of postoperative care in the PACU. Guidelines were established to define the candidates for enrollment in the same day LLD. A patient clinical pathway was established, and outcome monitors were selected. Twenty-seven patients were enrolled in this study. This article describes the process of development, application, and future implications of this study.

Ambulatory Surgical Procedures↗

PubMed2005

Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa.

Since identification of the genetic component in anorexia nervosa (AN), genes that partake in serotonergic and dopaminergic systems and in hormonal and weight regulation have been suggested as potential candidates for AN susceptibility. We propose another set of candidate genes. Those are genes that are involved in the signaling pathway using NMDA-R and SK channels and have been suggested as possible effectors of NMDA-R driven signaling. The role of NMDA-R in the etiology of schizophrenia has already been substantiated on various levels. Several studies based on population and family groups have implicated SK3 in schizophrenia and more recently in AN as well. Our study group consisted of 90 AN family trios. We examined the transmission of two potentially functional polymorphisms, 5073T>G polymorphism in the gene encoding the NR2B subunit of NMDA-R and CAG repeats in the coding region of SK3 channel gene. Using HHRR and TDT approaches, we found that both polymorphisms were preferentially transmitted to AN offspring (TDT yielded chi(2)=5.01, p=0.025 for NR2B 5073G alleles and chi(2)=11.75, p<0.001 for SK3 L alleles including >19 repeats). Distribution analysis of the combined NR2B/SK3 genotypes suggests that the contribution of both polymorphisms to AN risk is independent and cumulative (OR=2.44 for NR2B GG genotype and OR=3.01 for SK3 SL and LL genotypes, and OR=6.8 for the combined NR2B/SK3 genotypes including high-risk alleles). These findings point to the contribution of genes associated with the NMDA-R signaling pathway to predisposition and development of AN.

Adolescent↗

PubMed2005

The physiological role of GLP-1 in human: incretin, ileal brake or more?

The proglucagon-derived peptide glucagon-like peptide-1 (GLP-1) is an intestinal signal peptide postprandially released from the L cells of the lower gut. Exogenously administered the synthetic hormone exerts a glucose-dependent insulinotropic effect at the pancreatic beta-cells and lowers plasma glucagon by an inhibitory effect against the alpha-cells. It delays gastric emptying by relaxation of the gastric fundus, inhibition of antral contractility, and stimulation of both the tonic and phasic motility of the pyloric sphincter. Enhancement of insulin, suppression of glucagon, and inhibition of gastric emptying are the main determinants controlling glucose homeostasis with GLP-1. Human studies employing the specific GLP-1 receptor antagonist exendin(9-39) show that endogenously released GLP-1 likewise controls fasting plasma glucagon, stimulates insulin, and influences all the motoric mechanisms known to control gastric emptying. Therefore, GLP-1 is discussed as an incretin hormone and as an enterogastrone in man. Synthetic GLP-1 also suppresses gastric acid and pancreatic enzyme secretion. The inhibitory effects on upper gastrointestinal functions are at least partly mediated by vagal-cholinergic inhibition and may involve interactions with vagal afferent pathways and/or circumventricular regions within the CNS. GLP-1 is a candidate humoral mediator of the 'ileal brake' exerting inhibition of upper gastrointestinal function preventing malabsorption and postprandial metabolic disturbances. As human studies indicate a central action of GLP-1 in reduction of food intake, it is uncertain if this is a consequence of induction of satiety or of transduction of visceral aversive stress signals.

Gastrointestinal Hormones↗

PubMed2005

The nanos translational control element represses translation in somatic cells by a Bearded box-like motif.

Developmental control of translation is frequently mediated by regulatory elements that reside within 3' untranslated regions (3' UTRs). Two stem-loops within the nanos 3' UTR translational control element (TCE) act independently to direct translational repression of maternal nanos mRNA in the ovary or embryo. We have previously shown that the nanos TCE can also function in select somatic sites. Using an ectopic expression screen, we now identify a new site of TCE function, the dorsal pouch epithelium. Analysis of TCE mutants reveals that TCE activity in the dorsal pouch does not depend on either of the stem-loops required for maternal TCE function, but instead requires a third feature-a sequence that closely matches the Bearded box, a regulatory motif found in the 3' UTRs of several Notch pathway genes. In addition, we identify pleiohomeotic mRNA as an endogenous candidate for regulation by Bearded box-like motifs in the dorsal pouch. Together, these results suggest that the TCE has appropriated a conserved regulatory motif to expand its function to somatic tissues.

3' Untranslated Regions↗

PubMed2006

Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease.

Mulefoot disease (MFD) is an autosomal recessive disorder of phenotypically variable expression that causes syndactyly in certain strains of cows. MFD maps to a narrow interval on bovine chromosome 15 that is syntenic to human chromosome 11p12-p11.2. This region contains MEGF7/LRP4 (approved gene symbol LRP4), a gene that encodes a member of the multifunctional low-density lipoprotein receptor gene family. Targeted and naturally occurring mutations in the murine Megf7/Lrp4 gene, a putative coreceptor in the Wnt signaling pathway, cause polysyndactyly in the rodent. Thus, Megf7/Lrp4 is a strong candidate for the MFD mutation. Using PCR analysis of tissue samples and sperm from confirmed homozygous MFD carriers, we have identified a functional single base pair mutation in the affected animals. We show that a G --> A transition at the first nucleotide in the splice donor site of intron 37 completely disables this splice site. The abnormal splicing that is caused by this mutation predicts the generation of a dysfunctional membrane-anchored receptor lacking the normal cytoplasmic domain. These findings confirm that autosomal recessive loss-of-function mutations in Megf7/Lrp4 result in phenotypically similar forms of syndactyly in different mammalian species and that such mutations are the cause of MFD in bovines.

Amino Acid Sequence↗

PubMed2026

Integrated GWAS and methylation analysis identify DNMT3A as an important regulator of growth in rabbits.

The parameters of individual growth curve can serve as pseudo-phenotype for genetic evaluation in livestock. In this study, we compared five nonlinear growth models using post-weaning body weights of 706 New Zealand White rabbits. Under the best-fitting model, two parameters of mature weight and maturity rate were subjected to GWAS through single-step genomic BLUP framework that integrated phenotypic records from non-genotyped animals with 41,359 SNPs genotyped in 198 individuals. Association analysis identified 147 relevant genomic regions, and also highlighted DNMT3A as a promising candidate gene for further functional investigation. siRNA-mediated knockdown of DNMT3A significantly impaired myoblast proliferation. Whole-genome bisulfite sequencing of DNMT3A-knockdown myoblasts identified 69,480 differentially methylated regions (DMRs). Integrative analyses revealed substantial overlap between DMR-associated genes and GWAS candidate genes, with significant enrichment in vitamin B6 and tyrosine metabolism pathways. These findings suggest that DNMT3A may regulate rabbit growth via mediating DNA methylation of downstream genes.

Animals↗

PubMed2006

The role of vascular and hormonal genes in migraine susceptibility.

Migraine is a primary headache disorder that involves both genetic and environmental components. Migraine is considered to be a polygenic disorder with a number of susceptibility genes having a minor but nonetheless significant impact on susceptibility. Migraine candidate gene studies have concentrated mainly on genes involved in neurotransmitter pathways, however evidence also exists for a role for alterations in vascular and hormonal function in migraine susceptibility. We present here a mini-review of genetic studies, investigating the potential role of vascular and hormonal gene variants, and discuss how vascular and hormonal dysfunction may impact on migraine susceptibility. We propose that the potential role of vascular and hormonal genes in this disorder warrants further investigation.

Blood Vessels↗

PubMed2001

Validation of surrogate endpoint biomarkers in prostate cancer chemoprevention trials.

Phase 2 cancer chemoprevention trials are designed to provide estimates of the efficacy of an agent at a specified dose, and the expected size of the risk reduction that may be achieved in a subsequent phase 3 randomized trial. To allow these trials to be rapid and efficient, the study outcome is modulation of a surrogate endpoint biomarker (SEB), that is, a molecular event assumed to be on the causal pathway between the chemopreventive agent and the desired reduction in cancer incidence. However, SEBs commonly used in prostate cancer chemoprevention studies, such as prostate-specific antigen, high grade prostatic intraepithelial neoplasia, proliferation, and apoptosis, have not been validated by documenting that changes in the SEBs ultimately translate to decreased prostate cancer risk. Because of uncertainty in the pathway from SEBs to cancer, additional considerations are necessary to permit valid inferences from phase 2 trial data. This article considers the framework underlying validation and use of SEBs in specific chemoprevention models and methodologic issues in quantifying the effect of an agent. In particular, inferences depend on whether a single pathway involving the SEBs is assumed to mediate the effect of the agent on cancer incidence. If there are competing pathways of equal or greater importance than the one involving the candidate SEB, then the estimate of chemopreventive efficacy will be biased and may greatly underestimate the magnitude of the achievable risk reduction. Strategies for validating biomarkers and minimizing the degree of bias in the risk reduction estimate are discussed. Finally, problems associated with phase 2 study designs commonly used for prostate cancer chemoprevention are discussed, along with possible solutions.

Apoptosis↗

PubMedDate not supplied

Transient receptor potential (TRP) channels as potential drug targets in respiratory disease.

Calcium-permeable channels have traditionally been thought of as therapeutic targets in excitable cells. For instance, voltage-operated Ca2+ channels in neurones and smooth muscle cells for neurological and cardiovascular diseases although calcium-permeable channels are also functionally important in electrically non-excitable cells. In the lung, calcium channels play a pivotal role in the activation of all the cell types present, whether resident cells such as airway smooth muscle cells and macrophages or migratory cells such as neutrophils or lymphocytes.Previously, research in this area has been hindered by the lack of obvious molecular identity. More recently, the emergence of the transient receptor potential (TRP) cation family has yielded promising candidates which may underpin the different receptor-operated calcium influx pathways. The challenge now, is to ascribe function to the TRP channels expressed in each cell type as a first step in identifying which TRP channels may be potential drug targets for asthma and chronic obstructive pulmonary disease (COPD) (Fig. 1).

Asthma↗

PubMed1999

Head in the WNT: the molecular nature of Spemann's head organizer.

Formation of the head during vertebrate embryogenesis has been one of the most-studied topics in development, probably because we are such cephalized beings ourselves. Early experimenters found that the head is induced during gastrulation by Spemann's organizer. In 1999 we celebrate the 75th anniversary of the discovery of the organizer by Spemann and Mangold, a group of cells in amphibia that secretes powerful signalling molecules. Recently, advances have been made in identifying candidate head inducers. Not surprisingly, these inducers act in familiar molecular pathways, namely transforming growth factor beta (TGF-beta) and WNT signalling.

Animals↗

PubMed2002

G-protein-coupled signaling in Arabidopsis.

With an essentially complete plant genome in hand, it is now possible to conclude that a single or possibly just two canonical heterotrimeric G-protein complexes are present in Arabidopsis. In stark contrast, more than one hundred such complexes are found in some metazoans. Nonetheless, it appears that heterotrimeric G-protein complexes couple or affect many different signaling pathways in plants. In addition, there are very few, if any, candidate G-protein-coupled receptors through which this single complex can couple to downstream effectors. Furthermore, some of the classical downstream effectors that are activated by heterotrimeric G proteins in metazoans are also lacking in plants. Thus, we are left with the urgent challenge to determine the novel mechanism of G-protein signaling in plant cells. Recent advances using reverse and molecular genetic approaches have re-opened this topic for plant biologists and the resulting tools will accelerate our progress.

Arabidopsis↗

PubMed2004

Fusion of HIV-1 Tat protein transduction domain to poly-lysine as a new DNA delivery tool.

Effective gene therapy depends on the efficient transfer of therapeutic genes to target cells. None of the current technologies, however, satisfy all of the requirements necessary for gene therapy, because the plasma and nuclear membranes of mammalian cells are tight barriers against gene transfer using synthetic delivery systems. The protein transduction domain (PTD) of human immunodeficiency virus type 1 (HIV-1) Tat protein greatly facilitates protein transfer via membrane destabilisation. We synthesised polylysine peptides containing Tat PTD (TAT-pK), or other sequences, and investigated their potential as agents for gene transfer. The synthesised polypeptide TAT-pK retains DNA binding function and mediates delivery of a reporter gene to cultured cells. RGD motif binds with low affinity to alpha integrins which induce cell activation. Two control polypeptides, GGG-pK and RGD-pK, were synthesised and tested, but their gene transfer abilities were weaker than those of TAT-pK. TAT-pK-mediated gene transfer was enhanced in the presence of chloroquine or ammonium chloride, to a greater extent than that of cationic lipid-mediated gene transfer in most cancer cell lines tested. These data suggest that TAT-pK may be a potent candidate delivery vehicle that promotes gene transfer, dependent on the endocytic pathway. We conclude that the TAT-pK/DNA complex is useful as a minimal unit to package therapeutic genes and to transduce them into mammalian cells.

Carcinoma↗

PubMed2001

Monosomy for the most telomeric, gene-rich region of the short arm of human chromosome 16 causes minimal phenotypic effects.

We have examined the phenotypic effects of 21 independent deletions from the fully sequenced and annotated 356 kb telomeric region of the short arm of chromosome 16 (16p13.3). Fifteen genes contained within this region have been highly conserved throughout evolution and encode proteins involved in important housekeeping functions, synthesis of haemoglobin, signalling pathways and critical developmental pathways. Although a priori many of these genes would be considered candidates for critical haploinsufficient genes, none of the deletions within the 356 kb interval cause any discernible phenotype other than alpha thalassaemia whether inherited via the maternal or paternal line. These findings contrast with previous observations on patients with larger (> 1 Mb) deletions from the 16p telomere and therefore address the mechanisms by which monosomy gives rise to human genetic disease.

Adolescent↗

PubMed2006

Blockade of the tumor necrosis factor-related apoptosis inducing ligand death receptor DR5 prevents beta-amyloid neurotoxicity.

We originally suggested that inhibition of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) death pathway could be taken into consideration as a potential therapeutic strategy for Alzheimer's disease (AD). However, because the critical role of TRAIL in immune surveillance, the neutralization of TRAIL protein by an antibody to prevent its binding to death receptors is definitely a risky approach. Here, we demonstrated that the blockade of the TRAIL death receptor DR5 with a specific antibody completely prevented amyloid beta peptide (A beta) neurotoxicity in both neuronal cell line and primary cortical neurons. DR5 was demonstrated to be a key factor in TRAIL death pathway. In fact, whereas TRAIL expression was enhanced dose-dependently by concentrations of beta amyloid ranging from 10 nM to 1 microM, only the highest toxic dose of A beta (25 microM) induced the increased expression of DR5 and neuronal cell death. In addition, the increased expression of DR5 receptor after beta amyloid treatment was sustained by p53 transcriptional activity, as demonstrated by the data showing that the p53 inhibitor Pifithrin alpha prevented both beta amyloid-induced DR5 induction and cell death. These data suggest a sequential activation of p53 and DR5 upon beta amyloid exposure. Further insight into the key role of DR5 in AD was suggested by data showing a significant increase of DR5 receptor in cortical slices of AD brain. Thus, these findings may give intracellular TRAIL pathway a role in AD pathophysiology, making DR5 receptor a possible candidate as a pharmacological target.

Aged↗