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PubMed2026

Integrative analysis and experiment validation of SLC12A8 as a biomarker for the malignant transition from endometriosis to endometriosis associated ovarian cancer.

Endometriosis (EM) is a chronic inflammatory, estrogen‑dependent benign gynecological disorder. A subset of patients with EM may subsequently develop endometriosis‑associated ovarian cancer (EAOC), implying a biological continuum between these two conditions. Nevertheless, the molecular events underlying the progression from benign endometriotic lesions toward EAOC remain incompletely characterized. In this study, transcriptomic datasets retrieved from the GEO database were interrogated through differentially expressed gene screening, functional enrichment analysis, and weighted gene co‑expression network analysis (WGCNA) to identify key genes and pathways relevant to EM and EAOC. Candidate genes were further prioritized by integrating survival analysis via the Kaplan‑Meier Plotter, LASSO regression, random‑forest modeling, and CIBERSORT immune‑infiltration profiling. Loss and gain‑of‑function cellular models were established using siRNA and overexpression plasmids, and in‑vitro functional assays were performed to characterize the phenotypic effects of target genes.We identified several candidate genes associated with EM and EAOC and evaluated their discriminatory performance. Among them, SLC12A8 elevated expression across EM and EAOC tissues and exhibited moderate diagnostic capacity. Higher SLC12A8 expression was also associated with poorer prognosis in EAOC patients. In‑vitro experiments further demonstrated that SLC12A8 modulates proliferation, invasion, and migration in both EM and EAOC cell lines. Collectively, our exploratory research findings support SLC12A8 as a candidate functional mediator and potential biomarker linked to EM‑EAOC pathological progression, thereby extending the mechanistic understanding of these disorders.

Female↗

PubMedDate not supplied

The chromaffin cell and its development.

This article summarizes some of the recent progress in understanding the development of chromaffin cells. These cells are derivatives of the neural crest and are intimately associated with the sympathetic nervous system. Although a common sympathoadrenal (SA) progenitor cell for chromaffin cells and sympathetic neurons has been postulated, there is evidence to suggest that chromaffin progenitors are already distinct, at least in part, from neuronal SA progenitors prior to invading the adrenal gland. The concept of an essential role of glucocorticoid signalling for chromaffin cell development has been shaken by the observation that chromaffin cells in mice lacking the glucocorticoid receptor develop largely normal. Distinct developmental requirements of chromaffin cells and sympathetic neurons must also be assumed based on the analyses of mice carrying targeted mutations of the genes for two transcription factors, MASH1 and Phox2B. Both genes are expressed by SA progenitors, but are distinctly required for the development of chromaffin cells and sympathetic neurons. There is an ongoing search for molecules selectively operating at the sites, where chromaffin cells develop. Such molecules may be candidates for triggering the distinct developmental pathway of chromaffin cells, as opposed to sympathetic neurons.

Adrenal Glands↗

PubMed2001

The genetics of alcoholism and alcohol abuse.

Twin studies have established that there are substantial genetic influences on alcoholism (0.5-0.6) in both men and women. Our knowledge of behaviors predisposing to alcoholism, including anxiety and impulsivity, is advancing rapidly through animal and human studies. Although alcoholism is often comorbid with other substance abuse and psychiatric disorders, recent studies have shown that, with the exception of nicotine, the heritability of alcoholism is largely substance-specific. Increasing understanding of the neurobiology of addiction has identified neural pathways in which genetic variation at candidate genes could influence vulnerability. Some functional variants of these genes have been identified. Recent linkage analyses in humans and rodents have pointed to genomic regions harboring genes that influence alcoholism. Refinement of clinical phenotypes and use of intermediate phenotypes will improve chances of gene identification. All these advances in the understanding of the genetics of alcoholism should facilitate the development of more accurately targeted therapies using molecular diagnostic approaches.

Alcoholism↗

PubMed1996

Long-range interactions in visual perception.

Classical receptive-field concepts have been used to explain local perceptual effects such as border contrast and Mach bands, but are not sufficient to explain global perceptual effects. Examples are the perception of illusory contours, area contrast, color constancy, depth planes, coherent motion and texture contrast. These diverse effects require neurophysiological mechanisms within the visual pathways with long-range interactions. Candidate mechanisms are suggested, including converging feedforward projection to account for the emergence of new response properties at higher levels, recruitment of lateral connections to compensate for loss of afference and explain filling-in, and re-entrant projections from higher levels using synchronization of neuronal responses to account for binding.

Animals↗

PubMed1985

2-Amino-4-phosphonobutyric acid selectively blocks two-way avoidance learning in the mouse.

There seems to be ample evidence supporting the view that glutamate plays a significant role in the mammalian brain as a neurotransmitter. It is considered to be a likely transmitter candidate in one or more hippocampal pathways. Recently it has been visualized in excitatory, possibly glutamatergic, neurons in the hippocampus. Glutamate has been proposed to mediate memory formation. We wanted to see if blocking glutamate action by a specific glutamate antagonist could result in reduction of learning ability. 2-Amino-4-phosphonobutyric acid (APB) is an analogue of glutamic acid and has been used as a glutamate antagonist in electrophysiological studies on invertebrate neuromuscular junction, retina and hippocampus. We tested the influence of APB on the acquisition of two way avoidance learning in the shuttle box and on learning in the water maze. Our results show that intraperitoneal injection of APB led to a reduction in avoidance learning, whereas learning in the water maze was unaffected.

Aminobutyrates↗

PubMed2005

A genetically encoded indicator for assaying bioactive chemicals that induce nuclear transport of glucocorticoid receptor.

Glucocorticoids, the adrenal steroid hormones secreted during stress, are essential to homeostasis and metabolism in the human body. An impaired glucocorticoid signaling due to dysfunction of the glucocorticoid receptor (GR) by synthetic chemicals can cause diseases and disruptions of the homeostasis and metabolism. Here we demonstrate the development of a method for screening endocrine-disrupting chemicals and potent risk factors of human diseases based on the nuclear trafficking of the GR. We constructed a new assay using a pair of genetic indicators with the full length of the GR, split Renilla luciferase (RLuc), and split DnaE (a protein splicing element). The GR-containing fusion protein with C-terminal halves of DnaE and RLuc is localized in cytosol due to the cytosolic character of the GR, whereas the fusion protein with N-terminal halves of DnaE and RLuc stays in the nucleus due to the cofused nucleus localization signal. On being stimulated with a ligand, the GR is translocated into the cellular nucleus. Thus, a protein splicing occurs in the nucleus by an interaction between the splicing junctions of each DnaE fragment. The enzymatic activities from the reconstituted RLuc allow the ligand-dependent luminescence intensities. The feasibility of the method was evaluated by quantifying the hormonal activities of 20 different kinds of steroids and synthetic chemicals using the NIH 3T3 cells carrying the pair of indicators. The hormonal activities of tested ligands are discussed based on the chemical structure-activity relationship. We found that androgens, testosterone, and 19-nortestosterone weakly induce the nuclear transport of the GR. The current assay allows high-throughput screening of risk chemicals and drug candidates influential to a signal transduction pathway of the GR.

Active Transport, Cell Nucleus↗

PubMed2006

Pharmacogenetics of cancer chemotherapy.

Significant heterogeneity in the efficacy and toxicity of chemotherapeutic agents is observed within cancer populations. Pharmacogenetics (PGx) is the study of inheritance in interindividual variation in drug disposition. The allure of pharmacogenetics, in the treatment of cancer patients, comes from the potential for individualisation of cancer therapy, minimizing toxicity, while maximizing efficacy. In this review we will focus on the current and potential clinical applications of pharmacogenetics in cancer therapy by citing relevant examples and discussing the possible approaches which may be used to establish a reliable, reproducible and cost-effective test for clinically relevant genetic polymorphisms, using easily accessible biological samples (e.g., blood and tumour samples). Ideally, routine management of patients would include analysis of their single nucleotide polymorphism linkage disequilibrium (SNP-LD) profile prior to treatment, allowing stratification of patients into treatment groups, thus individualising their therapy. In order to achieve this ambition, a combination of different approaches (candidate gene, genome-wide and pathway driven) will be required from scientists and clinician scientists, as well as an increased understanding and incorporation of pharmacogenetic aims and endpoints into current and future clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Gene-diet interactions on body weight changes.

Obesity is one of the most pressing problems in the industrialized world. The susceptibility to obesity is partly determined by genetic factors, but an "obesity-promoting environment" is typically necessary for its phenotypic expression. Such a genetically mediated susceptibility to environmental exposure is referred to as gene-environment interaction. This article reviews the effect of genotype-diet interactions on body weight and body composition changes. A few well-controlled studies with monozygotic twins have specifically addressed the genetic background of interindividual variation in response to overfeeding or energy restriction. Some individuals will gain or lose weight more easily than others, but subjects sharing the same genotype (monozygotic twins) will respond in a similar way, suggesting that the responsiveness to diet is mediated by their genotype. Further evidence for gene-environment interactions comes from candidate gene studies. Genes involved in pathways regulating energy expenditure and food intake may play a role in the predisposition to obesity. For example, DNA sequence variation in genes encoding the adrenergic receptors and uncoupling proteins are of particular relevance. This growing body of research may help in the development of antiobesity treatments and perhaps genetic tests to predict the risk for obesity.

Body Composition↗

PubMed2005

Expression profiling of human fetal growth plate cartilage by EST sequencing.

The differentiation of mesenchymal stem cells into hypertrophic chondrocytes is an integral and multistep process important in pattern formation, endochondral ossification, and postnatal growth of the skeleton. In recent years, novel genes involved in these processes have been identified, but still only little is known about the large-scale gene expression profile during skeletal development. We initiated an expressed sequence tag (EST) project aiming at the identification of genes and pathways involved in this complex process. Candidate genes are expected to be of value for diagnosis and treatment of monogenic and multigenic heritable disorders of the skeleton. Here, we describe the sequences of 4,748 clones from a human growth plate cartilage cDNA library generated from 20 weeks prenatal-2 years postnatal specimens. In silico analysis of these sequences revealed 1,688 individual transcription units, corresponding to known (1,274) and to novel, yet uncharacterised potential genes (414). The tissue specificity of the library was reflected by its corresponding EST profile representing a total of approximately 10% proteins already shown to be involved in cartilage/bone development or homeostasis. The EST profile also reflects the developmental stage of the tissue with significant differences in the expression of matrix proteins compared to corresponding EST profiles from 8-12 and 12-20 week human fetal cartilage. Calculation of the relative frequency of transcripts in our cDNA library, as compared to their abundance in other EST datasets, revealed a set of approximately 200 genes, including 81 novel, yet uncharacterised genes, showing increased expression. These genes represent candidates for the large number of osteochondrodysplasias for which the causative gene defects have not yet been identified.

Expressed Sequence Tags↗

PubMed2005

Photoinducible and rhythmic ICER-CREM immunoreactivity in the rat suprachiasmatic nucleus.

Several genes expressed in the suprachiasmatic nucleus (SCN) are induced by light and are candidate links in the photic entrainment pathway of the SCN's circadian clock. Since the cAMP response element binding protein (CREB) and CRE-mediated gene transcription in the SCN appears to be crucial for light-induced phase shifts of circadian rhythmicity, we analyzed the immunohistochemical expression of proteins encoded by the cAMP response element modulator (CREM) gene, including a repressor isoform (inducible cAMP early repressor [ICER]). ICER-CREM immunoreactivity was detected in cells of the ventrolateral subdivision of the rat SCN after light administration during the subjective night in constant darkness; but only late after light onset (at 240 min), following earlier successive peaks of phosphorylated CREB protein (by 5 min), c-fos mRNA (by 40 min), per 1 mRNA (by 55 min), and c-Fos protein (by 60 min). In constant darkness, there was a modest but significant endogenous rhythm of ICER-CREM immunoreactivity, with a two-fold difference between high levels at circadian time (CT) 10 and low levels at CT 22. Our data raise the possibility that ICER-CREM might be involved in downregulating the SCN expression of immediate-early and "clock" genes after their induction by phase-shifting light pulses.

Analysis of Variance↗

PubMed2026

Genetic structure and selection signatures of Beijing-You chicken populations provide insight into breed conservation.

Preserving genetic diversity and maintaining population viability are critical yet challenging goals that demand rigorous evaluation of conservation strategies. Beijing-You chicken, as the sole indigenous chicken breed originating from Beijing, China, is currently maintained as four independent populations under distinct conservation programs. How different conservation regimes have shaped its genomic architecture remains largely unknown, limiting evidence-based evaluation. Here, we generated whole-genome resequencing data from 240 individuals representing four Beijing-You chicken populations to assess population structure, genetic diversity, and signatures of selection over decades of conservation. All four populations formed distinct clusters, reflecting measurable differentiation after decades of separate conservation. The differences in genetic diversity were broadly consistent with the variation in effective population size estimates. Runs of homozygosity and linkage disequilibrium decay patterns further characterized each population, with extended values indicating reduced effective population size and increased inbreeding under long-term conservation. We applied the fixation index (FST) and pairwise diversity ratio (θπ) methods to identify selection signatures. A total of 171 genes were identified as candidates. These genes were enriched in pathways related to reproduction, growth regulation, and environmental adaptation. These findings highlight patterns of reduced diversity and skewed relatedness, which could arise from management-related factors such as breeding preferences or mating strategies. Still, they are also compatible with neutral processes, including drift and founder effects. Regardless of the underlying cause, integrating scientifically informed conservation strategies with routine genomic monitoring across generations is essential for sustaining genetic diversity in Beijing-You chicken and other indigenous breeds.

Beijing-You chicken↗

PubMed2026

Effects of domestication on the body morphology and genetic diversity of the yellowfin seabream (Acanthopagrus latus).

The yellowfin seabream (Acanthopagrus latus) is a significant economic fish along the southeast coast of China. Recently, the drastic decline in the wild populations, exacerbated by overfishing and climate change, has heightened our reliance on aquaculture. However, the current lack of research on its domestication hinders effective conservation of wild populations and balanced management alongside the aquaculture industry. Studies on body characteristics have shown that wild yellowfin seabream possess a higher body, while cultured ones exhibit a wider body. Whole-genome SNP analysis revealed moderate genetic differentiation between cultured and wild populations. Further analyses of linkage disequilibrium, heterozygosity, and genetic diversity revealed that the degree of SNP linkage was lower in the wild population compared to the cultured population. In contrast, heterozygosity and nucleotide polymorphisms were significantly higher in the wild population (P < 0.001 and P < 0.05, respectively). Additionally, over 300 candidate genes were identified in each cultured population through genomic selection signature analysis, with 67 key genes shared among all three, which were linked to growth and development (ghrb, ghsra, and cfl1), immune response (aire, cd36, and igbp1), and salinity adaptation (abcc3, clic4, and kcnk15). Enrichment analysis indicated that the key candidate genes were significantly enriched in pathways related to protein kinase activity, ion binding and growth hormone synthesis, secretion and action (FDR < 0.05). The findings provide valuable insights into the variation in body size of yellowfin seabream under domestication selection and offer an important theoretical basis for the genetic improvement of yellowfin seabream.

Animals↗

PubMed1992

Cognitive components of naming in children: effects of referential uncertainty and stimulus realism.

The ease of picture naming in children was assessed as a function of two stimulus characteristics: (a) the number of available correct names for a picture (referential uncertainty) and (b) the degree to which a picture realistically represents the depicted object (stimulus realism). Two experiments employing different methods demonstrated that: (a) children named low uncertainty objects (those with a single dominant name, e.g., key, elephant) faster than high uncertainty objects (those with multiple possible correct names, e.g., lamp/light, stove/oven) and (b) this uncertainty effect arose at a stage of naming subsequent to object identification. Possible underlying mechanisms for the uncertainty effect include passive diffusion of activation over multiple object-name pathways or active inhibition among competing candidate names. Stimulus realism (colored photographs vs uncolored line drawings) did not consistently influence naming performance. Implications for understanding children's naming behavior are discussed.

Attention↗

PubMed1999

Neuregulin and erbB receptor expression in normal and diseased human white matter.

Human white matter from non-neurologic cases, multiple sclerosis (MS) and other neurologic diseases (OND, inflammatory and non-inflammatory), was subjected to immunocytochemistry and Western blotting for expression of the neuregulin, glial growth factor-2 (GGF2), and its receptors, erbB2, erbB3 and erbB4. GGF2 has previously been shown to have mitogenic effects upon oligodendrocytes in vitro and an enhancing effect upon remyelination in animals with autoimmune demyelination. In all types of human white matter examined, expression of the ligand GGF2 and its three receptors was consistently found on oligodendrocytes, with higher levels being seen in cases of MS. Expression was also seen, albeit at lower levels, on astrocytes and microglial cells, the latter most commonly in MS and OND. In human lymph node tissue, some lymphocytes were positive for erbB2, erbB3 and erbB4. Western blots confirmed the presence of all three receptors in normal, MS and OND white matter. GGF2 and erbB receptor expression did not correlate with areas of remyelination and reactivity occurred throughout the tissue, with some increase in intensity at the edge of MS lesions. Examination of precursor oligodendrocyte immunoreactivity (with anti-PDGF-Ralpha and NG2), revealed widespread expression throughout both normal and diseased white matter. The presence of GGF2 and its receptors on oligodendrocytes and lymphocytes render this cell type a candidate for functional signaling via this pathway, perhaps in relationship to myelinating activity.

Blotting, Western↗

PubMed2002

Mouse models for psychiatric disorders.

Genes involved in psychiatric disorders are difficult to identify, and those that have been proposed so far remain ambiguous. As it is unrealistic to expect the development of, say, a 'schizophrenic' or 'autistic' mouse, mice are unlikely to have the same role in gene identification in psychiatry as circling mice did in the discovery of human deafness genes. However, many psychiatric disorders are associated with intermediate phenotypes that can be modeled and studied in mice, including physiological or anatomical brain changes and behavioral traits. Mouse models help to evaluate the effect of a human candidate gene mutation on an intermediate trait, and to identify new candidate genes. Once a gene or pathway has been identified, mice are also used to study the interplay of different genes in that system.

Animals↗

PubMed2001

Dopamine and glutamate release in the nucleus accumbens and ventral tegmental area of rat following lateral hypothalamic self-stimulation.

Rewarding hypothalamic brain stimulation is thought to depend on trans-synaptic activation of high-threshold (and thus rarely directly depolarized by rewarding stimulation) dopaminergic fibers of the medial forebrain bundle. We used in vivo microdialysis and high-performance liquid chromatography coupled with electrochemical or fluorometric detection to investigate the concurrent release of dopamine and glutamate in the nucleus accumbens septi and in the ventral tegmental area, as a function of lateral hypothalamic self-stimulation.Self-stimulation at a variety of stimulation frequencies and pulse widths increased levels of dopamine and its primary metabolites, dihydroxyphenylacetic acid and homovanillic acid in the nucleus accumbens. Lateral hypothalamic self-stimulation also induced significant increases in ventral tegmental area dopamine and metabolite levels, and the percentage increase of dopamine was higher in this region than in the nucleus accumbens. Local perfusion with the dopamine uptake inhibitor nomifensine (10 microM) increased dopamine levels in the nucleus accumbens about three-fold and potentiated the increase of dopamine levels induced by self-stimulation. Nomifensine perfusion also induced a delayed decrease in nucleus accumbens glutamate levels, and self-stimulation did not modify this effect of the drug. Local perfusion with the D2-type dopamine receptor antagonist raclopride significantly increased both basal and self-stimulation induced dopamine release in the nucleus accumbens. Neither nomifensine nor raclopride perfusion significantly affected the maximal rates of self-stimulation. Perfusion with tetrodotoxin (2 microM) into nucleus accumbens significantly decreased basal and prevented stimulation-induced increases in accumbens dopamine levels but only slightly decreased the rate of self-stimulation. In contrast, perfusion of tetrodotoxin (0.5 microM) into the ventral tegmental area decreased basal and blocked stimulation-induced increases in both nucleus accumbens and ventral tegmental area dopamine levels; this treatment also blocked or strongly inhibited self-stimulation. While it had no effect on glutamate levels in the nucleus accumbens, lateral hypothalamic self-stimulation induced a significant and tetrodotoxin-sensitive increase in glutamate levels in the ventral tegmental area. Taken together, the present results indicate that, across a broad range of stimulation parameters, rewarding lateral hypothalamus stimulation causes major and persistent activation of the mesolimbic dopamine system, and suggest descending glutamatergic fibers in the medial forebrain bundle as a candidate for the directly activated descending pathway in lateral hypothalamus brain stimulation reward.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2026

Time- and Dose-Resolved DIA-PASEF Proteomics Maps the Transition from Adaptive Stress to Apoptotic Collapse in Melittin-Treated MDA-MB-231 Cells.

Melittin, the cytolytic peptide of honeybee venom, exhibits potent anticancer activity in triple-negative breast cancer (TNBC), yet the molecular programs underlying its cytotoxic effects remain incompletely defined. To address this gap, MDA-MB-231 TNBC cells were exposed to melittin at half-maximal inhibitory concentration(half IC50) and IC50 across early(0.5, 1, and 2 h), mid(3, 4 h), and late (12, 24 h) time windows. Proteomic profiling was performed using label-free data-independent acquisition(DIA) parallel accumulation-serial fragmentation(PASEF). Approximately 5800 proteins were quantified, revealing distinct dose-dependent stress responses. An integrative exploratory framework combining time-resolved log2 fold-change trajectories, area-under-the-curve(AUC) based temporal prioritization, and independent heatmap visualization identified proteins associated with melittin-induced stress remodeling. Half IC50 exposure showed a transient stress-adaptive signature characterized by chromatin remodeling(HMGN2, H2AZ1), structural and RNA-associated buffering(LRRC7), and indirect mitochondrial quality-control signaling(CPAMD8, SPATA4), which progressively weakened over time. In contrast, IC50 treatment induced rapid chromatin remodeling dominated by histone H1 variants(H1.4, H1.2), early RNA instability(LRRC7), and late-stage cytoskeletal disassembly marked by MICAL3 induction, consistent with progression toward apoptosis. These trajectories paralleled dose-dependent apoptotic phenotypes. Overall, data suggest that melittin elicits dose- and time-dependent proteomic stress responses in TNBC cells and identify candidate trajectory-associated proteins and pathways linked to adaptive stress remodeling or progression toward cytotoxic collapse.

Melitten↗

PubMed2005

14-3-3 protein down-regulates key enzyme activities of nitrate and carbohydrate metabolism in potato plants.

The 14-3-3 protein is one of the best candidates for coordinating all plant metabolic pathways. To verify this suggestion transgenic potato plants with repression of one (J4 and J5 plants), two (G1 plants), and six (G3 plants) constitutive 14-3-3 protein isoforms as well as plants overexpressing the 14-3-3 protein were studied. Reduction in the 14-3-3 protein level in the J4 and J5 transformants, the G1 transformants, and the G3 transformants was close to 29, 41.5, 38, and 55%, respectively. In the case of the 14-3-3 overexpressing plants (J2), a 30% increase in protein content was detected. Changes in nitrate reductase (NR), sucrose phosphate synthase (SPS), and starch synthase (SS) activities in the transgenic plants perfectly reflect the overall 14-3-3 protein level. The highest increase in enzyme activities was observed for the G3 plants and the lowest for the J4 transformants. The same was detected for the measured metabolites. The highest increase in the protein, starch, and sucrose levels was detected in the tubers from the G3 transgenic plants. Because there was almost no change in the isoform ratio in the transgenic plants when compared to the control, it is suggested that it is the overall content of the 14-3-3 protein, rather than the content of particular isoforms, which plays a crucial role in the regulation of enzyme activities and thus in metabolite synthesis. The properties of the 14-3-3 overexpressing plants are very similar to those of the control ones, suggesting that the protein is in excess in the nontransformants and a further increase in its content is not recognized by cell metabolism. A considerable influence of the 14-3-3 protein level on potato plant metabolism was demonstrated. This effect was observed in key metabolic enzyme activities and metabolite content as well. A high variability between mean values, representing individual transgenes, with respect to nitrate reductase, sucrose phosphate synthase, and starch synthase activities in the examined genotypes was noted. These changes were closely correlated with metabolite levels, among them protein, starch, reducing sugars, and sucrose. The results obtained for the five types of transgenic potato plants in comparison with the control were statistically assessed using discriminate function and cluster analyses.

14-3-3 Proteins↗