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PubMed1993

The assembly of signalling complexes by receptor tyrosine kinases.

Cell proliferation in response to growth factors is mediated by specific high affinity receptors. Ligand-binding by receptors of the protein tyrosine kinase family results in the stimulation of several intracellular signal transduction pathways. Key signalling enzymes are recruited to the plasma membrane through the formation of stable complexes with activated receptors. These interactions are mediated by the conserved, non-catalytic SH2 domains present in the signalling molecules, which bind with high affinity and specificity to tyrosine-phosphorylated sequences on the receptors. The assembly of enzyme complexes is emerging as a major mechanism of signal transduction and may regulate the pleiotropic effects of growth factors.

Models, Biological↗
PubMed2002

The cognitive-behavioral model of bulimia nervosa: a direct evaluation.

OBJECTIVE: This study represented the first attempt to directly evaluate Fairburn et al's (1986) cognitive-behavioral model of bulimia nervosa--the model on which the most widely used treatment for bulimia nervosa is based. METHOD: The major predictions of the model were tested using structural equation modeling. Data were collected from the responses of 526 subjects to a number of self-report measures. RESULTS: The factors of self-esteem, overconcern with weight and shape, and dietary restraint accounted for a large proportion of the variance in binge eating and purging. The key pathway in the model was the link between overconcern with weight and shape and the adoption of purgative behaviors, which then fed into a vicious cycle of binge eating and purging. Contrary to Fairburn's hypothesis, high levels of dietary restraint did not predict increased binge eating. DISCUSSION: The results suggest that the components of Fairburn's model may operate to maintain the bulimic cycle in a slightly different way to that originally proposed.

Body Image↗
PubMed1998

Cloning oncogenic ras-regulated genes by differential display.

The coordinated regulation of gene expression is a key cellular function that specifies cell characteristics as well as controls normal physiological processes of the organism. Deregulation of this gene expression leads to a variety of abnormal conditions such as cancer. The ras oncogene is one of the most frequently found mutations in various types of human cancer. The mutated Ras protein constitutively elicits multiple mitogenic signals to the nucleus to alter gene expression of target genes that are involved in a broad range of normal cellular functions. Thus the identification of these genes may provide an important tool toward the understanding of these pathogenic processes. As a first step to reveal these processes at the molecular level and to dissect the key pathway employed by oncogenic Ras protein, we have looked for its target genes in rodent model cell lines using the differential display method. Our initial screening has isolated a number of genes either up- or downregulated by oncogenic ras activation. Although the functional analyses of these genes in terms of ras-mediated cell transformation will be the major challenge, differential display has come to be a very efficient tool that helped us move to the next step. In this short report, we focus primarily on the technical aspects of differential display and experimental designs used in this study.

Animals↗
PubMed1993

SERP1, a serine proteinase inhibitor encoded by myxoma virus, is a secreted glycoprotein that interferes with inflammation.

Myxoma virus is a leporipoxvirus that causes a rapidly lethal, generalized infection known as myxomatosis in the European rabbit (Oryctolagus cuniculus). A characteristic feature of myxomatosis is the specific downregulation of key pathways important for numerous host defenses against the viral infection. The SERP1 gene has significant sequence similarity to the serpin superfamily of serine proteinase inhibitors and is one of many virulence factor genes located within the terminal regions of the myxoma virus genome. Transcriptional analysis of the SERP1 gene in myxoma virus (strain Lausanne) indicates that it is expressed as a late gene and studies using a polyclonal anti-SERP1 antiserum indicate that it encodes a secreted protein with an apparent molecular weight of 55 kDa. Using myxoma virus and recombinant vaccinia virus constructs for experiments with tunicamycin and peptide N-glycosidase F, it is shown that the secreted SERP1 protein is modified by N-linked glycosylation. Mutation of both copies of the SERP1 gene in myxoma virus results in a significant attenuation of the virus, such that more than 50% of infected animals are able to recover from the otherwise lethal infection. Histological analyses of lesions taken from infected animals suggest that in the absence of the SERP1 protein, a more effective inflammatory response occurs, allowing a more rapid resolution of the infection. This suggests that SERP1 contributes to viral pathogenesis by interacting with cellular component(s) involved in the regulation of inflammation.

Animals↗
PubMed2000

Local somatothermal stimulation inhibits motility of the internal anal sphincter through nitrergic neural release of nitric oxide.

PURPOSE: A somatoanal reflex had been demonstrated in our previous work. Because nitric oxide plays an important role in mediating relaxation of the internal anal sphincter, our purpose was to examine whether and how local somatothermal stimulation inhibits the function of the internal anal sphincter by stimulating nitric oxide release via nitrergic neurons and to elucidate the possible mechanism. METHODS: The activity of the internal anal sphincter in anesthetized rabbits was measured by use of continuously perfused, open-tip manometric methods. Local somatothermal stimulation was achieved by applying an electroheating rod 1 cm away from the skin area at the right popliteal region. The responses were further manipulated by pre-treating the rabbits with agonists or antagonists linked to nitric oxide synthesis. RESULTS: The motility of the internal anal sphincter before and during local somatothermal stimulation was significantly different (tonic pressure (mean +/-standard error of the mean), 5.4 +/- 0.3 vs. 4.9 +/- 0.3 mmHg, P = 0.0195; phasic pressure, 3.9 +/- 0.6 vs. 2.9 +/- 0.4 mmHg, P = 0.0002; frequency distribution of the phasic contractions (peak-to-peak interval), 28.9 +/- 3.7 vs. 65.3 +/- 10.4 seconds, P = 0.0001). The response began at approximately one minute after local somatothermal stimulation when the skin temperature was 41 +/- 0.3 degrees C. No anal response was observed when local somatothermal stimulation was applied at the control area. The local somatothermal stimulation-induced internal anal sphincter relaxation was not inhibited by pretreatment with atropine, propranolol, or phentolamine (tonic pressure, 5.8 +/- 1 vs. 5.2 +/- 0.8 mmHg, P = 0.038; phasic pressure, 4.2 +/- 0.9 vs. 3.1 +/- 0.6 mmHg, P = 0.020; peak-to-peak interval, 27.2 +/- 4.3 vs. 52.9 +/- 14.5 seconds, P = 0.043) but was completely blocked by pretreatment with a nitric oxide synthesis inhibitor. The effect of the nitric oxide synthesis inhibitor could be reversed by pretreatment with L-arginine (tonic pressure, 6 +/- 0.7 vs. 5.6 +/- 0.7 mmHg, P = 0.047; phasic pressure, 4.7 +/- 0.7 vs. 3.9 +/- 0.5 mmHg, P = 0.048; peak-to-peak interval, 23.8 +/- 3 vs. 33 +/- 3.7 seconds, P = 0.048), but not by D-arginine. CONCLUSION: Local somatothermal stimulation inhibits internal anal sphincter motility through the activation of nonadrenergic noncholinergic neural release of nitric oxide. This procedure may represent a simplified approach for the treatment of anorectal diseases with hypofunction of the L-arginine/nitric oxide pathway. [Key words: Local somatothermal stimulation; Nitric oxide; Internal anal sphincter; Motility; Moxibustion] Jiang J-K, Chiu J-H, Lin J-K. Local somatothermal stimulation inhibits motility of the internal anal sphincter through nitrergic neural release of nitric oxide.

Anal Canal↗
PubMed1998

Social psychophysiology, social circumstances, and health.

Health varies markedly with social circumstances. While we are still without a comprehensive account of the mechanisms which underlie this variation, it is clear that psychological factors are involved and that key pathways may prove to be psychophysiological. Thus, social psychophysiological research of the kind illustrated in this Special Issue is ideally placed to help unravel some of the mechanisms by which social circumstances impact on health. Nevertheless, the success of this sort of social psychophysiological enterprise most likely depends on reconceptualizing psychophysiological reactivity as a situational, or psychological exposure, concept rather than as an individual difference concept. This shifts the research goal from one of identifying individuals at risk for disease to identifying the psychological exposures that put individuals and groups at risk.

Adaptation, Psychological↗
PubMed2026

Role of semaphorin 4f in cardiac fibroblasts to regulate matrix production through actin remodeling and YAP/TAZ activation.

Cardiac fibrosis remains a critical determinant of adverse outcomes in heart disease, yet effective anti-fibrotic therapies are lacking. While multiple semaphorin family members participate in cardiovascular pathophysiology, the role of semaphorin 4f (Sema4f) in cardiac fibrosis remains unexplored. This study investigates the role and mechanisms of Sema4f in fibrotic remodeling post-myocardial infarction (MI). We employed flow cytometry to characterize cell type-specific Sema4f expression patterns in post-MI hearts. Lineage-specific knockout mice (fibroblast vs. myeloid) were subjected to left anterior descending ligation to assess functional consequences. Proteomic analysis of Sema4f-deficient cardiac fibroblasts was conducted to identify downstream effectors. Key pathways were subsequently validated using pharmacological inhibitors. We found that Sema4f expression was markedly upregulated during the fibrotic phase post-MI, primarily due to fibroblast activation. Fibroblast-, but not myeloid-, specific Sema4f deletion significantly reduced fibrosis and improved cardiac function. Proteomic profiling revealed that Sema4f deficiency led to downregulation of pro-fibrotic gene expression, which was associated with impaired actin cytoskeletal remodeling and decreased nuclear translocation of YAP/TAZ. Pharmacological inhibition of either actin remodeling or YAP/TAZ activity attenuated fibrosis, whereas YAP/TAZ activation abolished the anti-fibrotic effects of Sema4f knockout. Our study provides the first evidence demonstrating the functional role of Sema4f in cardiac fibroblast activation and fibrosis progression. We have identified a fibroblast-specific mechanism mediated by the Sema4f-actin cytoskeleton-YAP/TAZ axis, offering novel mechanistic insights into fibrosis regulation and revealing a promising therapeutic target for cardiac fibrosis with potential clinical applications.

Animals↗
PubMed2000

Hypertension and single nucleotide polymorphisms.

Hypertension is a common, complex disease phenotype that has been intensively studied to identify susceptibility loci in humans. Candidate genes continue to be uncovered via genetic analysis in model organisms through linkage analysis with families and/or sib-pairs and through association studies using sequence variants in genes that play a role in key pathways regulating blood pressure in humans, such as the renin-angiotensin system (RAS). Recent studies exploring the sequence diversity in human candidate genes suggest that the distribution and organization of single nucleotide polymorphisms (SNPs) within and among human populations is complex. Issues related to the use of SNPs in analyzing the genetic determinants of hypertension are illustrated using recent studies on the angiotensin-converting enzyme (ACE).

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2026

Genetic determinants of obesity: mechanisms, clinical implications, and targeted therapies.

PURPOSE: Obesity is a major global health crisis with rising prevalence in both pediatric and adult populations, leading to an increased risk of cardiovascular, metabolic, and other chronic complications affecting all organ systems. A clear understanding of the genetic contributors to polygenic, syndromic, and monogenic obesity is essential for early diagnosis and targeted management. METHODS: Advances in genome-wide association studies (GWAS) and sequencing technologies have greatly expanded our understanding of the genetic alterations underlying this multifaceted disease and have helped in delivering personalized treatment. RESULTS: The pathogenesis of common, polygenic obesity is related to a complex interplay between genetic susceptibility and environmental factors. Syndromic obesity, a less common form, is characterized by early-onset accompanied by additional features such as developmental delay, dysmorphic traits, and various organ system involvement. The rarest form, monogenic obesity, is characterized by severe early-onset non-syndromic obesity caused by mutations in single genes regulating appetite within the hypothalamus. These monogenic obesity cases, though infrequent, have been instrumental in elucidating key pathways involved in hunger and satiety. CONCLUSION: This review provides a comprehensive summary of the most recent findings on the genetic basis of obesity across all age groups, highlighting clinical implications and emerging therapeutic opportunities.

Humans↗
PubMed2025

Synergic impact mechanisms of cover crop residue on Cd and As availability and native organic carbon mineralization in Cd and As co-contaminated paddy soil.

The synergic impacts of cover crop residue on heavy metal and metalloid availability and soil organic carbon (SOC) mineralization in contaminated paddy soil and the underlying microbial mechanism remain unclear. This study investigated the availability of cadmium (Cd) and arsenic (As) and mineralization of native SOC in paddy soil treated with 0, 0.4 %, 0.8 % and 1.2 % of δ13C-labeled cover crop residue (Astragalus sinicus L.) via 90-day incubation experiments, the related functional genes and functional microbial communities were analyzed using metagenomic binning assembly. Cover crop residue with addition rate from 0.4 % to 1.2 % significantly decreased available Cd by 56 %-85 % but increased available As by 39 %-66 % compared to the control treatment. Cover crop residue resulted in a positive priming effect on native SOC mineralization but benefited SOC sequestration. Cover crop residue increased the abundance of genes encoding iron reductase (mtrABC, pilA, omcB), sulfate reductase (sir, fpr), As(V) reductase (ArsC), organic carbon hydrolases, methanogenesis, and methylotrophy. Genomes associated with Chloroflexota and Bacteroidota encoded all these key pathways, and their abundance increased with cover crop residue application. Cover crop residue decreased soil Eh, dissolved crystalline iron oxides, enriched specific microorganisms, including Chloroflexota and Bacteroidota, and then synergistically promoted the decrease in Cd availability and the increase in As availability and native SOC mineralization in the examined paddy soil. These findings provided practical and feasible guidance for achieving both safe production and carbon sequestration in contaminated paddy fields, highlighting the requirement to cautious utilization of cover crop residue in As-contaminated paddy fileds.

Soil Pollutants↗
PubMed2003

Alzheimer's disease and total plasma aminothiols.

BACKGROUND: Plasma homocysteine is elevated in Alzheimer's disease, but little is known regarding levels of related aminothiols in the disease. We therefore determined total plasma homocysteine, cysteine, and glutathione levels in patients and control subjects and investigated their relationship with cognitive scores. METHODS: We performed a prospective, case-controlled survey based in two UK Psychogeriatric Assessment Centres. Fifty patients with features compatible with DSM-IV criteria for primary degenerative dementia of Alzheimer type were recruited together with 57 cognitively intact age- and gender-matched control subjects. Mini-Mental State and Alzheimer's Disease Assessment Scale-Cognitive Subsection (ADAS-Cog) scores were determined for patients and control subjects. Aminothiols were assayed with an automated high-performance liquid chromatography (HPLC) system. RESULTS: Patients had significantly elevated total plasma homocysteine (p <.001) and cysteine (p <.01), but there were no group differences for total plasma glutathione. Glutathione was, however, a highly significant and independent predictor of cognitive scores in patients (p =.002); lower plasma levels were associated with more severe cognitive impairment. CONCLUSIONS: Total plasma homocysteine and cysteine are elevated in Alzheimer's disease, suggesting intact transsulphuration but defective remethylation of homocysteine in the disease. Total plasma glutathione levels in patients correlate with cognitive scores. Taken together, these observations perhaps reflect the differential effects of Alzheimer's disease-related oxidative stress on the two key pathways of homocysteine metabolism.

Aged↗
PubMed2002

New therapies in sickle cell disease.

CONTEXT: New therapies have evolved from our improved understanding of the biology of sickle cell disease (SCD) and the availability of a useful transgenic animal model. Several therapeutic options are available that interrupt the sickling process at various key pathways. Nitric oxide (NO)is a critical factor in the pathophysiology of SCD and is a promising antisickling agent with vasodilation properties. NO regulates blood vessel tone, endothelial adhesion, and the severity of ischaemia-reperfusion injury and anaemia in SCD. Although NO is difficult to administer, its precursor, L-arginine, is an oral supplement. STARTING POINT: J R Romero and colleagues recently demonstrated in sickle transgenic mice that oral arginine supplementation induced NO production and reduced red-cell density by inhibiting the Gardos channel, which modulates cell hydration and polymerisation of haemoglobin S (Blood 2002; 99:1103-08). Haemoglobinopathies can be cured by stem-cell transplantation. This therapy is now accepted treatment in symptomatic children. However, most patients lack a genotypically identical family donor. G La Nasa and colleagues demonstrated unrelated-donor stem-cell transplantation may give similar results to related-donor stem-cell transplantation when extended phenotypic matching is used (Blood 2002; 99: 4350-56). This pilot study offers the possibility of cure to patients without a family donor. WHERE NEXT: Although potential opportunities to prevent morbidity in SCD through new therapies are exciting, most patients do not have access to standard multidisciplinary specialty care. Patients require both.

Anemia, Sickle Cell↗
PubMed1996

Role of rate-limiting enzymes of nucleotide metabolism in taurocholate-induced DNA synthesis inhibition.

BACKGROUND/AIMS: In previous studies we have shown the ability of bile acids to reduce the rate of thymidine incorporation into DNA by the regenerating rodent liver. The aim of the present work was to investigate the sensitivity of the key pathways involved in thymidine metabolism to taurocholate. METHODS/RESULTS: Incubation of [14C]-thymidine with mouse liver extracts revealed that addition of taurocholate to the reaction medium induced significant dose-dependent inhibition in the activity of the salvage nucleotide pathway rate-limiting enzyme, thymidine kinase, while other steps of nucleotide metabolism machinery, such as the rate-limiting enzyme of de novo deoxyribonucleotide synthesis, ribonucleotide reductase and the rate-limiting enzyme of thymidine catabolism, dihydropyrimidine dehydrogenase were found to be insensitive to inhibition by taurocholate. Additional experiments were carried out on isolated perfused rat livers whose regeneration was induced by two-thirds hepatectomy and synchronized by intravenous administration of reversible ribonucleic reductase inhibitor hydroxyurea (bolus: 170 mumol/100 g body weight, plus 10 h infusion: 2.0 mumol/min per 100 g body weight, from 14 to 24 h after hepatectomy). Hydroxyurea treatment was interrupted and liver perfusions were carried out 0, 2, 4 or 8 h later. Thymidine incorporation into DNA over 30 min perfusion with media containing [14C]-thymidine was measured after separating DNA from acid-soluble fraction. A marked increase in DNA synthesis was observed up to 4 h after stopping ribonucleotide reductase inhibition. At this time, reduced relevance of the salvage pathway can be expected as compared with the de novo released pathway. In contrast with the inhibitory effect observed when taurocholate was added to the perfusate of untreated regenerating livers, taurocholate was found to have no effect on DNA synthesis, at the peak of synchronized DNA synthesis, although taurocholate-induced alteration in thymidine metabolism was suggested from h.p.l.c. analysis of acid-soluble fraction. CONCLUSIONS: These results suggest that effects on the nucleotide metabolism machinery, and hence changes in deoxyribonucleotide phosphate pools may underlie the ability of taurocholate to affect DNA synthesis by the regenerating rodent liver.

Animals↗
PubMed2002

Physical activity increases the dissociation between subjective sleepiness and objective performance levels during extended wakefulness in human.

The process of heat loss has been shown to be a key pathway regulating sleepiness in humans. The influence of physical exercise with its attending heat production on subjective sleepiness and performance levels during total sleep deprivation (SD) was assessed in eight healthy young volunteers (mean age 21.1 years). Each subject participated in a SD cross-over study in which sleepiness and performance levels were tested under exercise and non-exercise conditions. The exercise entailed 15 min walking/h (3.0 Kcal/kg per h caloric consumption). Physical exercise significantly alleviated subjective sleepiness depending on the magnitude of the core body temperature elevation. This indicates that suppressing heat loss could prevent progression of subjective sleepiness during the nighttime. We found a strong positive correlation between increased sleepiness and decreased performance levels in each of the two experimental sessions. However, ANCOVA revealed a significant difference in the slope of the regression lines representing two sessions, indicating less subjective sleepiness with physical exercise despite the same decrease in performance. The present findings alert us to the possibility that increased physical activity during extended wakefulness could increase the dissociation between subjective evaluation of sleepiness and actual brain function, resulting in increased risk of human error.

Adult↗
PubMed2000

Protein phosphatases and the regulation of mitogen-activated protein kinase signalling.

The magnitude and duration of signalling through mitogen- and stress-activated kinases are critical determinants of biological effect. This reflects a balance between the activities of upstream activators and a complex regulatory network of protein phosphatases. These mitogen-activated protein kinase phosphatases include both dual-specificity (threonine/tyrosine) and tyrosine-specific enzymes, and recent evidence suggests that a single mitogen-activated protein kinase isoform may be acted upon by both classes of protein phosphatase. In both cases, substrate selectivity is determined by specific protein-protein interactions mediated through noncatalytic amino-terminal mitogen-activated protein kinase binding domains. Future challenges include the determination of exactly how this network of protein phosphatases interacts selectively with mitogen-activated protein kinase signalling complexes to achieve precise regulation of these key pathways in mammalian cells.

Animals↗
PubMed2024

Role of RNA G-Quadruplexes in the Japanese Encephalitis Virus Genome and Their Recognition as Prospective Antiviral Targets.

G-quadruplexes (GQs) have been primarily studied in the context of cancer and neurodegenerative pathologies. However, recent research has shifted focus to their existence and functional roles in viral genomes, revealing GQ-regulated key pathways in various human pathogenic viruses. While GQ structures have been reported in the genomes of emerging and re-emerging viruses, RNA viruses have been understudied compared to DNA viruses, including notable examples such as human immunodeficiency virus-1, hepatitis C virus, Ebola virus, Nipah virus, Zika virus, and SARS-CoV-2. The flavivirus family, comprising the Japanese encephalitis virus (JEV), poses a significant global threat due to recurring outbreaks yet lacks approved antivirals. In this study, we identified and characterized eight putative G-quadruplex-forming motifs within essential genes involved in genome replication, assembly, and internalization in the host cell, conserved across different JEV isolates. The formation and stability of these motifs were validated through a multitude of biophysical and cell-based assays. The interaction and binding affinity of these motifs with the known GQ-binding ligand BRACO-19 were supported by biophysical assays, confirming the capability of these motifs to form GQ structures. Notably, BRACO-19 also exerted antiviral properties through reduction of viral replication and infectious virus titers as well as inhibition of viral protein expression, as evaluated by the cell-based assays. This comprehensive molecular characterization of G-quadruplex structures within the JEV genome highlights their potential as promising antiviral targets for intervention strategies against JEV infection through GQ-specific ligands.

G-Quadruplexes↗
PubMed2000

Aspects of the biosynthesis of non-aromatic fungal polyketides by iterative polyketide synthases.

Lovastatin biosynthesis in Aspergillus terreus involves two unusual type I multifunctional polyketide syntheses (PKSs). Lovastatin nonaketide synthase (LNKS), the product of the lovB gene, is an iterative PKS that interacts with LovC, a putative enoyl reductase, to catalyze the 35 separate reactions in the biosynthesis of dihydromonacolin L, a lovastatin precursor. LNKS also displays Diels-Alderase activity in vitro. Lovastatin diketide synthase (LDKS) made by lovF, in contrast, acts non-iteratively like the bacterial modular PKSs to make (2R)-2-methylbutyric acid. Then, like LNKS, LDKS interacts closely with another protein, the LovD transesterase enzyme that catalyzes attachment of the 2-methylbutyric acid to monacolin J in the final step of the lovastatin pathway. Key features of the genes for these four enzymes and others, plus the regulatory and self-resistance factors involved in lovastatin production, are also described.

Anti-Bacterial Agents↗
PubMed2025

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities.

Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal ( https://public.cgr.astrazeneca.com/t2d-pgs/v1/ ).

Humans↗