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PubMed2026

Proteomic signatures for sudden cardiac death and related intermediate phenotypes.

BACKGROUND: Novel markers for sudden cardiac death (SCD) are needed. OBJECTIVE: This study aimed to explore whether a protein risk score derived from a large-scale proteomics dataset improves risk prediction of SCD in the general population. METHODS: A total of 52,705 individuals with 1459 unique plasma protein measurements were included from the UK Biobank Pharma Proteomics Project. A protein risk score was developed using lasso-penalized Cox regression on 40,722 participants enrolled at the English centers and validated on 11,983 participants enrolled at the remaining centers. RESULTS: The protein risk score formula developed from the derivation set comprised 64 unique plasma proteins including latent-transforming growth factor beta-binding protein 2, protein tyrosine phosphatase receptor sigma, and spondin-1. In the test set, a per standard deviation increase in protein risk score was associated with a hazard ratio of 2.60 (95% confidence interval [CI] 2.12-3.18) for SCD. Adding a protein risk score to SCD clinical risk factors resulted in a concordance index increase of 0.063 (95% CI 0.037-0.105) for SCD. For ventricular arrhythmia-mediated SCDs, an increase in concordance index when a protein risk score was added to SCD clinical risk factors was 0.070 (95% CI 0.010-0.188). A protein risk score added to SCD clinical risk factors resulted in a risk reclassification of 16.9% (95% CI 9.0-24.7) at a 10-year risk threshold of 5%. A protein risk score was significantly associated with intermediate phenotypes of SCD including corrected QT prolongation, an increase in left ventricular mean myocardial thickness, and a decrease in left ventricular global longitudinal strain. CONCLUSION: A protein risk score derived from a single plasma sample significantly improved risk prediction of SCD and related intermediate phenotypes.

Humans↗

PubMed2026

The Sigma1 ER membrane receptor promotes structural protein folding and genome packaging of dengue virus.

Dengue virus (DENV) exploits the host endoplasmic reticulum (ER) to support viral protein translation and folding, replication, and assembly, although the identity of ER factors that promote these distinct steps during infection remain unclear. Here we demonstrate that the ER-resident Sigma1 ER membrane receptor (S1R) promotes virus structural protein folding and genome packaging of DENV during infection. Under S1R knockdown (KD), DENV infection is impaired without compromising virus translation or replication. Strikingly, EM analysis revealed that DENV particles in and secreted from S1R-depleted cells are smaller, likely because they are empty particles devoid of the vRNA genome. Biochemical experiments demonstrated that S1R binds to the prM structural protein and under S1R KD, the prM, E and C structural proteins became detergent-insoluble. Thus, without S1R, all three virus structural proteins misfold, impairing efficient genome packaging. Together, these findings identify a novel ER chaperone that supports a critical DENV infection step.

Dengue Virus↗

PubMed1979

History and development of mixed opioid agonists, partial agonists and antagonists.

1 A brief history of the development of narcotic antagonists is outlined. 2 The clinical and pharmacological observations leading to the discovery of dualism of opiate receptors are reviewed. 3 An extension of this theory to a three-receptor model (mu, kappa and sigma) is required to rationalize the pharmacology of the antagonists analgesics cyclazocine, pentazocine and nalorphine. 4 The methodologies available for the study of compounds with dual agonist-antagonist activity are discussed in the light of the above receptor multiplicity, and data appertaining to the kappa-partial agonist, nalorphine and the mu-partial agonist buprenorphine are outlined.

Animals↗

PubMed1976

Sigma effects of nalorphine in the chronic spinal dog.

The effects of graded doses of nalorphine and morphine were studied in nondependent chronic spinal dogs. Morphine and low doses of nalorphine produced behavioral changes characterized by indifference, whereas the largest dose of nalorphine produced canine delirium indistinguishable from that produced by SKF-10, 047 or cyclazocine. Nalorphine depressed the flexor reflex; however, a plateau was observed. The data suggest that nalorphine is a partial agonist of the kappa type and a sigma agonist in addition to being a competitive antagonist at the mu receptor, and further, that the dysphoric and hallucinogenic effects of nalorphine-like drugs are due to their sigma activity.

Animals↗

PubMed1977

Ultrastructural visualization of cellular carbohydrate components by means of lectins on ultrathin glycol methacrylate sections.

A method for the visualization of cellular carbohydrate components by both light and electron microscopy using lectins on glycol methacrylate sections is proposed. This method, which is an application of the lectin-peroxidase affinity technique, solves the problem of limited penetration when it is attempted to demonstrated lectins receptors within the tissue block. Following partial dissolution of glycol methacrylate from thin sections using alcohol, they are incubated successively with lectin (Concanavalin A or wheat germ agglutinin), horseradish peroxidase (Sigma, type II), 3-3' diaminobenzidine and H2O2 and then with OsO4-Different kinds of tissues and cells have been used to test the method: mouse myocardium, rat epididymis, a protozoon Gregarina blaberae and the bacterium Escherichia coli. The localization of carbohydrate residues deomonstrated by this method within the different tissues and cells is consistent with the findings from other published studies. Controls have been performed (i.e., omission of the lectin, lectin and its inhibitor) and these demonstrate the specificity of the method.

Animals↗

PubMed1977

Structure and biological function of human IgD. IX. Anti-IgD activation of human lymphocytes.

Human peripheral lymphocytes were stimulated to incorporate tritiated thymidine when cultured with anti-sigma. The stimulation of lymphocytes by anti-sigma inversely correlates to PHA-induced lymphocyte transformation. In addition, lymphocytes from individuals with low serum IgD levels exhibited a significant response to anti-sigma, whereas, those with normal or slightly elevated levels of serum IgD showed minimal stimulation. This study is the first to provide evidence that cell surface IgD may regulate metabolic functions of lymphocytes and is consistent with the idea that IgD is a 'triggering' receptor.

Antibodies, Anti-Idiotypic↗

PubMed1978

Changes in pigeon cone photocurrent caused by reduction in extracellular calcium activity.

1. Photocurrents have been recorded from the red spot of the isolated superfused pigeon retina. The technique used was to record photovoltage gradients and extracellular fluid resistivity in a direction parallel with the long axes of the receptors. 2. Cone and rod responses were identified, and experiments designed so that only the former were elicited. 3. In the outer portion of the receptor layer, the wave form of the cone photoresponse lacks the initial transient (the 'nose') seen in the portions of the receptor layer nearer the synapses. It is argued that this observation permits the use of a simple equivalent circuit for the generation of the extracellular photocurrent, to infer membrane properties from extracellular recordings. 4. When the superfusing Ringer is changed to one which has a very low calcium activity (2 X 10(-7)M) the first result is that photoresponses increase in magnitude (X 7.7) but the relationship between light intensity and response amplitude and the light intensity (sigma) required to produce a half maximal response remains unchanged. 5. This increase in photocurrent in low calcium also occurs if the superfusing fluid is cooled to 10 degrees. 6. After 2--3 min, the photoresponses in low calcium begin to decrease in amplitude, and the value of sigma is progressively reduced, tenfold in 10 min. 7. During this time, the wave form of the photocurrent alters, the rate of increase and decrease of the responses being slowed. 8. The relationship between peak photocurrent and duration of light flash is modified. 9. The response to a step of light is not well maintained in higher calcium, but is well maintained in low calcium. 10. In higher calcium, the current overshoots during recovery from a flash to below the previous dark level. This does not happen in low calcium. 11. In low calcium, a light adapting background illumination desensitizes the cones. All changes in wave form of the response can be accounted for in terms of the membrane non-linearities. The calculated time course of the change in concentration of the 'internal transmitter' is unaffected. The same is true of desensitization, in the dark, following exposure to intense illumination.

Animals↗