Clinical impact of myositis-specific autoantibodies on long-term prognosis of juvenile idiopathic inflammatory myopathies: multicentre study

Objectives This study aimed to investigate the clinical characteristics, treatment and prognosis of juvenile idiopathic inflammatory myopathies (JIIM) in Japan for each myositis-specific autoantibody (MSA) profile. Methods A multicentre, retrospective study was conducted using data of patients with JIIM at nine paediatric rheumatology centres in Japan. Patients with MSA profiles, determined by immunoprecipitation using stored serum from the active stage, were included. Results MSA were detected in 85 of 96 cases eligible for the analyses. Over 90% of the patients in this study had one of the following three MSA types: anti-melanoma differentiation-associated protein 5 (MDA5) (n = 31), anti-transcriptional intermediary factor 1 alpha and/or gamma subunits (TIF1γ) (n = 25) and anti-nuclear matrix protein 2 (NXP2) (n = 25) antibodies. Gottron papules and periungual capillary abnormalities were the most common signs of every MSA group in the initial phase. The presence of interstitial lung disease (ILD) was the highest risk factor for patients with anti-MDA5 antibodies. Most patients were administered multiple drug therapies: glucocorticoids and MTX were administered to patients with anti-TIF1γ or anti-NXP2 antibodies. Half of the patients with anti-MDA5 antibodies received more than three medications including i.v. CYC, especially patients with ILD. Patients with anti-MDA5 antibodies were more likely to achieve drug-free remission (29 vs 21%) and less likely to relapse (26 vs 44%) than others. Conclusion Anti-MDA5 antibodies are the most common MSA type in Japan, and patients with this antibody are characterized by ILD at onset, multiple medications including i.v. CYC, drug-free remission, and a lower frequency of relapse. New therapeutic strategies are required for other MSA types.

Toll-like receptor-4 synthesis is regulated by JNK signaling by three glucocorticoids isoforms and by three interferons isoforms, also its advantages in activities depending on the Containment from Arg, proline and hydrophobic amino acids in its compositions

Toll-like receptor-4 (TLR4), synthesis is regulated by JNK signaling , by three glucocorticoids isoforms, and by the three interferons isoforms, also depending on avaliablities of LPS & on long fatty acids chains with Arg and proline availabilities For performing and running the mitochondrial oxidative processes for producing fatty-acyl-CoA-synthetase followed by fatty-acyl-CoA-synthase followed by fatty-acyl-CoA-phospholipase productions for linear TLR4 active beta-subunits which will be transformed into TLR4-alpha upon phospholipase effects , which will follow phosphorylation process (alpha-oxidations) for generate Guanosine triphosphate cyclohydrolase (GTP-Chase) subunits which supposed to contain specific hydrophobic amino acids including Arg, Tyr, leu, proline…. Etc, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, which is essential for inducible iNOS from fatty-acyl-CoA-synthase upon the nitric oxidesynthase (NO-S) regulations effects. Proline can accelerate anabolic oxidative processes by OPA1 enzymes and provides site-specific flexibility for collagen synthesis in vivo, and also plays an necessary important roles in TLR4 and TGF-gamma/beta/& alpha synthesis and activities, where the presence of proline in IFN-gamma, in TLR4 genes and in IFN-beta will accelerate oxidative OPA1 anabolic processes and direct the flow of biological processes to proliferations of plasma-membranes , collagen synthesis and blood platelets biosynthesis. Vitamin E & K-dependent protein C are the key components of anticoagulant serine protease, And therefore vit E and vit k are providing specific advantages to TLR4 synthesis and modulated first in vivo as proper fatty-acyl-CoAsynthetase subunits (gamma-subunits) then modified fatty-acyl-CoA-synthase subunits upon synthase effects on gamma-subunits for producing IL-beta upon which will promote linear TLR4 upon both synthase and phospholipase effects for starting proliferation stepes started by catalyzing Arg for producing GTP-Chase and citrulline which the main basis for Erythropoietin productions , for Plasma membrane synthesis… etc. Both IFN-beta and glucocorticoid-beta are designed anti-inflammatory subunits are depending on each others and on the activities of OPA1-synthase enzyme for producing the long fatty acyl-CoA-synthase (Beta-subunit) with specific compositions and sequences from amino acids which can determine their advantages in immunity functions eg their containment of tyr, proline, Arg, gly.. etc, where, Both glucocorticoid-beta and IFN-beta are able to recover each others in their different tissues.

Agonist-selective recruitment of engineered protein probes and of GRK2 by opioid receptors in living cells

G protein-coupled receptors (GPCRs) signal through allostery, and it is increasingly clear that chemically distinct agonists can produce different receptor-based effects. It has been proposed that agonists selectively promote receptors to recruit one cellular interacting partner over another, introducing allosteric ‘bias’ into the signaling system. However, the underlying hypothesis - that different agonists drive GPCRs to engage different cytoplasmic proteins in living cells - remains untested due to the complexity of readouts through which receptor-proximal interactions are typically inferred. We describe a cell-based assay to overcome this challenge, based on GPCR-interacting biosensors that are disconnected from endogenous transduction mechanisms. Focusing on opioid receptors, we directly demonstrate differences between biosensor recruitment produced by chemically distinct opioid ligands in living cells. We then show that selective recruitment applies to GRK2, a biologically relevant GPCR regulator, through discrete interactions of GRK2 with receptors or with G protein beta-gamma subunits which are differentially promoted by agonists.

The role of heterotrimeric G proteins in the control of symbiosis development in legume plants

Heterotrimeric G proteins are involved in the regulation of signaling pathways in eukaryotes. Previously, the data about possible participation of heterotrimeric G proteins in the regulation of nodulation in legumes were obtained, however, specific proteins, their composition and role in this process remain poorly understood. In this work searching of the genes encoding the alpha, beta, and gamma subunits of heterotrimeric G proteins based on an analysis of the Pisum sativum L. genome was performed, as well as the dynamics of the gene expression encoding the particular subunits of G proteins in the process of symbiosis was studied. In addition, a significant effect of beta 1-subunit gene suppression by RNA interference on the nodulation process was revealed.

Agonist-selective recruitment of engineered protein probes and of GRK2 by opioid receptors in living cells

G protein-coupled receptors (GPCRs) signal through allostery, and it is increasingly clear that chemically distinct agonists can produce different receptor-based effects. It has been proposed that agonists selectively promote receptors to recruit one cellular interacting partner over another, introducing allosteric ‘bias’ into the signaling system. However, the core underlying hypothesis - that different agonists drive GPCRs to engage different cytoplasmic proteins in living cells - remains untested due to the complexity of downstream readouts through which receptor-proximal interactions are typically inferred. Here we describe a scalable cell-based assay to overcome this challenge, based on the use of engineered GPCR-interacting proteins as orthogonal biosensors that are disconnected from endogenous transduction mechanisms. Focusing on opioid receptors, we directly demonstrate differences between protein probe recruitment produced by chemically distinct opioid ligands in living cells. We then show how the selective recruitment applies to GRK2, a biologically relevant opioid receptor regulator protein, through discrete interactions of GRK2 with receptors or with G protein beta-gamma subunits which are differentially promoted by agonists.

The Emerging Role of Gβ Subunits in Human Genetic Diseases

Environmental stimuli are perceived and transduced inside the cell through the activation of signaling pathways. One common type of cell signaling transduction network is initiated by G-proteins. G-proteins are activated by G-protein-coupled receptors (GPCRs) and transmit signals from hormones, neurotransmitters, and other signaling factors, thus controlling a number of biological processes that include synaptic transmission, visual photoreception, hormone and growth factors release, regulation of cell contraction and migration, as well as cell growth and differentiation. G-proteins mainly act as heterotrimeric complexes, composed of alpha, beta, and gamma subunits. In the last few years, whole exome sequencing and biochemical studies have shown causality of disease-causing variants in genes encoding G-proteins and human genetic diseases. This review focuses on the G-protein β subunits and their emerging role in the etiology of genetically inherited rare diseases in humans.

Regulation of BK Channels by Beta and Gamma Subunits

Ca2+- and voltage-gated K+ channels of large conductance (BK channels) are expressed in a diverse variety of both excitable and inexcitable cells, with functional properties presumably uniquely calibrated for the cells in which they are found. Although some diversity in BK channel function, localization, and regulation apparently arises from cell-specific alternative splice variants of the single pore–forming α subunit ( KCa1.1, Kcnma1, Slo1) gene, two families of regulatory subunits, β and γ, define BK channels that span a diverse range of functional properties. We are just beginning to unravel the cell-specific, physiological roles served by BK channels of different subunit composition.