proper S6K /BTK and PLCγ2 are main regulations for thromboxane-A synthesis, and necessary for B-cell maturations and T-cells modulations and functions. The main factors that cause the Osteoarthritis “OA” and diabetes and linked between them are the deficiency of Ser amino acids and decreasing or down regulations of Ser phosphorylation signalling pathway which necessary for proper S6K productions, where normally the Ser phosphorylation signalling pathway is the basis of Ser /Thr phosphorylation signalling which normally necessary for proper Akt, S6K1 synthesis and necessary for RORs and IFNs synthesis and also necessary for running proper BTK and proper PLCγ2 productions , where S6K is main regulator for ATPase and for proper PLCγ1 and for PLCγ2 synthesis which necessary for bone growth and for increasing and modulating immune efficiency
G protein-coupled receptors (GPCRs) usually regulate cellular processes via activation of intracellular signaling pathways. However, we have previously shown that in several cell lines, GqPCRs induce immediate inactivation of the AKT pathway, which leads to JNK-dependent apoptosis. This apoptosis-inducing AKT inactivation is essential for physiological functions of several GqPCRs, including those for PGF2α and GnRH.
Here we used kinase activity assays of PI3K and followed phosphorylation state of proteins using specific antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein–protein interactions. Apoptosis was detected by TUNEL assay and PARP1 cleavage.
We identified the mechanism that allows the unique stimulated inactivation of AKT and show that the main regulator of this process is the phosphatase PP2A, operating with the non-canonical regulatory subunit IGBP1. In resting cells, an IGBP1-PP2Ac dimer binds to PI3K, dephosphorylates the inhibitory pSer608-p85 of PI3K and thus maintains its high basal activity. Upon GqPCR activation, the PP2Ac-IGBP1 dimer detaches from PI3K and thus allows the inhibitory dephosphorylation. At this stage, the free PP2Ac together with IGBP1 and PP2Aa binds to AKT, causing its dephosphorylation and inactivation.
Our results show a stimulated shift of PP2Ac from PI3K to AKT termed “PP2A switch” that represses the PI3K/AKT pathway, providing a unique mechanism of GPCR-stimulated dephosphorylation.
The article is devoted to the comparative analysis of the essence of consumer and credit cooperatives in the context of attracting citizens' funds, the transformation of their economic processes and functions in the genesis of microeconomic development. The research is based on the analysis of historical documents and Russian publications, as well as on statistical conclusions of economic data. The aim of the study was to study the evolution of consumer societies and credit cooperatives as instruments for attracting household finances on the example of Russian and foreign companies since the middle of the XIX century. Semantic definitions of the categories consumer society and consumer credit cooperative, tasks and historical stages of the development of the studied communication tools in the field of attracting the means of the population are determined. The author's experience of comparative characteristics of the analyzed economic entities is proposed, reflecting the risks, advantages and disadvantages of the studied communication objects. The functions of the Bank of Russia as the main regulator of consumer credit cooperatives are disclosed. The final results of the study substantiate the importance of financial literacy and present an algorithm that allows the population to distinguish the legal activities of consumer credit cooperatives from fraudsters.
Single-walled carbon nanotubes (SWCNTs) are characterized by a combination of rather unique physical and chemical properties, which makes them interesting biocompatible nanostructured materials for various applications, including in the biomedical field. SWCNTs are not inert carriers of drug molecules, as they may interact with various biological macromolecules, including ion channels. To investigate the mechanisms of the inhibitory effects of SWCNTs on the muscarinic receptor cation current (mICAT), induced by intracellular GTPγs (200 μM), in isolated mouse ileal myocytes, we have used the patch-clamp method in the whole-cell configuration. Here, we use molecular docking/molecular dynamics simulations and direct patch-clamp recordings of whole-cell currents to show that SWCNTs, purified and functionalized by carboxylation in water suspension containing single SWCNTs with a diameter of 0.5–1.5 nm, can inhibit mICAT, which is mainly carried by TRPC4 cation channels in ileal smooth muscle cells, and is the main regulator of cholinergic excitation–contraction coupling in the small intestinal tract. This inhibition was voltage-independent and associated with a shortening of the mean open time of the channel. These results suggest that SWCNTs cause a direct blockage of the TRPC4 channel and may represent a novel class of TRPC4 modulators.
The literature review presents data on the role of pathological angiogenesis in the development of psoriasis. Several recent studies have shown, in addition to cytokine imbalance and activation of the T-cell link of immunity, an important pathogenetic link is pathological vascularization. Vascular changes in the dermis appear before clinically visible skin manifestations and can persist for a long time after treatment, as well as the phenomena of neoangigenesis in the synovial membrane and enthesises contribute to the chronicization of inﬂammatory process in psoriatic arthritis. The article presents an overview of the modern literature on the main regulator of angiogenesis – vascular endothelial growth factor, its role in the pathogenesis of psoriasis and possible therapeutic prospects.
AbstractTumor necrosis factor-α (TNF) is described as a main regulator of cell survival and apoptosis in multiple types of cells, including hepatocytes. Dysregulation in TNF-induced apoptosis is associated with many autoimmune diseases and various liver diseases. Here, we demonstrated a crucial role of Bcl-3, an IκB family member, in regulating TNF-induced hepatic cell death. Specifically, we found that the presence of Bcl-3 promoted TNF-induced cell death in the liver, while Bcl-3 deficiency protected mice against TNF/D-GalN induced hepatoxicity and lethality. Consistently, Bcl-3-depleted hepatic cells exhibited decreased sensitivity to TNF-induced apoptosis when stimulated with TNF/CHX. Mechanistically, the in vitro results showed that Bcl-3 interacted with the deubiquitinase CYLD to synergistically switch the ubiquitination status of RIP1 and facilitate the formation of death-inducing Complex II. This complex further resulted in activation of the caspase cascade to induce apoptosis. By revealing this novel role of Bcl-3 in regulating TNF-induced hepatic cell death, this study provides a potential therapeutic target for liver diseases caused by TNF-related apoptosis.
In the modern global world, a study on mentality as a main characteristic of the nation which defines the unity of the religious and cultural tradition of the society is conditioned with the need to develop an effective international religious and cultural cooperation. The purpose of the analysis is to determine religious factors in shaping the Ukrainian mentality taking into account its historical background and the challenges of modernity. The study methodology is based on the principles of the non-confessional approach and philosophical pluralism, involving a system of methods, namely: historical, dialectical, comparative methods, synthesis, and generalization. In the conclusions it is emphasized that mentality is one of the forms of the social experience accumulation, the set of historically accepted ideas, viewpoints, stereotypes, forms and behavior which are laid down is the public consciousness by means of education, culture, religion, a language through the years. Every mental formation has its imaginary lines of a friend and foe which were formed by ideologies, beliefs, and religious values. The religious factors in the formation of mentality reflect the role of the Church as the main regulator of the social life. In the social environment of the Ukrainian nation, a temple can be seen as a peculiar archetypical formation, the part of the landmark, symbolic, communicative, and informational religious system which regulates the public consciousness and it is an integral part of the national memory. The mental archetypes of the national identity stem from the phenomenon of the borderlands, and have shaped in the social context the desire for personal freedom, patriotism, social activity; in the spiritual dimension, it is a willing for the inner world to be protected, sacrifice, mercy, non-violence.
At present, most units adopt the superheated steam temperature control system with cascade PID control structure. However, because most cascade PID control algorithms have no anti-integral saturation function, the automatic control of boiler superheated steam temperature cannot be put into operation normally. On the existing cascade PID superheated steam temperature regulation system, we judge the deviation value of the main regulator and the output value of the auxiliary regulator, and cancel the integration function at an appropriate time. When the input deviation signal turns over, the regulating system can immediately enter the normal regulating state, so that the cascade PID superheated steam temperature regulating system can timely and accurately regulate the superheated steam temperature. The fuel cost is saved by about 155,600 yuan per year.
Photoperiod impacts reproduction in many species of mammals. Mating occurs at specific seasons to achieve reproductive advantages, such as optimization of offspring survival. Light is the main regulator of these changes during the photoperiod. Seasonally breeding mammals detect and transduce light signals through extraocular photoreceptor, regulating downstream melatonin-dependent peripheral circadian events. In rodents, hormonal reduction and gonadal atrophy occur quickly, and consensually with short-day periods. It remains unclear whether photoperiod influences human reproduction. Seasonal fluctuations of sex hormones have been described in humans, although they seem to not imply adaptative seasonal pattern in human gonads. This review discusses current knowledge about seasonal changes in the gonadal function of vertebrates, including humans. The photoperiod-dependent regulation of hypothalamic–pituitary-gonadal axis, as well as morphological and functional changes of the gonads are evaluated herein. Endocrine and morphological variations of reproductive functions, in response to photoperiod, are of interest as they may reflect the nature of past population selection for adaptative mechanisms that occurred during evolution.
Introduction: The programmed death receptor ligand 1 (PD-L1) immunohistochemistry (IHC) assay is a widely used selection method for pembrolizumab treatment in gastric cancer (GC) patients. PD-L1 is the main regulator of immunity in oncogenesis. Material and methods: The study included 38 patients with GC. The combined treatment consisted of neoadjuvant FOLFOX6, or FLOT, chemotherapy and surgery. PD-L1 + tumor status was recorded in 12 patients (CPS > 5), with a negative status recorded in 26 patients. RT-PCR determined the expression of molecular markers. The level of LC3B protein was detected by Western Blotting analysis. Results: An overexpression of PD-1, PD-L2 in the tumor is associated with AKT/mTOR mRNA profile change and autophagy initiation in IHC PD-L1 positive GCs. NACT influences these biological features, modifying the expression of AKT/mTOR components and autophagic flux. In PD-L1 positive cancers, the effect of NACT and molecular markers rearrangements are essential compared to the PD-L1 negative cancers. Conclusion: The IHC PD-L1 status in gastric cancers is the significant marker of cancer progression, recovering the multiple inner mechanisms of cancer spreading and leading to ineffective therapy. Autophagy induction and angiogenesis are found in PD-L1 positive gastric cancers.