Separating cytokine twins with a small molecule

The cytokine macrophage migration inhibitory factor (MIF) has been characterized as a key immunomodulator and mediator of various diseases. Small molecule inhibitors based on the conserved enzymatic pocket of MIF have been valuable in elucidating MIF mechanisms and developing translational strategies. In contrast, our mechanistic understanding of the MIF homolog MIF-2/d-dopachrome tautomerase (d-DT) and its clinical translation has been hampered, partly because MIF-2?selective inhibitors have been elusive. Here, Tilstam et al. characterize a small-molecule inhibitor selective for MIF-2 that interferes with receptor binding and cell signaling. That could be a promising therapeutic lead and a valuable research tool

The Multitasking Potential of Alarmins and Atypical Chemokines

When the human genome was sequenced, it came as a surprise that it contains “only” 21,306 protein-coding genes. However, complexity and diversity are multiplied by alternative splicing, non-protein-coding transcripts, or post-translational modifications (PTMs) on proteome level. Here, we discuss how the multi-tasking potential of proteins can substantially enhance the complexity of the proteome further, while at the same time offering mechanisms for the fine-regulation of cell responses. Discoveries over the past two decades have led to the identification of “surprising” and previously unrecognized functionalities of long known cytokines, inflammatory mediators, and intracellular proteins that have established novel molecular networks in physiology, inflammation, and cardiovascular disease. In this mini-review, we focus on alarmins and atypical chemokines such as high-mobility group box protein-1 (HMGB-1) and macrophage migration-inhibitory factor (MIF)-type proteins that are prototypical examples of these classes, featuring a remarkable multitasking potential that allows for an elaborate fine-tuning of molecular networks in the extra- and intracellular space that may eventually give rise to novel “task”-based precision medicine intervention strategies

The Multitasking Potential of Alarmins and Atypical Chemokines

When the human genome was sequenced, it came as a surprise that it contains “only” 21,306 protein-coding genes. However, complexity and diversity are multiplied by alternative splicing, non-protein-coding transcripts, or post-translational modifications (PTMs) on proteome level. Here, we discuss how the multi-tasking potential of proteins can substantially enhance the complexity of the proteome further, while at the same time offering mechanisms for the fine-regulation of cell responses. Discoveries over the past two decades have led to the identification of “surprising” and previously unrecognized functionalities of long known cytokines, inflammatory mediators, and intracellular proteins that have established novel molecular networks in physiology, inflammation, and cardiovascular disease. In this mini-review, we focus on alarmins and atypical chemokines such as high-mobility group box protein-1 (HMGB-1) and macrophage migration-inhibitory factor (MIF)-type proteins that are prototypical examples of these classes, featuring a remarkable multitasking potential that allows for an elaborate fine-tuning of molecular networks in the extra- and intracellular space that may eventually give rise to novel “task”-based precision medicine intervention strategies

Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is an evolutionarily conserved multi-protein complex, consisting of eight subunits termed CSN1-CSN8. The main biochemical function of the CSN is the control of protein degradation via the ubiquitin-proteasome-system through regulation of cullin-RING E3-ligase (CRL) activity by deNEDDylation of cullins, but the CSN also serves as a docking platform for signaling proteins. The catalytic deNEDDylase (isopeptidase) activity of the complex is executed by CSN5, but only efficiently occurs in the three-dimensional architectural context of the complex. Due to its positioning in a central cellular pathway connected to cell responses such as cell-cycle, proliferation, and signaling, the CSN has been implicated in several human diseases, with most evidence available for a role in cancer. However, emerging evidence also suggests that the CSN is involved in inflammation and cardiovascular diseases. This is both due to its role in controlling CRLs, regulating components of key inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B), and complex-independent interactions of subunits such as CSN5 with inflammatory proteins. In this case, we summarize and discuss studies suggesting that the CSN may have a key role in cardiovascular diseases such as atherosclerosis and heart failure. We discuss the implicated molecular mechanisms ranging from inflammatory NF-kappa B signaling to proteotoxicity and necrosis, covering disease-relevant cell types such as myeloid and endothelial cells or cardiomyocytes. While the CSN is considered to be disease-exacerbating in most cancer entities, the cardiovascular studies suggest potent protective activities in the vasculature and heart. The underlying mechanisms and potential therapeutic avenues will be critically discussed

Проект ректификационной установки разделения пропилен-пропановой смеси

Объектом исследования является ректификационная колонна разделения пропилен-пропановой смеси.Цель работы-рассчитать ректификационную колонну для заданных технологических условий. В ходе выполнения работы был произведен технологический расчет для определения основных габаритных параметров аппарата , а также механический расчет для проверки обеспечения механической надежности аппарата.The object of research is a distillation column for separating propylene-propane mixture.The purpose of this work is to calculate the rectification column for the specified technological conditions. During the work, a technological calculation was made to determine the main overall parameters of the device, as well as a mechanical calculation to check the mechanical reliability of the device

Editorial: The CXCr4 Ligand/Receptor Family and the DPP4 Protease in High-Risk Cardiovascular Patients

Cardiovascular disease (CVD) is the most common cause of morbidity and mortality worldwide, putting a major burden on life quality and social health care systems. Type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) have been identified as important risk factors for CVD, severely increasing the risk on e.g. myocardial infarction, and cardiovascular complications constitute the main cause of death in patients presenting with T2DM, CKD or a combination of both. As these pathologies are expected to rise alarmingly in the next decades, a better understanding of molecular and cellular mechanisms contributing to T2DM, CKD and CVD is required to improve prevention and treatment of these diseases. Furthermore, insight into the interplay between these pathologies and identification of molecular players interconnecting these comorbidities is of tremendous importance for optimal health management in the future. This Research Topic will focus on the chemokine receptor CXCR4 and its ligands CXCL12/SDF-1a and macrophage migration inhibitory factor (MIF) in the context of CVD and its link with T2DM and CKD, as well as address dipeptidyl peptidase-4 (DPP4) as an important protease destabilizing CXCL12. Chemokines and their receptors are important mediators of cell mobilization, recruitment and arrest, and also more broadly induce cell activation by triggering various intracellular signalling tracks. They control homeostatic conditions, but are also critically involved in inflammatory and pathological processes. Genome-wide association studies revealed single nucleotide polymorphisms connecting CXCL12 as well as MIF with CVD, and a role for both chemokines in T2DM and CKD has also been reported. In this review collection, current knowledge on molecular aspects of the CXCR4 ligand/receptor family and associated signalling pathways will be discussed. The physiological roles of CXCR4, CXCL12, MIF and DPP4 will be summarized, and recent findings on their function in pathological conditions of CVD, T2DM and CKD will be highlighted. This is combined with an extensive introduction providing insight into the pathologies of CVD, T2DM and CKD, discussing clinical features and common pathological aspects of these comorbidities on cellular and molecular level. Also, an overview of available animal models to study these diseases will be provided. This way, this Research Topic summarizes latest knowledge on this crucial molecular axis and its relationship with cardiovascular pathologies for both specialists and interested non-specialists and aims to stimulate further initiatives to unravel the mechanistic involvement of the CXCR4 ligand/receptor family in these morbidities, potentially paving the way for new therapeutical initiatives in the future

Концепция клиентоориентированного маркетинга в компании ООО «Свободная энергия»

Разработка концепции и плана внедрения клиентоориентированного маркетинга в компании ООО "Свободная энергия".Development of the concept and introducing customer-oriented marketing's plan in the company "Free Energy"

Marketing As Tool of Resource Efficiency

This paper shows the role of marketing in ensuring resource efficiency. It is found that the marketing is one of the methods of saving resources, making them effective in use. The conclusion about the need to use marketing to increase the efficiency of resource management in the organization is justified. It is suggested to use SWOT-analysis as a marketing technique for choosing a particular strategy, significant for the company in the management of resource efficiency. The forecasting of demand allows receiving evidence-based options in tendencies of change, indicators of quality, expenses and other indicators. Therefore, the system of the resource efficiency at an enterprise has to be guided by forecasting the demand and its task. Improved analysis cost methods (such as the factorial analysis, the functional and cost analysis) help to solve a problem of resource efficiency at the stage of design or production improvement. It is proved that application of the concept of social and ethic marketing promotes development of the resource efficiency program in management

Influence of glass component for sintering process of LTCC composite materials

In this work two BaO-ZnO-B[2]O[3]-SiO[2] glass-forming systems with different components content and similar properties were compared for using in LTCC materials. Glass-ceramics sintering characteristics and their phase composition were researched by hydrostatic weighing. Causes of the differences in properties of the composites based on two glasses were identified