The Stiffness of Cardiac Fibroblast Substrates Exerts a Regulatory Influence on Collagen Metabolism via α2β1 Integrin, FAK and Src Kinases

Information about mechanical strain in the extracellular space is conducted along collagen fibers connected with integrins and then transmitted within cells. An aim of the study is to verify the hypothesis that the stiffness of cardiac human fibroblast substrates exerts a regulatory effect on collagen metabolism via integrin α2β1 and downstream signaling. The experiments were performed on human cardiac fibroblasts cultured on stiff or soft polyacrylamide gels. Extracellular and intracellular collagen content, metalloproteinase-1 (MMP-1), metalloproteinase-9 (MMP-9) and expression of the α1 chain of the procollagen type I gene (Col1A1) were elevated in cultures settled on soft substrate. The substrate stiffness did not modify tissue inhibitors of matrix metalloproteinase capacity (TIMPs 1–4). Integrin α2β1 inhibition (TC-I 15) or α2 subunit silencing resulted in augmentation of collagen content within the culture. Expression of Col1A1 and Col3A1 genes was increased in TC-I 15-treated fibroblasts. Total and phosphorylated levels of both FAK and Src kinases were elevated in fibroblasts cultured on stiff substrate. Inhibition of FAK (FAK kinase inhibitor 14) or Src kinase (AZM 47527) increased collagen content within the culture. The substrate stiffness exerted a regulatory influence on collagen metabolism via integrin α2β1 and its downstream signaling (FAK and Src kinases) in cardiac fibroblasts.

The inner mechanics of Rhodopsin Guanylyl Cyclase during 2cGMP-formation revealed by real-time FTIR spectroscopy

Enzymerhodopsins represent a recently discovered class of rhodopsins which includes histidine kinase rhodopsin, rhodopsin phosphodiesterases and rhodopsin guanylyl cyclases (RGCs). The regulatory influence of the rhodopsin domain on the enzyme activity is only partially understood and holds the key for a deeper understanding of intra-molecular signaling pathways. Here we present a UV-Vis and FTIR study about the light-induced dynamics of a RGC from the fungus Catenaria anguillulae, which provides insights into the catalytic process. After the spectroscopic characterization of the late rhodopsin photoproducts, we analyzed truncated variants and revealed the involvement of the cytosolic N-terminus in the structural rearrangements upon photo-activation of the protein. We tracked the catalytic reaction of RGC and the free GC domain independently by UV-light induced release of GTP from the photolabile NPE-GTP substrate. Our results show substrate binding to the dark-adapted RGC and GC alike and reveal differences between the constructs attributable to the regulatory influence of the rhodopsin on the conformation of the binding pocket. By monitoring the phosphate rearrangement during cGMP and pyrophosphate formation in light-activated RGC, we were able to confirm the M state as the active state of the protein. The described setup and experimental design enable real-time monitoring of substrate turnover in light-activated enzymes on a molecular scale, thus opening the pathway to a deeper understanding of enzyme activity and protein-protein interactions.

Object of systematization of labor legislation.

The article analyzes and clarifies that the systematization of labor legislation, like any other social activity, is characterized by the presence of its own object, the study of which will allow a more meaningful understanding of its essence, purpose and mechanism of operation. The article states that the object of knowledge can be all reality, but only to the extent that it has entered the scope of the subject. The concepts of «object» and «objective reality» are related, but not identical in meaning. The object is not the whole objective reality, but only that part of it which has already entered the practice of mankind and constitutes the circle of its cognitive interests. In the field of law, the object is understood as the purpose of the regulatory influence of law, activities and interests of legal entities. Analyzing the essence of the object of legal relations, it is determined that the issues related to the object of legal regulation are the most complex in the theory of legal relations. An object is a part of the objective reality with which the subject interacts. This understanding of the object can be applied to the field of law. The article analyzes the concept of «object» in both philosophical and legal sense, and concludes that the object of systematization of labor law - is what it is aimed at, to which the measures of this systematization. From the very concept of «systematization of labor law» it follows that the object of study is the specified area of national law. However, this approach to understanding the object of systematization is quite superficial, because, first, the concept of «legislation» has both broad and narrow interpretation; secondly, legislation is a form of law, so, thinking about the systematization of labor legislation, we can talk about both its external and internal regulation. In addition, revealing the essence and purpose of systematization, along with its object also distinguishes the subject. It is determined that the object of systematization of labor legislation is a set of regulations governing labor and closely related legal relations, is the object of systematization is a certain part of objective law and its sources, regardless of whether they are purely external streamlining or revision of the content of these sources; the law acts as a certain objectively existing fact, which is influenced by the subjects of systematization; in turn, the subject of systematization is the form and / or normative-legal content of certain specific normative-legal acts, in respect of which the corresponding forms and methods of systematization are applied.

Polyvariety of the Structure of the Normative Element in the Mechanism of Legal Regulation of Civil Relations: Theoretical Aspect

The mechanism of legal regulation of relations is considered as a system of legal means, methods and forms with the help of which social relations are regulated. The author argues about the variability of the normative element of the mechanism under consideration, since it is not always possible to include the multiplicity of parameters that form its content and essence exclusively into the content of a legal norm. It is argued that the rule of law is not the main element of the mechanism of legal regulation through which relations between members of the society are being regulated. The corresponding regulatory influence is ensured with the help of individual regulators that have a different legal nature due to their limited, personalized obligatoriness. The author proves that, along with a legal norm, an individual normative prescription acts as a legal means of ensuring the operation of the mechanism of legal regulation of social relations, and its form is represented by alter-normative regulators (contract, custom). In addition, along with normative and alter-normative regulators, super-normative (principles of law) and quasi-normative (judicial acts) are highlighted.

Regulatory Influence of Galanin and GALR1/GALR2 Receptors on Inflamed Uterus Contractility in Pigs

Uterine inflammation is a very common and serious pathology in domestic animals, the development and progression of which often result from disturbed myometrial contractility. We investigated the effect of inflammation on the protein expression of galanin (GAL) receptor subtypes (GALR)1 and GALR2 in myometrium and their role in the contractile amplitude and frequency of an inflamed gilt uterus. The gilts of the E. coli and SAL groups received E. coli suspension or saline in their uteri, respectively, and only laparotomy was performed (CON group). Eight days later, the E. coli group developed severe acute endometritis and lowered GALR1 protein expression in the myometrium. Compared to the pretreatment period, GAL (10−7 M) reduced the amplitude and frequency in myometrium and endometrium/myometrium of the CON and SAL groups, the amplitude in both stripes and frequency in endometrium/myometrium of the E. coli group. In this group, myometrial frequency after using GAL increased, and it was higher than in other groups. GALR2 antagonist diminished the decrease in amplitude in myometrium and the frequency in endometrium/myometrium (SAL, E. coli groups) induced by GAL (10−7 M). GALR1/GALR2 antagonist and GAL (10−7 M) reversed the decrease in amplitude and diminished the decrease in frequency in both examined stripes (CON, SAL groups), and diminished the drop in amplitude and abolished the rise in the frequency in the myometrium (E. coli group). In summary, the inflammation reduced GALR1 protein expression in pig myometrium, and GALR1 and GALR2 participated in the contractile regulation of an inflamed uterus.

Globa:Local Architecture

How essential is it to understand the local context in a globalized world? Globalization is a rapid traversing of ideas, attitudes and values across national borders that lead to an interconnectedness and interaction between peoples of diverse cultures and ways of life. What if the local architectural mosaic depends on strengthening the capacity to invite people with different backgrounds and ideas to establish a connection to their heritage, whilst at the same time complying with globalized architecture? Is there a way to combine the freedom and flexibility of local cultures with the restrictive and regulatory influence of a globalized hierarchy? This thesis explores the architecture that emerges out of the hybridization of multiple forces to be both locally unique and globally adaptable.

Globa:Local Architecture

How essential is it to understand the local context in a globalized world? Globalization is a rapid traversing of ideas, attitudes and values across national borders that lead to an interconnectedness and interaction between peoples of diverse cultures and ways of life. What if the local architectural mosaic depends on strengthening the capacity to invite people with different backgrounds and ideas to establish a connection to their heritage, whilst at the same time complying with globalized architecture? Is there a way to combine the freedom and flexibility of local cultures with the restrictive and regulatory influence of a globalized hierarchy? This thesis explores the architecture that emerges out of the hybridization of multiple forces to be both locally unique and globally adaptable.

Political machines: a framework for studying politics in social machines

In the age of ubiquitous computing and artificially intelligent applications, social machines serves as a powerful framework for understanding and interpreting interactions in socio-algorithmic ecosystems. Although researchers have largely used it to analyze the interactions of individuals and algorithms, limited attempts have been made to investigate the politics in social machines. In this study, I claim that social machines are per se political machines, and introduce a five-point framework for classifying influence processes in socio-algorithmic ecosystems. By drawing from scholars from political theory, I use a notion of influence that functions as a meta-concept for connecting and comparing different conceptions of politics. In this way, I can associate multiple political aspects of social machines from a cybernetic perspective. I show that the framework efficiently categorizes dimensions of influence that shape interactions between individuals and algorithms. These categories are symbolic influence, political conduct, algorithmic influence, design, and regulatory influence. Using case studies, I describe how they interact with each other on online social networks and in algorithmic decision-making systems and illustrate how the framework is able to guide scientists in further research.