Itaconate-mediated inhibition of succinate dehydrogenase regulates cytokine production in LPS-induced inflammation

Itaconate is an immunoregulatory metabolite produced by myeloid cells and plays a key role in the regulation of the immune response. Itaconate, on the one hand, is able to suppress the activity of succinate dehydrogenase (SDH), thereby making a significant contribution to the metabolic reprogramming of the cell. On the other hand, itaconate can regulate the activity of a number of transcription factors and transcription regulators, thereby affecting gene expression. In most experimental studies, itaconate has been characterized predominantly as an anti-inflammatory agent. In particular, itaconate produced by activated macrophages inhibits the production of cytokines TNF, IL-1b, IL-6, IL-10. However, some evidence suggests a pro- inflammatory role for itaconate in a number of mouse disease models. Thus, the deletion of the Acod1 gene responsible for the production of itaconate leads to the suppression of the production of TNF and IL-6 in the mouse polymicrobial sepsis model, which means that in the context of inflammation in vivo, itaconate can act as an inducer of pro-inflammatory cytokines. The mechanism of itaconate regulation of cytokine production in systemic inflammation remains unexplored. In this work, we have shown that injection of itaconate and its derivative dimethyl itaconate into mice, followed by induction of inflammation by bacterial lipopolysaccharide (LPS), leads to changes in the content of cytokines in the blood. Interestingly, the systemic production of IL-6 and IL-10 in response to itaconate is increased, contrary to the results previously obtained in cell cultures. At the same time, IFNg production, on the contrary, is suppressed. Apparently, itaconate regulates the production of cytokines in vivo by suppressing the activity of SDH. Injection of the SDH inhibitor, dimethylmalonate, followed by induction of inflammation in mice, results in similar changes in blood cytokines observed in response to itaconate: increased production of IL-6, IL-10 and suppression of IFNg production. On the contrary, the addition of succinate, a SDH substrate, leads to the opposite effect on cytokine production. Thus, it can be assumed that the observed effects of itaconate on cytokine production in the model of LPS-induced inflammation are mediated by its ability to inhibit SDH. These results help to understand the controversial role of itaconate in inflammation and shed light on a previously undescribed relationship between SDH and cytokine production in inflammation in vivo

A Creative Nondeterministic Computability

This paper shows a range of fundamental limitations inherent to any process realized in a standard theory of deterministic computability that significantly hamper its application to an analysis of philosophical problems concerning time-flow phenomena. Here a method based on a non-standard generalization of a computability concept is proposed that allows an adequate investigation of such philosophical problems. This goal is achieved by means of rejecting determinism in computational processes

Maginations, opinions, values and knowledge

In article from a position of philosophy and semiotics such sign types of ideas, as imaginations, opinions, values and knowledge are analyzed. The background of features of ideas of these types includes their definition, ways of fixing in statements, the basic and maximum forms of display supporting the global and local organizations. Typology of statements derivative from the allocated types of signs. It is offered to divide statements on descriptive and estimate. The role of judgements of the named types in natural sciences, public and humanitarian disciplines, philosophies and religions is investigated. Appropriating criteria of definition of types of judgements are developed for this purpose

The principle of reductio ad absurdum as an ontological problem

The ontological status of evidence is reduced to reducing to absurdity. The problem is that in such evidence, an impossible (or still possible?) Situation is allowed as the initial one. What is the ontological status of such situations, do they have an ontological justification? The answer to this question involves considering the structure of evidence by reducing to absurdity, choosing the appropriate logic and searching for an adequate ontology. The article shows that in the classical calculus of predicates of the first order, proofs by reduction to absurdity are included as a special case of proof by contradiction. The intuitionistic predicate calculus uses evidence to reduce to absurdity, but evidence from the contrary is not accepted in it. Further, the key concept of “absurdity” is discussed. It is shown that the treatment of absurdity as nonsense leads to a dead end, because the problem of meaning does not have an adequate solution in modern science. We can not guarantee the presence of a semantic meaning for correctly constructed expressions of the sign system, but we can ensure the presence of a denotational value for such expressions in artificial sign systems. As applied to our problem, this indicates the need to search for the denotational significance of contradictions. Since the models of logical calculi are constructed by means of set theory, the domain of the search is narrowed to the choice of an appropriate set theory. The modified set theory ZF is considered in which the axiom of the existence of an empty set is replaced by its negation. In this case, it is possible to give the denotational significance to the contradictions, but then the contradictions of the type A and not- A get an ontological justification, since both A and non- A are fulfilled

Formal metaontology

Ontologies scientific theories arise from the deeper principles, which also have an ontological nature. These principles and their justification form ontology ontology or metaontology. Metaontology lies in the foundations of logic and mathematics, and through them the whole of science as a demonstrative knowledge of reality. Metaontological basis of logical and mathematical structures has the perfect character, requiring for their adequate representation of the use of formal methods of reasoning

Science - what is It?

A phenomenon of science is considered from a logical-semiotic angle. Existing research methods and definitions of science are analyzed too. Furthermore a place of science in the universe of sign systems is determined. Finally, science is put as a an evidential or inference knowledge. Different imitative means of pseudo-scientific reasoning is exposed and specific examples of such included

Not theoretical forms of systematization of ideas

In article such not theoretical forms of ordering of ideas, as concepts (a floor of the theory), doctrines (quasi theories) and doctrines (pseudo theories) are entered into consideration. The logic of citing with the well-determined syntax and semantics is under construction. Comparison of the constructed logic with other logical systems is carried out. Such operations, as definition (concepts and objects), classification are briefly analysed. Comparison theoretical and not theoretical forms of ordering of ideas is spent

PROBLEM OF TIME: THE FUTURE REVOLUTION IN A SCIENCE

Some properties of time may be conceived geometrically, i.e. envisioned with the help of spatial tools. But it would be incorrect to reduce the time phenomenon to space as it is actually assumed in modern physics and in the theory of unified time-space. Attempting to express the essence of time in a few words it is admissible to assert that time is a computation process. A transition from the present to the past and to the future is a result of calculations carried out by nature. Therefore computer models should be utilized as a basic means for presenting time. Unfortunately computation theories available in science today are mostly unsuitable for the purpose and demand far-reaching generalizations that concern modeling time in particular

Ontology currents of time: abstract computing models

In article by means of abstract computing models on the basis of the language of programming ABT created by the author is under construction ontology currents of time. One of models specifies the original concept of atomic time which has arisen in medieval Arabian philosophy