Die Rolle des EGF-Rezeptors bei der mitogenen Signaltransduktion des ß2-adrenergen Rezeptors

In der vorliegenden Arbeit wurde am Expressionsmodell COS- 7 unter endogenen Bedingungen gezeigt, dass die Transaktivierung des EGFR durch den β2- adrenergen Rezeptor (β2- AR) unabhängig von der MMP- Aktivierung und somit Ligand- unabhängig induziert wird. Dadurch scheint der β2- AR nur eine partielle Transaktivierung des EGFR auszulösen, bei der nur die Aktivierung von ERK1/2, nicht aber der PLCγ1 und des PI3- Kinase/PKB- Signalweges vermittelt werden kann. Im Gegensatz dazu führt die Stimulierung des Lysophosphatidsäure- Rezeptors (LPA- Rezeptor) durch die Freisetzung von HB- EGF zu einer Ligand- abhängigen und vollständigen Transaktivierung, bei der das komplette ’’downstream Signalling’’ des EGFR ausgelöst wird (Aktivierung der PLCγ1, des PI3- Kinase/PKB- Signalweges und von ERK1/2). Durch die Erhöhung der Tyrosinkinaseaktivität des EGFR, die durch Stimulierung der Zellen mit EGF oder durch die Überexpression des EGFR hervorgerufen werden kann, wird der β2- AR jedoch dazu befähigt, neben der Aktivierung von ERK1/2 auch die PLCγ1 zu aktivieren. Die Erhöhung der Tyrosinkinaseaktivität wird dabei als Präaktivierung des EGFR definiert und ist essentiell für die β2- AR- vermittelte Aktivierung der PLCγ1. Durch die Präaktivierung des EGFR konnte in dieser Arbeit somit zum ersten Mal mit der EGFR- /Ligand- unterstützten Transaktivierung ein neuartiger GPCR- vermittelter Transaktivierungs-mechanismus identifiziert werden, bei dem die Aktivierung bestimmter Signalwege von der Aktivität des EGFR abhängig ist

The Heat Shock Protein 90 (HSP90) Is Required for the IL-33-Induced Cytokine Production in Mast Cells (MCs)

The alarmin interleukin-33 (IL-33) is released upon cell stress and damage in peripheral tissues. The receptor for IL-33 is the Toll/Interleukin-1 receptor (TIR)-family member T1/ST2 (the IL-33R), which is highly and constitutively expressed on MCs. The sensing of IL-33 by MCs induces the MyD88−TAK1−IKK2-dependent activation of p65/RelA and MAP-kinases, which mediate the production of pro-inflammatory cytokines and amplify FcεRI-mediated MC-effector functions and the resulting allergic reactions. Therefore, the investigation of IL-33-induced signaling is of interest for developing therapeutic interventions effective against allergic reactions. Importantly, beside the release of IL-33, heat shock proteins (HSPs) are upregulated during allergic reactions. This maintains the biological functions of signaling molecules and/or cytokines but unfortunately also strengthens the severity of inflammatory reactions. Here, we demonstrate that HSP90 does not support the IL-33-induced and MyD88−TAK1−IKK2-dependent activation of p65/RelA and of mitogen-activated protein (MAP)-kinases. We found that HSP90 acts downstream of these signaling pathways, mediates the stability of produced cytokine mRNAs, and therefore facilitates the resulting cytokine production. These data show that IL-33 enables MCs to perform an effective cytokine production by the upregulation of HSP90. Consequently, HSP90 might be an attractive therapeutic target for blocking IL-33-mediated inflammatory reactions

A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients – indications for their potential involvement in the development of Long COVID?

Background Recovery from coronavirus disease 2019 (COVID-19) can be impaired by the persistence of symptoms or new-onset health complications, commonly referred to as Long COVID. In a subset of patients, Long COVID is associated with immune system perturbations of unknown etiology, which could be related to compromised immunoregulatory mechanisms. Objective The objective of this scoping review was to summarize the existing literature regarding the frequency and functionality of Tregs in convalescent COVID-19 patients and to explore indications for their potential involvement in the development of Long COVID Design A systematic search of studies investigating Tregs during COVID-19 convalescence was conducted on MEDLINE ( via Pubmed) and Web of Science. Results The literature search yielded 17 relevant studies, of which three included a distinct cohort of patients with Long COVID. The reviewed studies suggest that the Treg population of COVID-19 patients can reconstitute quantitatively and functionally during recovery. However, the comparison between recovered and seronegative controls revealed that an infection-induced dysregulation of the Treg compartment can be sustained for at least several months. The small number of studies investigating Tregs in Long COVID allowed no firm conclusions to be drawn about their involvement in the syndrome’s etiology. Yet, even almost one year post-infection Long COVID patients exhibit significantly altered proportions of Tregs within the CD4+ T cell population. Conclusions Persistent alterations in cell frequency in Long COVID patients indicate that Treg dysregulation might be linked to immune system-associated sequelae. Future studies should aim to address the association of Treg adaptations with different symptom clusters and blood parameters beyond the sole quantification of cell frequencies while adhering to consensualized phenotyping strategies

Оценивание финансово-экономической безопасности предприятий молокоперерабатывающей отрасли

The essence of the concept “financial and economic security of the enterprise” is covered. Methodological approaches to the enterprise financial and economic security evaluation are considered, enabling the method of index numberrating score of the enterprise financial and economic security to be found. Dynamics of milk anddairy production in Ukraine has been studied. Ukrainian regions leading in liquid processed milk production have been identified. Dynamics of milk and dairy production per man has been analyzed which allowed to find out the annual increase in demand per man. Integrated index of the dairy enterprise financial and economic security has been evaluated. As a result, the ways to increase the managerial efficiency of financial and economic security of the following enterprises:PJSC "Dubnomoloko", PJSC "Kupyans'ki milk canning plant", PJSC the "Yagotyns'ki creamery", PJSC the "Pervomais'ki milk canning plant" are offered.У статті розкрито сутність поняття фінансово-економічної безпеки підприємства. Розглянуто методичні підходи щодо оцінювання фінансово-економічної безпеки підприємства, що дозволило виявити підхід рейтингової оцінки показника фінансово-економічної безпеки підприємства. Досліджено динаміку виробництва молока та молочних продуктів України. Виявити області України, які є лідерами з виробництва молока рідкого обробленого. Проаналізовано динаміку виробництва молока та молочних продуктів на одну особу, що дозволило встановити щорічне зростання попиту на одну особу. Визначено підприємства молокопереробної галузі. Проведено оцінку інтегрального показника фінансово-економічної безпеки підприємств молокопереробної галузі. За результатами оцінки запропоновано шляхи підвищення ефективності управління фінансово-економічної безпеки таких підприємств, як: ПАТ «Дубномолоко», ПАТ «Куп’янський молочноконсервний комбінат», ПАТ «Яготинський маслозавод», ПАТ «Первомайський молочноконсервний комбінат».В статье раскрыто сущность понятия финансово-экономическая безопасность предприятия. Рассмотрено методические подходы относительно оценивания финансово-экономической безопасности предприятия, что позволило выявить поход рейтинговой оценки показателя финансово-экономической безопасности предприятия. Исследовано динамику производства молока и молочных продуктов Украины. Выявлены области Украины, которые являются лидерами по производству молока жидкого обработанного. Проанализировано динамику производства молока и молочных продуктов на одного человека, что позволило установить ежегодный рост спроса на одного человека. Определены предприятия молокоперерабатывающей отрасли. Проведена оценка интегрального показателя финансово-экономической безопасности предприятий молокоперерабатывающей отрасли. По результатам оценки предложены пути повышения эффективности управления финансово-экономической безопасности таких предприятий, как: ПАО «Дубномолоко», ПАО «Купянский молочноконсервный комбинат», ПАО «Яготинский маслозавод», ПАО «Первомайский молочноконсервный комбинат»

Key phosphorylation sites for robust β-arrestin2 binding at the MOR revisited

Desensitisation of the mu-opioid receptor (MOR) is proposed to underlie the initiation of opioid analgesic tolerance and previous work has shown that agonist-induced phosphorylation of the MOR C-tail contributes to this desensitisation. Moreover, phosphorylation is important for β-arrestin recruitment to the receptor, and ligands of different efficacies induce distinct phosphorylation barcodes. The C-tail 370TREHPSTANT379 motif harbours Ser/Thr residues important for these regulatory functions. 375Ser is the primary phosphorylation site of a ligand-dependent, hierarchical, and sequential process, whereby flanking 370Thr, 376Thr and 379Thr get subsequently and rapidly phosphorylated. Here we used GRK KO cells, phosphosite specific antibodies and site-directed mutagenesis to evaluate the contribution of the different GRK subfamilies to ligand-induced phosphorylation barcodes and β-arrestin2 recruitment. We show that both GRK2/3 and GRK5/6 subfamilies promote phosphorylation of 370Thr and 375Ser. Importantly, only GRK2/3 induce phosphorylation of 376Thr and 379Thr, and we identify these residues as key sites to promote robust β-arrestin recruitment to the MOR. These data provide insight into the mechanisms of MOR regulation and suggest that the cellular complement of GRK subfamilies plays an important role in determining the tissue responses of opioid agonists

Epidermal growth factor receptor expression licenses type-2 helper T cells to function in a T cell receptor-independent fashion

Gastro-intestinal helminth infections trigger the release of interleukin-33 (IL-33), which induces type-2 helper T cells (Th2 cells) at the site of infection to produce IL-13, thereby contributing to host resistance in a T cell receptor (TCR)-independent manner. Here, we show that, as a prerequisite for IL-33-induced IL-13 secretion, Th2 cells required the expression of the epidermal growth factor receptor (EGFR) and of its ligand, amphiregulin, for the formation of a signaling complex between T1/ST2 (the IL-33R) and EGFR. This shared signaling complex allowed IL-33 to induce the EGFR-mediated activation of the MAP-kinase signaling pathway and consequently the expression of IL-13. Lack of EGFR expression on T cells abrogated IL-13 expression in infected tissues and impaired host resistance. EGFR expression on Th2 cells was TCR-signaling dependent, and therefore, our data reveal a mechanism by which antigen presentation controls the innate effector function of Th2 cells at the site of inflammation

A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients – indications for their potential involvement in the development of Long COVID?

BackgroundRecovery from coronavirus disease 2019 (COVID-19) can be impaired by the persistence of symptoms or new-onset health complications, commonly referred to as Long COVID. In a subset of patients, Long COVID is associated with immune system perturbations of unknown etiology, which could be related to compromised immunoregulatory mechanisms.ObjectiveThe objective of this scoping review was to summarize the existing literature regarding the frequency and functionality of Tregs in convalescent COVID-19 patients and to explore indications for their potential involvement in the development of Long COVIDDesignA systematic search of studies investigating Tregs during COVID-19 convalescence was conducted on MEDLINE (via Pubmed) and Web of Science.ResultsThe literature search yielded 17 relevant studies, of which three included a distinct cohort of patients with Long COVID. The reviewed studies suggest that the Treg population of COVID-19 patients can reconstitute quantitatively and functionally during recovery. However, the comparison between recovered and seronegative controls revealed that an infection-induced dysregulation of the Treg compartment can be sustained for at least several months. The small number of studies investigating Tregs in Long COVID allowed no firm conclusions to be drawn about their involvement in the syndrome’s etiology. Yet, even almost one year post-infection Long COVID patients exhibit significantly altered proportions of Tregs within the CD4+ T cell population.ConclusionsPersistent alterations in cell frequency in Long COVID patients indicate that Treg dysregulation might be linked to immune system-associated sequelae. Future studies should aim to address the association of Treg adaptations with different symptom clusters and blood parameters beyond the sole quantification of cell frequencies while adhering to consensualized phenotyping strategies