Interleukin‑17A and Interleukin‑18 level in the blood serum of patients with different clinical course of Rosacea

Introduction. Rosacea is a common chronic dermatosis characterized by lesions of open areas of the skin (face) and torpidity to treatment. The objective of our study was to determine and analyze the content of proinflammatory cytokines – interleukin‑17A (IL‑17A) and interleukin‑18 (IL‑18) in the serum of patients with rosacea, depending on the nature of the clinical course of dermatosis. Material and methods. The study involved 36 patients with rosacea, 17 of them diagnosed with erythema‑telangiectatic form and 19 with papulo‑pustular form of rosacea. In 18 patients, the dermatosis lasted for up to 6 months, in the remaining 18 patients for more than 6 months. In patients with rosacea, the serum content of individual cytokines, interleukin‑17A and interleukin‑18 was determined by the immunoassay assay. Results. It has been established that the content of proinflammatory cytokines in the serum of patients with rosacea is reliably elevated compared to that in the control group – IL‑17A (4.11 times, p <0.001) and IL‑18 (1.63 times, p = 0.002). A more significant increase in the level of IL‑17A in the blood serum of patients with the papulo‑pustular form of rosacea compared to the erythema‑telangiectatic form and duration of dermatosis for more than six months has been found. At the same time, the level of IL‑18 tended to increase more significantly in the early stages of dermatosis – in patients with erythema‑telangiectatic stage of rosacea and duration of the disease up to 6 months, with subsequent decrease in the level of IL‑18 in patients with papulo‑pustular stage and duration of dermatosis more than 6 months. Conclusions. The patients with rosacea were found to have an elevated level of proinflammatory cytokines – interleukin‑17A and interleukin‑18. The changes in the cytokines depended on the nature of clinical course of rosacea, indicating a significant role in the regulation of inflammatory processes in the pathogenesis of dermatosis and the importance of monitoring the content of blood serum IL‑17A and IL‑18, as prognostic criteria for clinical course and effective treatment of rosacea

MutL Activates UvrD by Interaction Between the MutL C-terminal Domain and the UvrD 2B Domain

UvrD is a helicase vital for DNA replication and quality control processes. In its monomeric state, UvrD exhibits limited helicase activity, necessitating either dimerization or assistance from an accessory protein to efficiently unwind DNA. Within the DNA mismatch repair pathway, MutL plays a pivotal role in relaying the repair signal, enabling UvrD to unwind DNA from the strand incision site up to and beyond the mismatch. Although this interdependence is well-established, the precise mechanism of activation and the specific MutL-UvrD interactions that trigger helicase activity remain elusive. To address these questions, we employed site-specific crosslinking techniques using single-cysteine variants of MutL and UvrD followed by functional assays. Our investigation unveils that the C-terminal domain of MutL not only engages with UvrD but also acts as a self-sufficient activator of UvrD helicase activity on DNA substrates with 3′-single-stranded tails. Especially when MutL is covalently attached to the 2B or 1B domain the tail length can be reduced to a minimal substrate of 5 nucleotides without affecting unwinding efficiency.</p

MutL Activates UvrD by Interaction Between the MutL C-terminal Domain and the UvrD 2B Domain

UvrD is a helicase vital for DNA replication and quality control processes. In its monomeric state, UvrD exhibits limited helicase activity, necessitating either dimerization or assistance from an accessory protein to efficiently unwind DNA. Within the DNA mismatch repair pathway, MutL plays a pivotal role in relaying the repair signal, enabling UvrD to unwind DNA from the strand incision site up to and beyond the mismatch. Although this interdependence is well-established, the precise mechanism of activation and the specific MutL-UvrD interactions that trigger helicase activity remain elusive. To address these questions, we employed site-specific crosslinking techniques using single-cysteine variants of MutL and UvrD followed by functional assays. Our investigation unveils that the C-terminal domain of MutL not only engages with UvrD but also acts as a self-sufficient activator of UvrD helicase activity on DNA substrates with 3′-single-stranded tails. Especially when MutL is covalently attached to the 2B or 1B domain the tail length can be reduced to a minimal substrate of 5 nucleotides without affecting unwinding efficiency.</p

Neurofibromatosis Type 1 Gene Alterations Define Specific Features of a Subset of Glioblastomas

Neurofibromatosis type 1 (NF1) gene mutations or alterations occur within neurofibromatosis type 1 as well as in many different malignant tumours on the somatic level. In glioblastoma, NF1 loss of function plays a major role in inducing the mesenchymal (MES) subtype and, therefore defining the most aggressive glioblastoma. This is associated with an immune signature and mediated via the NF1&ndash;MAPK&ndash;FOSL1 axis. Specifically, increased invasion seems to be regulated via mutations in the leucine-rich domain (LRD) of the NF1 gene product neurofibromin. Novel targets for therapy may arise from neurofibromin deficiency-associated cellular mechanisms that are summarised in this review

Generation of two human induced pluripotent stem cell lines from a patient with Neurofibromatosis type 1 (NF1) and pathogenic NF1 gene variant c.1466 A>G BCRTi011-A as well as a first-degree healthy relative (BCRTi010-A)

We describe the generation of two human induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells (PBMCs) using a non-integrative episomal reprogramming strategy. The first cell line was derived from a NF1 patient with the genetic variant c.1466A>G (BCRTi011-A) which leads to a cryptic splice site and aberrant splicing. The second one was created from a healthy relative of first-degree (BCRTi010-A). The generated iPSC lines were shown to have tri-lineage differentiation potential, a normal karyotype, and expression of pluripotent markers. Both iPSC lines provide a powerful tool for in vitro disease modeling and therapy development

Generation of two human induced pluripotent stem cell lines from a patient with Neurofibromatosis type 1 (NF1) and pathogenic NF1 gene variant c.1466 A>G BCRTi011-A as well as a first-degree healthy relative (BCRTi010-A)

We describe the generation of two human induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells (PBMCs) using a non-integrative episomal reprogramming strategy. The first cell line was derived from a NF1 patient with the genetic variant c.1466A>G (BCRTi011-A) which leads to a cryptic splice site and aberrant splicing. The second one was created from a healthy relative of first-degree (BCRTi010-A). The generated iPSC lines were shown to have tri-lineage differentiation potential, a normal karyotype, and expression of pluripotent markers. Both iPSC lines provide a powerful tool for in vitro disease modeling and therapy development

Multimicrobial Kombucha Culture Tolerates Mars-Like Conditions Simulated on Low-Earth Orbit

A kombucha multimicrobial culture (KMC) was exposed to simulated Mars-like conditions in low-Earth orbit (LEO). The study was part of the Biology and Mars Experiment (BIOMEX), which was accommodated in the European Space Agency's EXPOSE-R2 facility, outside the International Space Station. The aim of the study was to investigate the capability of a KMC microecosystem to survive simulated Mars-like conditions in LEO. During the 18-month exposure period, desiccated KMC samples, represented by living cellulose-based films, were subjected to simulated anoxic Mars-like conditions and ultraviolet (UV) radiation, as prevalent at the surface of present-day Mars. Postexposure analysis demonstrated that growth of both the bacterial and yeast members of the KMC community was observed after 60 days of incubation; whereas growth was detected after 2 days in the initial KMC. The KMC that was exposed to extraterrestrial UV radiation showed degradation of DNA, alteration in the composition and structure of the cellular membranes, and an inhibition of cellulose synthesis. In the “space dark control” (exposed to LEO conditions without the UV radiation), the diversity of the microorganisms that survived in the biofilm was reduced compared with the ground-based controls. This was accompanied by structural dissimilarities in the extracellular membrane vesicles. After a series of subculturing, the revived communities restored partially their structure and associated activities

Multimicrobial kombucha culture tolerates Mars-like conditions simulated on low earth orbit

A kombucha multimicrobial culture (KMC) was exposed to simulated Mars-like conditions in low Earth orbit (LEO). The study was part of the BIOlogy and Mars EXperiment (BIOMEX), which was accommodated in the European Space Agency's EXPOSE-R2 facility, outside the International Space Station. The aim of the study was to investigate the capability of a KMC microecosystem to survive simulated Mars-like conditions in LEO. During the 18-month exposure period, desiccated KMC samples, represented by living cellulose-based films, were subjected to simulated anoxic Mars-like conditions and ultraviolet (UV) radiation, as prevalent at the surface of present-day Mars. Postexposure analysis demonstrated that growth of both the bacterial and yeast members of the KMC community was observed after 60 days of incubation; whereas growth was detected after 2 days in the initial KMC. The KMC that was exposed to extraterrestrial UV radiation showed degradation of DNA, alteration in the composition and structure of the cellular membranes, and an inhibition of cellulose synthesis. In the “space dark control” (exposed to LEO conditions without the UV radiation), the diversity of the microorganisms that survived in the biofilm was reduced compared with the ground-based controls. This was accompanied by structural dissimilarities in the extracellular membrane vesicles. After a series of subculturing, the revived communities restored partially their structure and associated activities.The National Academy of Sciences of Ukraine (Grant 47/2017).http://www.liebertpub.com/overview/astrobiology/992020-02-11hj2019BiochemistryGeneticsMicrobiology and Plant Patholog