Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice

Mitogen kinase kinase 4 (MKK4) and mitogen kinase kinase 7 (MKK7) are members of the MAP2K family that can activate downstream mitogen-activated protein kinases (MAPKs). MKK4 has been implicated in the activation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, while MKK7 has been reported to activate only JNK in response to different stimuli. The stimuli, as well as the cell type determine which MAP2K member will mediate a given response. In various cell types, MKK7 contributes to the activation of downstream MAPKs, JNK, which is known to regulate essential cellular processes, such as cell death, differentiation, stress response, and cytokine secretion. Previous studies have also implicated the role of MKK7 in stress signaling pathways and cytokine production. However, little is known about the degree to which MKK4 and MKK7 contribute to innate immune responses in macrophages or during inflammation in vivo. To address this question and to elucidate the role of MKK4 and MKK7 in macrophage and in vivo, we developed MKK4- and MKK7-deficient mouse models with tamoxifen-inducible Rosa26 Cre(ERT). This study reports that MKK7 is required for JNK activation both in vitro and in vivo. Additionally, we demonstrated that MKK7 in macrophages is necessary for lipopolysaccharide (LPS)-induced cytokine production, M1 polarization, and migration, which appear to be a major contributor to the inflammatory response in vivo. Conversely, MKK4 plays a significant, but minor role in cytokine production in vivo

Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice

From MDPI via Jisc Publications RouterHistory: accepted 2021-08-27, pub-electronic 2021-08-29Publication status: PublishedFunder: National Institutes of Health; Grant(s): HL151626, DK107220,Funder: American Heart Association; Grant(s): 16SDG29660007Mitogen kinase kinase 4 (MKK4) and mitogen kinase kinase 7 (MKK7) are members of the MAP2K family that can activate downstream mitogen-activated protein kinases (MAPKs). MKK4 has been implicated in the activation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, while MKK7 has been reported to activate only JNK in response to different stimuli. The stimuli, as well as the cell type determine which MAP2K member will mediate a given response. In various cell types, MKK7 contributes to the activation of downstream MAPKs, JNK, which is known to regulate essential cellular processes, such as cell death, differentiation, stress response, and cytokine secretion. Previous studies have also implicated the role of MKK7 in stress signaling pathways and cytokine production. However, little is known about the degree to which MKK4 and MKK7 contribute to innate immune responses in macrophages or during inflammation in vivo. To address this question and to elucidate the role of MKK4 and MKK7 in macrophage and in vivo, we developed MKK4- and MKK7-deficient mouse models with tamoxifen-inducible Rosa26 CreERT. This study reports that MKK7 is required for JNK activation both in vitro and in vivo. Additionally, we demonstrated that MKK7 in macrophages is necessary for lipopolysaccharide (LPS)-induced cytokine production, M1 polarization, and migration, which appear to be a major contributor to the inflammatory response in vivo. Conversely, MKK4 plays a significant, but minor role in cytokine production in vivo

Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study.

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA

PEMBERDAYAAN KOMUNITAS PEMUDA: MENUJU PALANGKA RAYA SEBAGAI IBUKOTA PEMERINTAHAN REPUBLIK INDONESIA

The article aimed to analyze and identify the readiness of the Palangka Raya city to be the Administrative Capital City of the Republic of Indonesia. An indicator is from the aspect of Youth readiness in the City of Palangka Raya in welcoming the transfer of the administrative capital city. As an important aspect in preparing the Palangka Raya city as the Capital of the future Government is the readiness of youth in the Palangka Raya itself in welcoming the transfer of the administrative capital city from Jakarta to Palangka Raya. Youth, in reality, is a pioneer of any changes occurring throughout the history of the Indonesian. The roles of youth always start from the National Awakening on 1908, the Youth Oath on 1928, the Independence Revolution on 1945, the Proclamation of Independence on 1945, and the Reformation Movement on 1998. Based on history on behalf of the Youth has sensitivity to the problems faced by the nation. Currently, there is a positive trend related to Youth activities in Palangka Raya. Today, there are a lot of youth communities in the Palangka Raya that are formed by young people on the basis of social awareness, voluntary and non-profit oriented aiming to improve competence. There needs a collaboration between the local government and the youth community aiming to invite more youth in Palangka Raya who are creative in an effort in welcoming the transfer of the administrative capital city of Republic of Indonesia, from Jakarta to Palangka Raya city

Heterozygosity at a single locus explains a large proportion of variation in two fitness-related traits in great tits: a general or a local effect?

In natural populations, mating between relatives can have important fitness consequences due to the negative effects of reduced heterozygosity. Parental level of inbreeding or heterozygosity has been also found to influence the performance of offspring, via direct and indirect parental effects that are independent of the progeny own level of genetic diversity. In this study, we first analysed the effects of parental heterozygosity and relatedness (i.e. an estimate of offspring genetic diversity) on four traits related to offspring viability in great tits (Parus major) using 15 microsatellite markers. Second, we tested whether significant heterozygosity–fitness correlations (HFCs) were due to ‘local’ (i.e. linkage to genes influencing fitness) and/or ‘general’ (genome-wide heterozygosity) effects. We found a significant negative relationship between parental genetic relatedness and hatching success, and maternal heterozygosity was positively associated with offspring body size. The characteristics of the studied populations (recent admixture, polygynous matings) together with the fact that we found evidence for identity disequilibrium across our set of neutral markers suggest that HFCs may have resulted from genome-wide inbreeding depression. However, one locus (Ase18) had disproportionately large effects on the observed HFCs: heterozygosity at this locus had significant positive effects on hatching success and offspring size. It suggests that this marker may lie near to a functional locus under selection (i.e. a local effect) or, alternatively, heterozygosity at this locus might be correlated to heterozygosity across the genome due to the extensive ID found in our populations (i.e. a general effect). Collectively, our results lend support to both the general and local effect hypotheses and reinforce the view that HFCs lie on a continuum from inbreeding depression to those strictly due to linkage between marker loci and genes under selection

The proportion of soil-borne pathogens increases with warming at the global scale

Understanding the present and future distribution of soil-borne plant pathogens is critical to supporting food and fibre production in a warmer world. Using data from a global field survey and a nine-year field experiment, we show that warmer temperatures increase the relative abundance of soil-borne potential fungal plant pathogens. Moreover, we provide a global atlas of these organisms along with future distribution projections under different climate change and land-use scenarios. These projections show an overall increase in the relative abundance of potential plant pathogens worldwide. This work advances our understanding of the global distribution of potential fungal plant pathogens and their sensitivity to ongoing climate and land-use changes, which is fundamental to reduce their incidence and impacts on terrestrial ecosystems globally.This project received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 702057 and the European Research Council (ERC) grant agreements no. 242658 (BIOCOM) and no. 647038 (BIODESERT). M.D.-B. is supported by a Ramón y Cajal grant from the Spanish Government (agreement no. RYC2018-025483-I) and a MUSGONET grant (LRA17\1193) from the British Ecological Society. F.T.M. also acknowledges funding from Generalitat Valenciana (CIDEGENT/2018/041) and from sDiv, the synthesis centre of the German Centre for Integrative Biodiversity Research Halle–Jena–Leipzig (iDiv). Work on microbial distribution and colonization in the B.K.S. laboratory is funded by the Australian Research Council (DP190103714). B.K.S. also acknowledges a research award by the Humboldt Foundation. C.A.G. and N.E. acknowledge support from iDiv, funded by the German Research Foundation (DFG FZT118) through flexpool proposals 34600850 and 34600844. N.E. also acknowledges support from the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 677232)