scholarly journals The crystal structure of phosphorylated MAPK13 reveals common structural features and differences in p38 MAPK family activation

2015 ◽  
Vol 71 (4) ◽  
pp. 790-799 ◽  
Author(s):  
Zeynep Yurtsever ◽  
Suzanne M. Scheaffer ◽  
Arthur G. Romero ◽  
Michael J. Holtzman ◽  
Tom J. Brett
Keyword(s):  
Family Member ◽  
P38 Mapk ◽  
Map Kinases ◽  
Sequence Similarity ◽  
Family Members ◽  
Structural Features ◽  
P38 Map Kinase ◽  
Structural Basis ◽  
Structure Based Drug Design ◽  
Specific Inhibitors

The p38 MAP kinases (p38 MAPKs) represent an important family centrally involved in mediating extracellular signaling. Recent studies indicate that family members such as MAPK13 (p38δ) display a selective cellular and tissue expression and are therefore involved in specific diseases. Detailed structural studies of all p38 MAPK family members are crucial for the design of specific inhibitors. In order to facilitate such ventures, the structure of MAPK13 was determined in both the inactive (unphosphorylated; MAPK13) and active (dual phosphorylated; MAPK13/pTpY) forms. Here, the first preparation, crystallization and structure determination of MAPK13/pTpY are presented and the structure is compared with the previously reported structure of MAPK13 in order to facilitate studies for structure-based drug design. A comprehensive analysis of inactiveversusactive structures for the p38 MAPK family is also presented. It is found that MAPK13 undergoes a larger interlobe configurational rearrangement upon activation compared with MAPK14. Surprisingly, the analysis of activated p38 MAPK structures (MAP12/pTpY, MAPK13/pTpY and MAPK14/pTpY) reveals that, despite a high degree of sequence similarity, different side chains are used to coordinate the phosphorylated residues. There are also differences in the rearrangement of the hinge region that occur in MAPK14 compared with MAPK13 which would affect inhibitor binding. A thorough examination of all of the active (phosphorylated) and inactive (unphosphorylated) p38 MAPK family member structures was performed to reveal a common structural basis of activation for the p38 MAP kinase family and to identify structural differences that may be exploited for developing family member-specific inhibitors.

p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli

2005 ◽  
Vol 288 (6) ◽  
pp. F1133-F1143 ◽  
Author(s):  
Sahoko Hirano ◽  
Xiankui Sun ◽  
Cheryl A. DeGuzman ◽  
Richard F. Ransom ◽  
Kenneth R. McLeish ◽  
...  
Keyword(s):  
Map Kinase ◽  
P38 Mapk ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Mesangial Cells ◽  
Smooth Muscle Contraction ◽  
Environmental Pollutant ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Kinase Activation

The environmental pollutant cadmium affects human health, with the kidney being a primary target. In addition to proximal tubules, glomeruli and their contractile mesangial cells have also been identified as targets of cadmium nephrotoxicity. Glomerular contraction is thought to contribute to reduced glomerular filtration, a characteristic of cadmium nephrotoxicity. Because p38 MAPK/HSP25 signaling has been implicated in smooth muscle contraction, we examined its role in cadmium-induced contraction of mesangial cells. We report that exposure of mesangial cells to cadmium resulted in 1) cell contraction, 2) activation of MAP kinases, 3) increased HSP25 phosphorylation coincident with p38 MAP kinase activation, 4) sequential phosphorylation of the two phosphorylation sites of mouse HSP25 with Ser15 being phosphorylated before Ser86, 5) reduction of oligomeric size of HSP25, and 6) association of HSP25 with microfilaments. Exposure of isolated rat glomeruli to cadmium also resulted in contraction and increased HSP25 phosphorylation. The cadmium-induced responses were inhibited by the specific p38 MAP kinase inhibitor SB-203580, and cadmium-induced phosphorylation of HSP25 was inhibited by expression of a dominant-negative p38 MAP kinase mutant. These findings tentatively suggest that cadmium-induced nephrotoxicity results, in part, from glomerular contraction due to p38 MAP kinase/HSP25 signaling-dependent contraction of mesangial cells. With regard to the cellular action of HSP25, these data support a change in paradigm: in addition to its well-established cytoprotective function, HSP25 may also be involved in processes that ultimately lead to adverse effects, as is observed in the response of mesangial cells to cadmium.

Direct neural induction and selective inhibition of mesoderm and epidermis inducers by Xnr3

Development ◽  
1997 ◽  
Vol 124 (2) ◽  
pp. 483-492 ◽  
Author(s):  
C.S. Hansen ◽  
C.D. Marion ◽  
K. Steele ◽  
S. George ◽  
W.C. Smith
Keyword(s):  
Family Members ◽  
Neural Induction ◽  
Structural Features ◽  
Site Directed Mutagenesis ◽  
Structural Basis ◽  
Mesoderm Induction ◽  
Related Factors ◽  
Spemann's Organizer ◽  
Secreted Factors ◽  
C Terminus

During gastrulation in amphibians, secreted factors from Spemann's organizer act on dorsal ectoderm to induce the central nervous system. A number of secreted factors produced by Spemann's organizer have recently been identified. The TGFbeta family member Xnr3 is similar in amino acid sequence to the mouse factor nodal and is expressed in a restricted group of cells in the superficial layer of Spemann's organizer. Xnr3, unlike the related factors nodal, Xnr1 and Xnr2, lacks mesoderm-inducing activity. We report here that Xnr3 can directly induce neural tissue in Xenopus ectoderm explants (animal caps). Injection of animal caps with either Xnr3 RNA or plasmids induces the expression of the pan-neural genes NCAM and nrp1, as well as the anterior neural marker Cpl1. A growing body of evidence suggests that neural induction in Xenopus proceeds as the default in the absence of epidermis inducers. The best candidates for the endogenous epidermis inducers are BMP-4 and BMP-7. The neural inducing activity of Xnr3 can be inhibited by overexpression of BMP-4, as has been observed with the neural inducers noggin, chordin and follistatin. Furthermore, Xnr3 can block mesoderm induction by BMP-4 and activin, but not by Xnr2. The structural basis underlying the divergent activities of Xnr2 and Xnr3 was analyzed using site-directed mutagenesis. Mutations introduced to the conserved cysteine residues characteristic of the TGFbeta family were found to inactivate Xnr2, but not Xnr3. The most unique feature of Xnr3 is the absence of a conserved cysteine at the C terminus of the protein. This feature distinguishes Xnr3 from other TGFbeta family members, including Xnr2. However, we observed that changing the C terminus of Xnr3 to more closely resemble other TGFbeta family members did not significantly alter its activity, suggesting that other structural features of Xnr3 distinguish its biological activity from Xnr2.

FAKTOR – FAKTOR YANG BERHUBUNGAN DENGAN KEJADIAN PNEUMONIA PADA BALITA DI WILAYAH KERJA PUSKESMAS WONOREJO SAMARINDA TAHUN 2017

2018 ◽  
Vol 3 (2) ◽  
pp. 76
Author(s):  
Novi Anggun Pusvitasary
Keyword(s):  
Environmental Factors ◽  
Family Member ◽  
Cause Of Death ◽  
Family Members ◽  
Smoking Behavior ◽  
Smoking Habits ◽  
P Value ◽  
Behavioral Factors ◽  
The World ◽  
Health Standards

Pneumonia disease is the leading cause of death of babies in the world. The prevalence of pneumonia in infants is 18.5 / mil. Data from Samarinda City Health Office during the last 1 year there are 91 cases of pneumonia in Karang Anyar Village and 63 cases in Teluk Lerong Ulu Village. Factors causing pneumonia are toddler factors, behavioral factors, and environmental factors. The results show there is a relationship between house humidity (p value = 0,013; OR = 0,192), house dwelling density (p value = 0,024; OR = 0,214), and family member smoking behavior (p value = 0,006; OR = 10,450) with incidence of pneumonia in toddlers in the Working Area of Puskesmas Wonorejo Samarinda. There was no correlation between house temperature (p value = 0,214; OR = 0,337), house lighting (p value = 0,095; OR = 3,188) and family disease history (p value = 0,707; OR = 0,753) with Pneumonia occurrence in infant in region Work Puskesmas Wonorejo Samarinda. It was concluded that there was a relationship between house humidity, home dwelling density, and smoking behavior of family members with the incidence of pneumonia in infants. It is recommended to be able to apply housing health requirements that meet health standards to reduce the incidence of pneumonia in infants and change smoking habits.

scholarly journals Long-Term Effects of Abuse in Later Life Perpetrated by Family Members

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 444-445
Author(s):  
Naomi Meinertz ◽  
Pi-Ju Liu ◽  
Ron Acierno
Keyword(s):  
Social Support ◽  
Depressive Symptoms ◽  
Family Member ◽  
Older Adult ◽  
Family Members ◽  
Later Life ◽  
Adult Health ◽  
Long Term Effects ◽  
Long Term Impact

Abstract Abuse in later life could potentially lead to lower levels of social support, especially when perpetrated by family members who are charged with protecting the older adult in their care. Using both waves of the National Elder Mistreatment longitudinal data (wave one collected in 2008 and wave two in 2015; N=774), long-term effects of abuse (i.e., physical, emotional, sexual, and financial) on levels of social support, physical health, and clinical depressive symptoms for respondents at or above the age of 60 years were analyzed. A multivariate analysis of variance showed that respondents abused at wave one (n=261) by a family member (B=-0.55, p≤0.001), a spouse or ex-partner (B=-0.349, p=0.02), or a non-relative or stranger (B=-0.301, p=0.026) had lower levels of social support eight years later at wave two. Those abused by a family member at wave one also experienced higher levels of depressive symptoms at wave two (B=-0.187, p=0.01). Perpetrator type did not predict general health at wave two. These results emphasize the long-term impact of abuse on the lives of older adults and highlight the importance trusted relationships, such as with family members, have on older adult health and wellbeing.

scholarly journals Validation of the German version of the Family Reported Outcome Measure (FROM-16) to assess the impact of disease on the partner or family member

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Susanne A. Elsner ◽  
Sam S. Salek ◽  
Andrew Y. Finlay ◽  
Anna Hagemeier ◽  
Catherine J. Bottomley ◽  
...  
Keyword(s):  
Factor Analysis ◽  
Family Member ◽  
Internal Consistency ◽  
Outcome Measure ◽  
Test Validity ◽  
Family Members ◽  
German Version ◽  
The Family ◽  
The Difference ◽  
The Impact

Abstract Background The Family Reported Outcome Measure (FROM-16) assesses the impact of a patient’s chronic illness on the quality of life (QoL) of the patient’s partner or family members. The aim of the study was to translate, explore the structure of and validate the FROM-16. Methods The questionnaire was translated from English into German (forward, backward, four independent translators). Six interviews with family members were conducted to confirm the questionnaire for linguistic, conceptual, semantic and experiential equivalence and its practicability. The final German translation was tested for internal consistency, reproducibility and test validity. Criterion validity was tested by correlating the scores of the FROM-16 and the Global Health Scale (GHS). Principal component analysis, factor analysis, and confirmatory factor analysis was used to assess the questionnaire’s structure and its domains. Reliability and reproducibility were tested computing the intraclass correlation coefficient (ICC) using one sample t-test for testing the hypothesis that the difference between the scores was not different from zero. Results Overall, 83 family members (61% female, median age: 61 years) completed the questionnaire at two different times (mean interval: 22 days). Internal consistency was good for the FROM-16 scores (Cronbach’s α for total score = 0.86). In those with stable GHS, the ICC for the total score was 0.87 and the difference was not different from zero (p = 0.262) indicating reproducible results. A bi-factor model with a general factor including all items, and two sub-factors comprising the items from the original 2-factor construct had the best fit. Conclusions The German FROM-16 has good reliability, test validity and practicability. It can be considered as an appropriate and generic tool to measure QoL of a patient’s partner or family member. Due to the presence of several cross-loadings we do not recommend the reporting of the scores of the two domains proposed for the original version of FROM-16 when using the German version. Thus, in reporting the results emphasis should be put on the total score. Trial registration: Retrospectively registered: DRKS00021070.

scholarly journals The Complete Chloroplast Genome of the Vulnerable Oreocharis esquirolii (Gesneriaceae): Structural Features, Comparative and Phylogenetic Analysis

Plants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1692
Author(s):  
Li Gu ◽  
Ting Su ◽  
Ming-Tai An ◽  
Guo-Xiong Hu
Keyword(s):  
Phylogenetic Analysis ◽  
Sequence Similarity ◽  
Single Copy ◽  
Structural Features ◽  
Rrna Genes ◽  
Trna Genes ◽  
Sequencing Data ◽  
High Sequence Similarity ◽  
Plastid Genomes ◽  
Cp Genome

Oreocharis esquirolii, a member of Gesneriaceae, is known as Thamnocharis esquirolii, which has been regarded a synonym of the former. The species is endemic to Guizhou, southwestern China, and is evaluated as vulnerable (VU) under the International Union for Conservation of Nature (IUCN) criteria. Until now, the sequence and genome information of O. esquirolii remains unknown. In this study, we assembled and characterized the complete chloroplast (cp) genome of O. esquirolii using Illumina sequencing data for the first time. The total length of the cp genome was 154,069 bp with a typical quadripartite structure consisting of a pair of inverted repeats (IRs) of 25,392 bp separated by a large single copy region (LSC) of 85,156 bp and a small single copy region (SSC) of18,129 bp. The genome comprised 114 unique genes with 80 protein-coding genes, 30 tRNA genes, and four rRNA genes. Thirty-one repeat sequences and 74 simple sequence repeats (SSRs) were identified. Genome alignment across five plastid genomes of Gesneriaceae indicated a high sequence similarity. Four highly variable sites (rps16-trnQ, trnS-trnG, ndhF-rpl32, and ycf 1) were identified. Phylogenetic analysis indicated that O. esquirolii grouped together with O. mileensis, supporting resurrection of the name Oreocharis esquirolii from Thamnocharisesquirolii. The complete cp genome sequence will contribute to further studies in molecular identification, genetic diversity, and phylogeny.

scholarly journals Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qin Gong ◽  
Kim Robinson ◽  
Chenrui Xu ◽  
Phuong Thao Huynh ◽  
Kelvin Han Chung Chong ◽  
...  
Keyword(s):  
Cell Death ◽  
Inner Core ◽  
Inflammatory Diseases ◽  
Structural Features ◽  
Structural Basis ◽  
Cultured Human Cells ◽  
Structural Insight ◽  
Sensor Proteins ◽  
Insight Into

AbstractNod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.

scholarly journals Reintegration of Women Post Obstetric Fistula Repair: Experience of Family Caregivers

2017 ◽  
Vol 4 ◽  
pp. 233339361771492 ◽  
Author(s):  
Kimberly Jarvis ◽  
Solina Richter ◽  
Helen Vallianatos ◽  
Lois Thornton
Keyword(s):  
Family Member ◽  
Family Caregivers ◽  
Obstetric Fistula ◽  
Family Members ◽  
Ethnographic Study ◽  
Northern Ghana ◽  
Fistula Repair ◽  
The Social ◽  
Return Home

In northern Ghana, families traditionally function as the main provider of care. The role of family, however, is becoming increasingly challenged with the social shifts in Ghanaian culture moving from extended kinship to nuclear households. This has implications for the care of women post obstetric fistula (OF) repair and their family members who assist them to integrate back into their lives prior to developing the condition. This research is part of a larger critical ethnographic study which explores a culture of reintegration. For this article, we draw attention to the findings related to the experience of family caregivers who care for women post OF repair in northern Ghana. It is suggested that although family caregivers are pleased to have their family member return home, there are many unanticipated physical, emotional, and economic challenges. Findings lead to recommendations for enhancing the reintegration process and the need for adequate caregiving support.

Effect of selective inhibition of the p38 MAP kinase pathway on platelet aggregation

2004 ◽  
Vol 92 (12) ◽  
pp. 1387-1393 ◽  
Author(s):  
Athan Kuliopulos ◽  
Ramon Mohanlal ◽  
Lidija Covic
Keyword(s):  
Platelet Aggregation ◽  
P38 Mapk ◽  
Coronary Intervention ◽  
Selective Inhibition ◽  
P38 Map Kinase ◽  
Significant Inhibition ◽  
Mitogen Activated Protein Kinase ◽  
Thromboxane Production ◽  
Mapk Inhibitor

SummarySystemic inflammation has been shown to be a contributing factor to the instability of atherosclerotic plaques in patients with acute coronary syndromes (ACS). VX-702, a novel p38 mitogen-activated protein kinase (MAPK) inhibitor, is currently under investigation in ACS patients with unstable angina to evaluate its safety and efficacy during percutaneous coronary intervention (PCI).The role of p38 MAPK in platelet aggregation of normal individuals was examined using the selective second generation p38 MAPK inhibitor VX-702. Treatment of platelets with thrombin (activates PAR1 and PAR4 thrombin receptors), SFLLRN (PAR1), AYPGKF (PAR4), collagen (α2β1 and GPVI/FCγIIR receptors) and U46619 (TXA2) resulted in strong activation of p38 MAPK. Activation of the GPIb von Willebrand factor receptor with ristocetin did not stimulate p38 MAPK. Pre-treatment of platelets with 1 μM VX-702 completely inhibited activation of p38 MAPK by thrombin, SFLLRN, AYPGKF, U46619, and collagen. There was no effect of VX-702 on platelet aggregation induced by any of the agonists in the presence or absence of aspirin, heparin or apyrase. It has been postulated that a potential role of p38 MAPK is to activate phospholipase A2 (cPLA2) which catalyses formation of arachidonic acid leading to production of thromboxane. Interestingly, we show contrasting effects of p38 MAPK inhibition as compared to aspirin inhibition on platelet aggregation in response to collagen. Blockade of TXA2 production by aspirin results in significant inhibition of collagen activation. However, VX-702 has no effect on collagen-mediated platelet aggregation, suggesting that blocking p38 MAPK does not effect thromboxane production in human platelets. Therefore, unlike aspirin blockade of thromboxane production in platelets, p38 MAPK inhibitors such as VX-702 do not significantly affect platelet function and would not be expected to contribute to an elevated risk of bleeding side-effects in treated patients.

Sign in / Sign up

Export Citation Format

Share Document