CAPRI and RASAL impose different modes of information processing on Ras due to contrasting temporal filtering of Ca(2+)

The versatility of Ca(2+) as a second messenger lies in the complex manner in which Ca(2+) signals are generated. How information contained within the Ca(2+) code is interpreted underlies cell function. Recently, we identified CAPRI and RASAL as related Ca(2+)-triggered Ras GTPase-activating proteins. RASAL tracks agonist-stimulated Ca(2+) oscillations by repetitively associating with the plasma membrane, yet CAPRI displays a long-lasting Ca(2+)-triggered translocation that is refractory to cytosolic Ca(2+) oscillations. CAPRI behavior is Ca(2+)- and C2 domain–dependent but sustained recruitment is predominantly Ca(2+) independent, necessitating integration of Ca(2+) by the C2 domains with agonist-evoked plasma membrane interaction sites for the pleckstrin homology domain. Using an assay to monitor Ras activity in real time, we correlate the spatial and temporal translocation of CAPRI with the deactivation of H-Ras. CAPRI seems to low-pass filter the Ca(2+) signal, converting different intensities of stimulation into different durations of Ras activity in contrast to the preservation of Ca(2+) frequency information by RASAL, suggesting sophisticated modes of Ca(2+)-regulated Ras deactivation

Mutation of the Diamond-Blackfan Anemia Gene Rps7 in Mouse Results in Morphological and Neuroanatomical Phenotypes

The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs) and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7(Mtu) and Rps7(Zma)) of ribosomal protein S7 (Rps7), a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes.This research was supported in part by the Intramural Research Program of NHGRI, NIH, and the Wellcome Trust and by NHMRC Australia grant 366746. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors

Women’s experiences of living with endometriosis : A literature review

Bakgrund: Endometrios är en sjukdom som drabbar ungefär var tionde kvinna i fertil ålder. Endometrios innebär att vävnad som liknar livmoderslemhinnan växer utanför livmodern, vilket kan medföra symtom som kronisk smärta i buken, dysmenoreé och dyspareuni. Symtomen debuterar ofta mellan 20-30 års ålder och kommer oftast i skov där smärtintensiteten varierar. Trots indikation på att kvinnan lider av endometrios tar det flera år att fastställa en diagnos. Syfte: Syftet var att beskriva kvinnors upplevelser av att leva med endometrios. Metod: En begränsad, systematisk litteraturöversikt baserad på 10 vetenskapliga artiklar hämtade från databaserna Academic search complete, Cinahl Complete, MEDLINE with full text och PubMed. Artiklarna är vetenskapligt granskade, på engelska och publicerade mellan 2004 och 2020. Resultat: Fyra huvudteman identifierades: (1) upplevelser av smärta, (2) en begränsad tillvaro, (3) vårdmöten och normalisering av symtom och (4) upplevelser av biverkningar. Sammanfattning: Utifrån denna litteraturöversikt framkommer att normer och okunskap i samhället och vården skapar ett lidande i kvinnornas liv. Detta bidrar till en begränsad tillvaro, då deras fysiska, psykiska, sociala och sexuella hälsa påverkas.Background: Endometriosis is a disease that affects about every tenth woman of fertile age. Endometriosis means that tissue similar to the endometrial tissue grows outside of the uterus, which can cause symptoms such as chronic abdominal pain, dysmenorrhea and dyspareunia. The onset of symptoms often occurs between the age of 20-30 and usually occurs in relapses where the intensity of the pain varies. Despite the indication that the woman is suffering from endometriosis, it takes several years to establish a diagnosis. Aim: The aim was to describe women’s experiences of living with endometriosis. Method: A limited, systematic literature review based on 10 scientific articles retrieved from the databases Academic search complete, Cinahl Complete, MEDLINE with full text and PubMed. The articles are scientifically reviewed, in English and published between 2004 and 2020. Results: Four main themes were identified: (1) experiences of pain, (2) a limited life, (3) healthcare encounters and normalization of symptoms and (4) experiences of side effects. Conclusion: Based on this literature review, it appears that norms and ignorance in society and health care creates suffering in women’s life. This contributes to a limited life, as her physical, mental, social and sexual health gets affected

Women’s experiences of living with endometriosis : A literature review

Bakgrund: Endometrios är en sjukdom som drabbar ungefär var tionde kvinna i fertil ålder. Endometrios innebär att vävnad som liknar livmoderslemhinnan växer utanför livmodern, vilket kan medföra symtom som kronisk smärta i buken, dysmenoreé och dyspareuni. Symtomen debuterar ofta mellan 20-30 års ålder och kommer oftast i skov där smärtintensiteten varierar. Trots indikation på att kvinnan lider av endometrios tar det flera år att fastställa en diagnos. Syfte: Syftet var att beskriva kvinnors upplevelser av att leva med endometrios. Metod: En begränsad, systematisk litteraturöversikt baserad på 10 vetenskapliga artiklar hämtade från databaserna Academic search complete, Cinahl Complete, MEDLINE with full text och PubMed. Artiklarna är vetenskapligt granskade, på engelska och publicerade mellan 2004 och 2020. Resultat: Fyra huvudteman identifierades: (1) upplevelser av smärta, (2) en begränsad tillvaro, (3) vårdmöten och normalisering av symtom och (4) upplevelser av biverkningar. Sammanfattning: Utifrån denna litteraturöversikt framkommer att normer och okunskap i samhället och vården skapar ett lidande i kvinnornas liv. Detta bidrar till en begränsad tillvaro, då deras fysiska, psykiska, sociala och sexuella hälsa påverkas.Background: Endometriosis is a disease that affects about every tenth woman of fertile age. Endometriosis means that tissue similar to the endometrial tissue grows outside of the uterus, which can cause symptoms such as chronic abdominal pain, dysmenorrhea and dyspareunia. The onset of symptoms often occurs between the age of 20-30 and usually occurs in relapses where the intensity of the pain varies. Despite the indication that the woman is suffering from endometriosis, it takes several years to establish a diagnosis. Aim: The aim was to describe women’s experiences of living with endometriosis. Method: A limited, systematic literature review based on 10 scientific articles retrieved from the databases Academic search complete, Cinahl Complete, MEDLINE with full text and PubMed. The articles are scientifically reviewed, in English and published between 2004 and 2020. Results: Four main themes were identified: (1) experiences of pain, (2) a limited life, (3) healthcare encounters and normalization of symptoms and (4) experiences of side effects. Conclusion: Based on this literature review, it appears that norms and ignorance in society and health care creates suffering in women’s life. This contributes to a limited life, as her physical, mental, social and sexual health gets affected