Calcium dependent activation of the NF-AT transcription factor by p59fyn

AbstractA reporter gene under the control of a T-cell antigen receptor response element was activated in Jurkat cells by antigen receptor triggering or by a combination of phorbol myristate acetate, which activates protein kinase C, and a calcium ionophore. Both these signals were necessary for expression of the reporter gene. When co-transfected with a construct capable of overexpressing the tyrosine kinase p59fyn, the reporter gene was activated by PMA alone. Thus p59fyn could replace the calcium ionophore but not activation of protein kinase C. The activation by p59fyn plus PMA was blocked by EGTA and by the immunosuppressant drug cyclosporin A

Grazing effect on the seed bank of a halophytic steppe of the Flooding Pampa, Argentina

El reemplazo del pastoreo continuo por rotativo, o su exclusión, mejoran el suelo y la estructura de lavegetación en la estepa de halófitas de la Depresión del Salado. Sin embargo, se desconoce el efecto del pastoreosobre el banco de semillas del suelo. El objetivo de este trabajo fue evaluar el efecto de distintos regímenes depastoreo sobre cuatro atributos del banco de semillas: 1) el tamaño total, 2) su composición en términos de gruposfuncionales de plantas (e.g., gramíneas invernales (anuales y perenes), gramíneas estivales (anuales y perenes),monocotiledóneas no gramíneas, leguminosas y dicotiledóneas), 3) la diversidad y 4) la composición florística.El trabajo se realizó en cinco parcelas sometidas a diferentes manejos del pastoreo durante 14 años (dos parcelasbajo pastoreo continuo; dos parcelas bajo pastoreo rotativo y una excluida al pastoreo). El muestreo se efectuóen junio y febrero para estudiar el banco estival e invernal. En las parcelas bajo pastoreo continuo, el tamañodel banco de semillas fue notablemente menor, y del mismo modo ocurrió con la diversidad, la equitatividady la riqueza florística, especialmente en el banco estival. El pastoreo continuo provocó remplazos de especiesmuy importantes de los distintos grupos funcionales, particularmente en las gramíneas invernales anuales, enlas gramíneas estivales perennes y en las dicotiledóneas, los tres grupos que explican la mayor proporción delbanco de semillas. En consecuencia, la composición florística del banco de semillas de las parcelas bajo pastoreocontinuo mostró claras diferencias respecto al de las parcelas no pastoreadas o pastoreadas rotativamente.Este trabajo sugiere que el pastoreo continuo constituye un disturbio grave sobre la vegetación de la estepa dehalófitas, que reduce de manera severa su potencial de regeneración a partir del banco de semillas respecto alas parcelas sometidas a pastoreo rotativo o no pastoreadas, que resultaron similares entre sí.Rotational grazing, or even grazing cessation, improves soil- and plant community structure on the halophytic steppe of the Flooding Pampa. However, no information exists about the effect of those grazing regimes on the soil seed bank of this fragile plant community. The objective of this work was to evaluate the effect of different grazing regimes on four attributes of the soil seed bank: 1) total size, 2) size and relative contribution of the functional groups of winter grasses (annual and perennial), summer grasses (annual and perennial), non-grass monocotyledonous, legumes and non-legume dicotyledonous, 3) diversity and 4) floristic composition. We studied five plots subjected to different grazing regimes for 14 years (two plots under continuous grazing; two plots under rotating grazing and one excluded from grazing), sampling in June and February to characterize the summer and winter soil seed bank. We found that continuous grazing reduced total seed bank size, and especially that of winter annual grasses and monocotyledonous, and also reduced floristic diversity, richness and evenness, especially in the summer seed bank. In addition, continuous grazing triggered important species replacements within each functional group, especially in the winter annual grasses, summer perennial grasses and dicotyledonous, the three groups explaining most proportion of the soil seed bank. Therefore, plots under continuous grazing were floristically different from those under rotational grazing or ungrazed. This work suggests that continuous grazing is a severe disturbance which can reduce the regeneration potential of the halophytic steppe.Fil: Vebbhio, María C.. Universidad Nacional de La Plata. Facultad de Ciencias Agrarias y Forestales; ArgentinaFil: Lissarrague, María Isabel. Universidad Nacional de La Plata. Facultad de Ciencias Agrarias y Forestales; ArgentinaFil: Heguy, Bárbara. Universidad Nacional de La Plata. Facultad de Ciencias Agrarias y Forestales; ArgentinaFil: Mendibino, Lorena. Universidad Nacional de La Plata. Facultad de Ciencias Agrarias y Forestales; ArgentinaFil: Rodríguez, Adriana Mabel. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Animal; ArgentinaFil: Golluscio, Rodolfo. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Producción Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentin

Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells.

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments

Prognostic role of elevated mir-24-3p in breast cancer and its association with the metastatic process

MicroRNAs have been shown to play important roles in breast cancer progression and can serve as biomarkers. To assess the prognostic role of a panel of miRNAs in breast cancer, we collected plasma prospectively at the time of initial diagnosis from 1,780 patients with stage I-III breast cancer prior to definitive treatment. We identified plasma from 115 patients who subsequently developed distant metastases and 115 patients without metastatic disease. Both groups were matched by: age at blood collection, year of blood collection, breast cancer subtype, and stage. The median follow up was 3.4 years (range, 1-9 years). We extracted RNA from plasma and analyzed the expression of 800 miRNAs using Nanostring technology. We then assessed the expression of miRNAs in primary and metastatic breast cancer samples from The Cancer Genome Atlas (TCGA). We found that, miR-24-3p was upregulated in patients with metastases, both in plasma and in breast cancer tissues. Patients whose primary tumors expressed high levels of miR-24-3p had a significantly lower survival rate compared to patients with low mir-24-3p levels in the TCGA cohort (n=1,024). RNA-Seq data of the samples with the highest miR-24-3p expression versus those with the lowest miR-24-3p in the TCGA cohort identified a specific gene expression signature for those tumors with high miR-24-3p. Possible target genes for miR-24-3p were predicted based on gene expression and binding site, and their effects on cancer pathways were evaluated. Cancer, breast cancer and proteoglycans were the top three pathways affected by miR-24-3p overexpression

Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma

Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13–1.43, p = 6.77×10−5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34–0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL

Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy:a translational study

AIMS: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. METHODS AND RESULTS: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. CONCLUSIONS: We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy

The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential