Qualitatively Different T Cell Phenotypic Responses to IL-2 versus IL-15 Are Unified by Identical Dependences on Receptor Signal Strength and Duration

IL-2 and IL-15 are common γ-chain family cytokines involved in regulation of T cell differentiation and homeostasis. Despite signaling through the same receptors, IL-2 and IL-15 have non-redundant roles in T cell biology, both physiologically and at the cellular level. The mechanisms by which IL-2 and IL-15 trigger distinct phenotypes in T cells remain elusive. To elucidate these mechanisms, we performed a quantitative comparison of the phosphotyrosine signaling network and resulting phenotypes triggered by IL-2 and IL-15. This study revealed that the signaling networks activated by IL-2 or IL-15 are highly similar and that T cell proliferation and metabolism are controlled in a quantitatively distinct manner through IL-2/15R signal strength independent of the cytokine identity. Distinct phenotypes associated with IL-2 or IL-15 stimulation therefore arise through differential regulation of IL-2/15R signal strength and duration because of differences in cytokine–receptor binding affinity, receptor expression levels, physiological cytokine levels, and cytokine–receptor intracellular trafficking kinetics. These results provide important insights into the function of other shared cytokine and growth factor receptors, quantitative regulation of cell proliferation and metabolism through signal transduction, and improved design of cytokine based clinical immunomodulatory therapies for cancer and infectious diseases.National Institutes of Health (U.S.) (Grant U54CA11927)National Institutes of Health (U.S.) (Grant R01 AI065824)United States. Army Research Office (Institute for Collaborative Biotechnologies Grant W911NF-09-0001

Eating disorders: the current status of molecular genetic research

Anorexia nervosa (AN) and bulimia nervosa (BN) are complex disorders characterized by disordered eating behavior where the patient’s attitude towards weight and shape, as well as their perception of body shape, are disturbed. Formal genetic studies on twins and families suggested a substantial genetic influence for AN and BN. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Hardly any of the positive findings achieved in these studies were unequivocally confirmed or substantiated in meta-analyses. This might be due to too small sample sizes and thus low power and/or the genes underlying eating disorders have not yet been analyzed. However, some studies that also used subphenotypes (e.g., restricting type of AN) led to more specific results; however, confirmation is as yet mostly lacking. Systematic genome-wide linkage scans based on families with at least two individuals with an eating disorder (AN or BN) revealed initial linkage regions on chromosomes 1, 3 and 4 (AN) and 10p (BN). Analyses on candidate genes in the chromosome 1 linkage region led to the (as yet unconfirmed) identification of certain variants associated with AN. Genome-wide association studies are under way and will presumably help to identify genes and pathways involved in these eating disorders. The elucidation of the molecular mechanisms underlying eating disorders might improve therapeutic approaches

Formation of nanocrystalline transition-metal ferrites inside a silica matrix

Nanocrystalline transition-metal ferrites were synthesized inside an amorphous silica matrix by the sol-gel method. The formation of spinel ferrites began above 400degreesC, giving fine particles of about 10 nm at 800degreesC. This is associated with a specific role of the silica matrix, which facilitates the diffusion of the reacting cations, enhancing the ferrite formation. Above 1000degreesC the MnFe2O4 and CuFe2O4 nanoparticles lost their fine nature. The dried gels and crystalline materials were characterized by X-ray diffraction, thermal, FTIR, and BET analyses as well as by high-resolution scanning transmission electron microscopy

Recent advances in karst research: From theory to fieldwork and applications

Karst landscapes and karst aquifers, which are composed of a variety of soluble rocks such as salt, gypsum, anhydrite, limestone, dolomite and quartzite, are fascinating areas of study. As karst rocks are abundant on the Earth's surface, the fast evolution of karst landscapes and the rapid flow of water through karst aquifers present challenges from a number of different perspectives. This collection of 25 papers deals with different aspects of these challenges, including karst geology, geomorphology and speleogenesis, karst hydrogeology, karst modelling, and karst hazards and management. Together these papers provide a state-of-the-art review of the current challenges and solutions in describing karst from a scientific perspective

Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart.

The human heart is a target organ for the octapeptide hormone, angiotensin II (Ang II). Recent studies suggest that the human heart contains a dual pathway of Ang II formation in which the major Ang II-forming enzymes are angiotensin I-converting enzyme (ACE) and chymase. Human heart chymase has recently been purified and its cDNA and gene cloned. This cardiac serine proteinase is the most efficient and specific Ang II-forming enzyme described. To obtain insights into the cardiac sites of chymase-dependent Ang II formation, we examined the cellular localization and regional distribution of chymase in the human heart. Electron microscope immunocytochemistry using an anti-human chymase antibody showed the presence of chymase-like immunoreactivity in the cardiac interstitium and in cytosolic granules of mast cells, endothelial cells, and some mesenchymal interstitial cells. In the cardiac interstitium, chymase-like immunoreactivity is associated with the extracellular matrix. In situ hybridization studies further indicated that chymase mRNA is expressed in endothelial cells and in interstitial cells, including mast cells. Tissue chymase levels were determined by activity assays and by Western blot analyses. Chymase levels were approximately twofold higher in ventricles than in atria. There were no significant differences in chymase levels in ventricular tissues obtained from non-failing donor hearts, failing ischemic hearts, or hearts from patients with ischemic cardiomyopathy. These findings suggest that a major site of chymase-dependent Ang II formation in the heart is the interstitium and that cardiac mast cells, mesenchymal interstitial cells, and endothelial cells are the cellular sites of synthesis and storage of chymase. In the human heart, because ACE levels are highest in the atria and chymase levels are highest in ventricles, it is likely that the relative contribution of ACE and chymase to cardiac Ang II formation varies with the cardiac chamber. Such differences may lead to differential suppression of cardiac Ang II levels during chronic ACE inhibitor therapy in patients with congestive heart failure

Cave genesis in the Alps between the Miocene and today : a review

International audienceNouvelles considerations sur la genèse des cavités dans les Alpes depuis le Miocène. Les progrès dans la compréhension des processus spéléogénétiques ainsi que les recherches intensives conduites dans les Alpes depuis quelques décennies donnent de nouvelles clefs à la compréhension des cavités alpines. Les parties noyées des réseaux karstiques se développent à proximité de la surface piézométrique, qui est déterminée par la position de l'émergence, elle-même généralement dépendante de la position du talweg. Par conséquent, les cavités sont directement en liaison avec l'évolution géomorphologique superficielle et enregistrent l'approfondissement des vallées. Les sédiments piégés dans les cavités permettent de reconstituer les phases morphogéniques et l'évolution paléoclimatique. De plus, ce sont les seules possibilités de dater les grottes et en conséquence l'évolution des paysages. Les grottes se forment dès lors que les calcaires émergent et qu'un gradient hydraulique est présent. Les paléokarsts du Mésozoïque et du Paléogène attestent de ces émersions précoces. Le karst hydrothermal semble beaucoup plus fréquent qu'envisagé auparavant, car les circulations postérieures ont souvent gommé les indices hydrothermaux originels. La fantômisation est décrite comme un nouvel agent spéléogénétique. En revanche, les glaciers ont plutôt ralenti les processus spéléogénétiques et colmaté les cavités. Leur influence n'est qu'indirecte, par l'approfondissement des vallées et le décapage des couvertures imperméables. L'ensemble des données chronologiques et morphologiques montrent que la plupart des cavités alpines ( à l'exception des paléokarsts) sont d'âge pliocène ou même miocène. Les progrès des méthodes de datation (particulièrement l'essor récent des nucléides cosmogéniques) devrait permettre de dater les sédiments karstiques, non seulement pléistocènes mais également pliocènes