Guanine Nucleotide Exchange Factor αPIX Leads to Activation of the Rac 1 GTPase/Glycogen Phosphorylase Pathway in Interleukin (IL)-2-stimulated T Cells

Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation. In the lymphoid system, Rac 1 and in general other small GTPases of the Rho family participate in the signaling cascades that are activated after engagement of the T cell antigen receptor. However, little is known about the IL-2-dependent Rac 1 activator molecules. For the first time, a signaling pathway leading to the activation of Rac 1/PYGM in response to IL-2-stimulated T cell proliferation is described. More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway. IL-2-stimulated serine phosphorylation was corroborated in Kit 225 T cells cultures. A parallel pharmacological and genetic approach identified PKCθ as the serine/threonine kinase responsible for αPIX serine phosphorylation. The phosphorylated state of αPIX was required to activate first Rac 1 and subsequently PYGM. These results demonstrate that the IL-2 receptor activation, among other early events, leads to activation of PKCθ. To activate Rac 1 and consequently PYGM, PKCθ phosphorylates αPIX in T cells. The biological significance of this PKCθ/αPIX/Rac 1 GTPase/PYGM signaling pathway seems to be the control of different cellular responses such as migration and proliferation.     

Organizing Polarized Delivery of Exosomes at Synapses

Exosomes are extracellular vesicles that transport different molecules between cells. They are formed and stored inside multivesicular bodies (MVB) until they are released to the extracellular environment. MVB fuse along the plasma membrane, driving non‐polarized secretion of exosomes. However, polarized signaling potentially directs MVBs to a specific point in the plasma membrane to mediate a focal delivery of exosomes. MVB polarization occurs across a broad set of cellular situations, e.g. in immune and neuronal synapses, cell migration and in epithelial sheets. In this review, we summarize the current state of the art of polarized MVB docking and the specification of secretory sites at the plasma membrane. The current view is that MVB positioning and subsequent exosome delivery requires a polarizing, cytoskeletal dependent‐trafficking mechanism. In this context, we propose scenarios in which biochemical and mechanical signals could drive the polarized delivery of exosomes in highly polarized cells, such as lymphocytes, neurons and epithelia.      

Intra‐clutch pattern of albumen δ13C and δ15N in yellow‐legged gulls Larus michahellis: female dietary shift or resource allocation strategy?

Energy or nutritional constraints associated to female dietary shifts during the clutch production period may play a role in generating intra‐clutch egg size variation in yellow‐legged gulls Larus michahellis. To explore this possibility, we determined albumen δ¹³C and δ¹⁵N values in three‐egg clutches (modal clutch size) from three different breeding episodes: Ebro Delta 2004 and 2006, and Columbretes Islands 2004. Rather than a shift in females’ diet, consistent intra‐clutch patterns of variation in egg size and albumen isotopic values (particularly in the case of albumen δ¹³C, which values held constant throughout the laying sequence) pointed to an intrinsic mechanism as the most feasible cause for the relatively smaller size of third/last‐laid eggs. However, diet “quality” for breeding females seemed to affect intra‐clutch egg size variation. In particular, a deficit of specific nutrients for egg formation associated to refuse scraps exploitation (as suggested by depleted albumen isotopic values) likely resulted in the more apparent intra‐clutch egg size profile for the Ebro Delta 2004. In the absence of dietary shifts, the observation of consistently higher δ¹⁵N values for third‐albumens suggested a greater contribution of endogenous resources to their synthesis, as conversion of stored reserves into egg proteins results in greater isotopic fractionation, thereby yielding enriched isotopic signatures (particularly for δ¹⁵N that shows greater isotopic fractionation with respect to that commonly assumed for δ¹³C). We point to reabsorbed material derived from the hormonally‐mediated regression of the female reproductive system (which is likely the intrinsic mechanisms resulting in the intra‐clutch pattern of egg size variation: the hormonal hypothesis) as the most feasible endogenous source of nutrients for the synthesis of last‐laid eggs, as optimize reproductive investment and maximize female fitness.     

Anti-inflammatory and cytotoxic activities of chichipegenin, peniocerol, and macdougallin isolated from Myrtillocactus geometrizans (Mart. ex Pfeiff.) Con

The oleanane-type triterpene chichipegenin and the sterols peniocerol and macdougallin, isolated from Myrtillocactus geometrizans, showed anti-inflammatory activities in both the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema model and the carrageenan-induced rat paw edema model. All tested compounds inhibited the TPA-induced edema in a dose-dependent manner, with ED50 values less than or equal to that shown by indomethacin. Among them, peniocerol was the most active compound. However, only peniocerol and macdougallin reduced carrageenan-induced rat paw edema. On the other hand, peniocerol and macdougallin showed cytotoxicity against several human cancer cell lines. These results indicate that compounds isolated from M. geometrizans possess antiinflammatory and cytotoxic properties, and the presence of chichipegenin in the aerial parts could justify the medicinal uses attributed to the plant.     

Stable linkage disequilibrium owing to sexual antagonism

Linkage disequilibrium (LD) is an association between genetic loci that is typically transient. Here, we identify a previously overlooked cause of stable LD that may be pervasive: sexual antagonism. This form of selection produces unequal allele frequencies in males and females each generation, which upon admixture at fertilization give rise to an excess of haplotypes that couple male-beneficial with male-beneficial and female-beneficial with female-beneficial alleles. Under sexual antagonism, LD is obtained for all recombination frequencies in the absence of epistasis. The extent of LD is highest at low recombination and for stronger selection. We provide a partition of the total LD into distinct components and compare our result for sexual antagonism with Li and Nei''s model of LD owing to population subdivision. Given the frequent observation of sexually antagonistic selection in natural populations and the number of traits that are often involved, these results suggest a major contribution of sexual antagonism to genomic structure.