We have mutated two regions within the yeast profilin gene in an effort to functionally dissect the roles of actin and phosphatidylinositol 4,5-bisphosphate (PIP2) binding in profilin function. A series of truncations was carried out at the C terminus of profilin, a region that has been implicated in actin binding. Removal of the last three amino acids nearly eliminated the ability of profilin to bind polyproline in vitro but had no Profilin is a low-molecular-size (12 to 15 kDa) protein that interacts with actin (16,30). Profilin can also bind to the acidic phospholipid L-a-phosphatidylinositol 4,5-bisphosphate (PIP2) and to a lesser extent, phosphatidylinositol monophosphate (23). It has been proposed that interaction with PIP2 may regulate the availability of profilin for interaction with actin (23). Alternatively, profilin may be present to prevent the cleavage of PIP2 by phospholipase C-yl (PLC); such inhibition can be overcome by phosphorylation of PLC (13,14,26), an event that can occur after stimulation of various growth factor receptor tyrosine kinases (39). Thus, activation of PLC by tyrosine kinase receptors could initiate signaling cascades by overcoming the profilin block, resulting in cleavage of PIP2 into the second messengers inositol triphosphate and diacylglycerol.In the yeast Saccharomyces cerevisiae, profilin is required (18) for the proper organization of the actin cytoskeleton into actin cables that generally run longitudinally through the cell and cortical actin spots that occur at regions of active growth (1,22 also known as SRV2 [9]) provided interesting links between the signal transduction machinery and cytoskeletal maintenance and reorganization. Adenylate cyclase-associated protein (hereafter referred to as Cap/Srv2p, and not to be confused with actin-capping protein subunits, encoded by the CAPI and CAP2 genes [3]) appears to be a bifunctional protein, apparently playing a role in the RAS-mediated activation of adenylate cyclase (however, see reference 40) and providing other functions that, when defective, result in abnormalities that are somewhat similar to the defects of a profilin-deficient strain (11,18,38). It is these latter defects that are suppressed by overexpression of profilin. We have found that the ability of two Acanthamoeba isoforms of profilin to suppress the latter defects of Cap/Srv2p correlates with their ability to bind PIP2 (38). This finding suggests that Cap/Srv2p as well as profilin may interact with the signaling pathway that involves PIP2 cleavage. Although little is known about PIP2 signaling in yeast cells, the observation that PIP2 is essential to growth (34) is an indication that it plays an important role. At our present level of knowledge, it is possible that both Cap/Srv2p and profilin are exerting effects on, or are being regulated by, actin and/or PIP2 and related elements. To address these questions, and in an attempt to dissect the known properties of profilin, we have sought to specifically alter profilin's ability to interact with actin or P...

In contrast to the well-established effects of stress on learning of declarative material, much less is known about stress effects on reward- or feedback-based learning. Differential effects on positive and negative feedback especially have received little attention. The objective of this study, thus, was to investigate effects of psychosocial stress on feedback-based learning with a particular focus on the use of negative and positive feedback during learning. Participants completed a probabilistic selection task in both a stress and a control condition. The task allowed quantification of how much participants relied on positive and negative feedback during learning. Although stress had no effect on general acquisition of the task, results indicate that participants used negative feedback significantly less during learning after stress compared with the control condition. An enhancing effect of stress on use of positive feedback failed to reach significance. These findings suggest that stress acts differentially on the use of positive and negative feedback during learning.

Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic β cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than β cell death, suggesting loss of β cell identity. We undertook this study to examine whether viral infection could induce human β cell dedifferentiation. Using the functional human β cell line EndoC-βH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in β cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-κB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-α. Lastly, we identified SOX9 targets in human β cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human β cell dedifferentiation.

Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it. Hence, it is still unknown if and how EVs are involved in the development of T1D. Here we review recent findings concerning the biology of EV in beta cells and the potential implications of this knowledge for the understanding of beta cell dysfunction and autoimmune destruction in T1D.