Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced ␤-cell apoptosis. First, ATF3 is induced in ␤ cells by signals relevant to ␤-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-B and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in ␤ cells develop abnormal islets and defects secondary to ␤-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine-or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced ␤-cell apoptosis.It is widely accepted that autoimmunity is the main cause of type 1 but not type 2 diabetes. Despite this difference, ␤-cell death plays an important role in the pathophysiological progression of both diseases (15,43,45). On one hand, proinflammatory cytokines (interleukin-1␤ , tumor necrosis factor alpha [TNF-␣], and gamma interferon [IFN-␥]) destroy ␤ cells in the islets of Langerhans, leading to the pathogenesis of type 1 diabetes (11,14,15,42); on the other hand, elevated glucose and free fatty acids (FFAs)-common metabolic abnormalities in type 2 diabetes-induce ␤-cell death, contributing to the progression of the disease (13,32,35,53,62). Emerging evidence indicates that activation of the NF-B and Jun N-terminal kinase/stress-activated protein kinase (JNK/ SAPK) signaling pathways is a key event leading to cell death, when ␤ cells are exposed to these signals: proinflammatory cytokines, elevated glucose, and elevated FFAs (12,15,16,43,49). Furthermore, activation of these pathways has been demonstrated to impair insulin signaling (1,17,18,36) and play a role in type 2 diabetes (63,71). Therefore, these stress-activated signaling pathways constitute a common molecular mechanism in the pathophysiological progression of type 1 and type 2 diabetes.Thus far, inducible nitric oxide (NO) synthase (iNOS), whose expression leads to NO production, is one of the best known target genes for these pathways (14-16, 42, 54). Several lines of evidence indicate that iNOS plays an important role in the pathogenesis of diabetes. (i) iNOS is induced in the islets by cytokines (16) and is expressed in the islets of diabetes prone BB rats (33) and nonobese diabetic (NOD) mice (55,58). (ii) Transgenic mice expressing iNOS in ␤ cells develop ␤-cell destruction and diabetes (60). (iii) ␤ cells lacking functional iNOS are partially protected ...

Studies showing that neurotrophin binding to p75NTR can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75 NTR in a monovalent manner, raise the possibility that small molecule p75 NTR ligands that positively regulate survival might be found. A pharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75 NTR was applied to in silico screening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75 NTR . In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75 NTR -dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75 NTR behaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.

Background: Both p75 and Par3 become localized in a polarized manner in Schwann cells. Results: BDNF activates Rac1 at the axon-glial interface, regulated by Par3, thereby facilitating proper alignment between the axon and Schwann cells. Conclusion: Polarized localization of Rac1 activation is critical for myelination. Significance: Par3 is involved in Rac1 activation by BDNF-p75 at the axon-glial interface, thereby promoting myelination.

Aging is a process associated with a decline in cognitive and motor functions, which can be attributed to neurological changes in the brain. Tai Chi, a multimodal mind-body exercise, can be practiced by people across all ages. Previous research identified effects of Tai Chi practice on delaying cognitive and motor degeneration. Benefits in behavioral performance included improved fine and gross motor skills, postural control, muscle strength, and so forth. Neural plasticity remained in the aging brain implies that Tai Chi-associated benefits may not be limited to the behavioral level. Instead, neurological changes in the human brain play a significant role in corresponding to the behavioral improvement. However, previous studies mainly focused on the effects of behavioral performance, leaving neurological changes largely unknown. This systematic review summarized extant studies that used brain imaging techniques and EEG to examine the effects of Tai Chi on older adults. Eleven articles were eligible for the final review. Three neuroimaging techniques including fMRI (N = 6), EEG (N = 4), and MRI (N = 1), were employed for different study interests. Significant changes were reported on subjects' cortical thickness, functional connectivity and homogeneity of the brain, and executive network neural function after Tai Chi intervention. The findings suggested that Tai Chi intervention give rise to beneficial neurological changes in the human brain. Future research should develop valid and convincing study design by applying neuroimaging techniques to detect effects of Tai Chi intervention on the central nervous system of older adults. By integrating neuroimaging techniques into randomized controlled trials involved with Tai Chi intervention, researchers can extend the current research focus from behavioral domain to neurological level.

Background:The role of p75 in Purkinje cells of the adult cerebellum has remained obscure. Results: In the absence of p75, RacGTP levels from the cerebellum were reduced, and the mean firing frequency for all phasic firing Purkinje cells was increased. Conclusion: p75 regulates Purkinje cell firing by activating Rac1, thereby targeting SK channel function. Significance: p75 signaling contributes to normal function of Purkinje cell firing.