Oxidatively damaged proteins accumulate with age in almost all cell types and tissues. The activity of chaperonemediated autophagy (CMA), a selective pathway for the degradation of cytosolic proteins in lysosomes, decreases with age. We have analyzed the possible participation of CMA in the removal of oxidized proteins in rat liver and cultured mouse fibroblasts. Added to the fact that CMA substrates, when oxidized, are more efficiently internalized into lysosomes, we have found a constitutive activation of CMA during oxidative stress. Oxidation-induced activation of CMA correlates with higher levels of several components of the lysosomal translocation complex, but in particular of the lumenal chaperone, required for substrate uptake, and of the lysosomal membrane protein (lamp) type 2a, previously identified as a receptor for this pathway. In contrast with the well characterized mechanism of CMA activation during nutritional stress, which does not require de novo synthesis of the receptor, oxidation-induced activation of CMA is attained through transcriptional up-regulation of lamp2a. We conclude that CMA is activated during oxidative stress and that the higher activity of this pathway under these conditions, along with the higher susceptibility of the oxidized proteins to be taken up by lysosomes, both contribute to the efficient removal of oxidized proteins. INTRODUCTIONAccumulation of oxidized protein is a common feature of aged cells (Dunlop et al., 2002;Grune et al., 2001Grune et al., , 2002bStadtman, 2001). Many physiological and pathological processes lead to the generation of free radicals and consequent damage of intracellular components, including proteins. In most of these oxidative events, damaged proteins are removed from the cell through degradation by proteases (Dunlop et al., 2002). The activity of different intracellular proteolytic systems decreases with age (Terman, 1995;Cuervo and Dice, 1998a;Friguet et al., 2000;Carrard et al., 2002;Donati et al., 2001;Merker et al., 2001;Friguet, 2002;Keller et al., 2002;Ward, 2002), and this impaired activity is considered responsible for the deficient removal of oxidized proteins in old organisms (Grune, 2000;Merker and Grune, 2000;Dunlop et al., 2002;Szweda et al., 2002).The susceptibility of oxidized proteins to proteases changes with the duration and degree of oxidative damage (Dunlop et al., 2002;Mehlhase and Grune, 2002). Thus, mild oxidation induces partial protein unfolding and facilitates proteolytic cleavage (Grune et al., 1995. However, persistent or extensive oxidative damage usually promotes protein aggregation, due to the exposure of patches of hydrophobic amino acids. Once a protein aggregates, it becomes less susceptible to proteolytic cleavage (Hoff et al., 1993;Davies, 2001;Demasi and Davies, 2003). Kinetics of degradation of oxidized proteins in vitro have been analyzed using different types of proteases (Merker and Grune, 2000;Dunlop et al., 2002;Szweda et al., 2002). One of the most extensively analyzed protease in this respect has be...

Numerous magnetic resonance (MR) studies have examined gray matter structural alterations in patients with obsessive-compulsive disorder (OCD). Few, however, have used automated, highly reliable techniques such as voxel-based morphometry (VBM) to examine the entire brain in contrast to selected regions of interest. Moreover, few studies have examined the functional correlates of gray matter abnormalities in OCD. We used VBM to evaluate regional gray matter differences between 21 OCD patients and 21 age-and sex-matched healthy volunteers. All patients had comprehensive neuropsychological assessments. MR images were normalized to a customized template and segmented using optimized VBM. OCD patients had significantly (P < 0.001; uncorrected) more gray matter in the left thalamus compared to healthy volunteers. OCD patients without major depression had significantly more gray matter in the thalamus (bilaterally) and left orbitofrontal cortex as well as an unpredicted region of more right dorsolateral prefrontal gray matter, which remained significant after correction for multiple comparisons, compared to healthy volunteers. In the subgroup of patients without depression greater right hemisphere thalamic and dorsolateral prefrontal gray matter correlated significantly with worse motor functioning and processing speed, respectively. In this subgroup there was also a tendency for more gray matter in the left orbitofrontal cortex and right dorsolateral prefrontal cortex to be associated with greater symptom severity. Our findings provide additional support for involvement of cortical-striatal-thalamic circuits in the pathophysiology of OCD and preliminary evidence that a defect involving the dorsolateral prefrontal cortex may also be implicated. Moreover, our data suggest that gray matter structural alterations in OCD have neuropsychological correlates, which may be useful in further characterizing structurefunction relations in this disorder.

The Gestalt psychologists reported a set of laws describing how vision groups elements to recognize objects. The Gestalt laws “prescribe for us what we are to recognize ‘as one thing’.” (Köhler, 1920). Were they right? Does object recognition involve grouping? Tests of the laws of grouping have been favorable, but mostly assessed only detection, not identification, of the compound object. The grouping of elements seen in the detection experiments with lattices and ‘snakes in the grass’ is compelling, but falls far short of the vivid everyday experience of recognizing a familiar, meaningful, named thing, which mediates the ordinary identification of an object. Thus, after nearly a century, there is hardly any evidence that grouping plays a role in ordinary object recognition. To assess grouping in object recognition, we made letters out of grating patches and measured threshold contrast for identifying these letters in visual noise as a function of perturbation of grating orientation, phase, and offset. We define a new measure, “wiggle,” to characterize the degree to which these various perturbations violate the Gestalt law of good continuation. We find that efficiency for letter identification is inversely proportional to wiggle, and is wholly determined by wiggle, independent of how the wiggle was produced. Thus the effects of three different kinds of shape perturbation on letter identifiability are predicted by a single measure of goodness of continuation. This shows that letter identification obeys the Gestalt law of good continuation, and may be the first confirmation of the original Gestalt claim that object recognition involves grouping.

Pituitary volumes were measured in 55 first-episode schizophrenia patients at a baseline timepoint with 38 receiving a followup scan after antipsychotic treatment. Fifty-nine healthy volunteers had baseline scans with 34 receiving a followup scan. There were no baseline group differences in pituitary volumes or changes in volume following antipsychotic treatment.