Kidney podocytes and their foot processes maintain the ultrafiltration barrier and prevent urinary protein loss (proteinuria). Here we show that the GTPase dynamin is essential for podocyte function. During proteinuric kidney disease, induction of cytoplasmic cathepsin L leads to cleavage of dynamin at an evolutionary conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lack the cathepsin L site, or render the cathepsin L site inaccessible through dynamin self-assembly, are resistant to cathepsin L cleavage. When delivered into mice, these mutants restored podocyte function and resolve proteinuria. Our study identifies dynamin as a critical regulator of renal permselectivity that is specifically targeted by proteolysis under pathological conditions.

Transforming growth factor-␤ (TGF-␤) has previously been implicated in the progression of diabetic nephropathy, including the onset of fibrosis and albuminuria. Here we report for the first time the use of a high-affinity TGF-␤1 binding molecule, the soluble human TGF-␤ type II receptor (sT␤RII.Fc), in the treatment of diabetic nephropathy in 12-week streptozotocin-induced diabetic Sprague-Dawley rats. In vitro studies using immortalized rat proximal tubule cells revealed that 50 pmol/l TGF-␤1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sT␤RII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sT␤RII.Fc reduced urinary albumin excretion by 36% at 4 weeks, 59% at 8 weeks (P < 0.001), and 45% at 12 weeks (P < 0.01 for diabetic vs. treated). This was correlated with an increase in megalin expression (P < 0.05 for diabetic vs. treated) and a reduction in collagen IV expression following sT␤RII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sT␤RII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-␤1-induced disruptions of renal proximal tubule cell uptake of albumin. Diabetes 56:380 -388, 2007

These results indicate that abnormalities in prosody processing occur at the three stages of EP processing, and are enhanced in SSC. Correlations between P200 amplitude for happy prosody and delusions suggest a role that abnormalities in the processing of emotionally salient acoustic cues may play in schizophrenia symptomatology. Correlations between ERP and behavioral data point to a relationship between early sensory abnormalities and prosody recognition in schizophrenia.

Recent evidence suggests that affect acts as modulator of cognitive processes and in particular that induced mood has an effect on the way semantic memory is used on-line. We used event-related potentials (ERPs) to examine affective modulation of semantic information processing under three different moods: neutral, positive and negative. Fifteen subjects read 324 pairs of sentences, after mood induction procedure with 30 pictures of neutral, 30 pictures of positive and 30 pictures of neutral valence: 108 sentences were read in each mood induction condition. Sentences ended with three word types: expected words, within-category violations, and between-category violations. N400 amplitude was measured to the three word types under each mood induction condition. Under neutral mood, a congruency (more negative N400 amplitude for unexpected relative to expected endings) and a category effect (more negative N400 amplitude for between- than to within-category violations) were observed. Also, results showed differences in N400 amplitude for both within- and between-category violations as a function of mood: while positive mood tended to facilitate the integration of unexpected but related items, negative mood made their integration as difficult as unexpected and unrelated items. These findings suggest the differential impact of mood on access to long-term semantic memory during sentence comprehension.

Transforming growth factor ␤ (TGF-␤) ligands exert their biological effects through type II (T␤RII) and type I receptors (T␤RI). Unlike TGF-␤1 and -␤3, TGF-␤2 appears to require the co-receptor betaglycan (type III receptor, T␤RIII) for high affinity binding and signaling. Recently, the T␤RIII null mouse was generated and revealed significant non-overlapping phenotypes with the TGF-␤2 null mouse, implying the existence of T␤RIII independent mechanisms for TGF-␤2 signaling. Because a variant of the type II receptor, the type II-B receptor (T␤RII-B), has been suggested to mediate TGF-␤2 signaling in the absence of T␤RIII, we directly tested the ability of T␤RII-B to bind TGF-␤2. Here we show that the soluble extracellular domain of the type II-B receptor (sT␤RII-B.Fc) bound TGF-␤1 and TGF-␤3 with high affinity (K d values ‫؍‬ 31.7 ؎ 22.8 and 74.6 ؎ 15.8 pM, respectively), but TGF-␤2 binding was undetectable at corresponding doses. Similar results were obtained for the soluble type II receptor (sT␤RII.Fc). However, sT␤RII.Fc or sT␤RII-B.Fc in combination with soluble type I receptor (sT␤RI.Fc) formed a high affinity complex that bound TGF-␤2, and this complex inhibited TGF-␤2 in a biological inhibition assay. These results show that TGF-␤2 has the potential to signal in the absence of T␤RIII when sufficient TGF-␤2, T␤RI, and T␤RII or T␤RII-B are present. Our data also support a cooperative model for receptor-ligand interactions, as has been suggested by crystallization studies of TGF-␤ receptors and ligands. Our cell-free binding assay system will allow for testing of models of receptor-ligand complexes prior to actual solution of crystal structures.Transforming growth factor-␤ (TGF-␤) 1 represents a large superfamily of dimeric growth factors that include the TGF-␤s, inhibins, activins, Mullerian inhibiting substance, growth and differentiation factors, and bone morphogenetic proteins (BMPs) in mammals (1, 2). These cytokines play important roles in an array of processes such as growth, differentiation, and development (3). There are three TGF-␤ isoforms that share a high degree of homology and overlapping biological activities (4). However, distinct expression patterns and unique, isoform-specific phenotypes of the corresponding knockout mice demonstrate significant non-redundancy of TGF-␤ function (5-9).TGF-␤s exert their biological effects through three cell surface receptors designated as type I, II, and III (T␤RI, T␤RII, and T␤RIII) (2), all of which have been cloned (10 -13). In addition, the type II-B receptor (T␤RII-B), an alternatively spliced isoform of T␤RII containing an insert of 26 amino acids replacing Val 51 , has also been identified (14 -16). Type I and type II receptors have intracellular serine/threonine kinase domains, whereas the type III receptor has only a short intracellular domain. On binding of TGF-␤ ligands, constitutively active type II receptors recruit and phosphorylate type I receptors; the activated type I receptor kinase then interacts with and phosphorylates downstream signaling ...

Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average rg = -.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population.

The clinical high risk (CHR) period is a phase denoting a risk for overt psychosis during which subacute symptoms often appear, and cognitive functions may deteriorate. To compare biological indices during this phase with those during first episode schizophrenia, we cross-sectionally examined sex- and age-matched clinical high risk (CHR, n=21), first episode schizophrenia patients (FESZ, n=20) and matched healthy controls (HC, n=25) on oddball and novelty paradigms and assessed the N100, P200, P3a and P3b as indices of perceptual, attentional and working memory processes. To our knowledge, this is the only such comparison using all of these event-related potentials (ERPs) in two paradigms. We hypothesized that the ERPs would differentiate between the three groups and allow prediction of a diagnostic group. The majority of ERPs were significantly affected in CHR and FESZ compared with controls, with similar effect sizes. Nonetheless, in logistic regression, only the P3a and N100 distinguished CHR and FESZ from healthy controls, suggesting that ERPs not associated with an overt task might be more sensitive to prediction of group membership.

Auditory hallucinations (AHs) are one of the most distressing symptoms of schizophrenia (SZ) and are often resistant to medication. Imaging studies of individuals with SZ show hyperactivation of the default mode network (DMN) and the superior temporal gyrus (STG). Studies in SZ show DMN hyperconnectivity and reduced anticorrelation between DMN and the central executive network (CEN). DMN hyperconnectivity has been associated with positive symptoms such as AHs ‡