Elisabetta del Re

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy Amelioration by Soluble TGF-β Type II Receptor

Transforming growth factor-β (TGF-β) 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-β1 binding molecule, the soluble human TGF-β type II receptor (sTβRII.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-β1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sTβRII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sTβRII.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 sTβRII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sTβRII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-β1–induced disruptions of renal proximal tubule cell uptake of albumin.

Reconstitution and Analysis of Soluble Inhibin and Activin Receptor Complexes in a Cell-free System

Activins and inhibins compose a heterogeneous subfamily within the transforming growth factor-β (TGF-β) superfamily of growth and differentiation factors with critical biological activities in embryos and adults. They signal through a heteromeric complex of type II, type I, and for inhibin, type III receptors. To characterize the affinity, specificity, and activity of these receptors (alone and in combination) for the inhibin/activin subfamily, we developed a cell-free assay system using soluble receptor-Fc fusion proteins. The soluble activin type II receptor (sActRII)-Fc fusion protein had a 7-fold higher affinity for activin A compared with sActRIIB-Fc, whereas both receptors had a marked preference for activin A over activin B. Although inhibin A and B binding was 20-fold lower compared with activin binding to either type II receptor alone, the mixture of either type II receptor with soluble TGF-β type III receptor (TβRIII; betaglycan)-Fc reconstituted a soluble high affinity inhibin receptor. In contrast, mixing either soluble activin type II receptor with soluble activin type I receptors did not substantially enhance activin binding. Our results support a cooperative model of binding for the inhibin receptor (ActRII·sTβRIII complex) but not for activin receptors (type II + type I) and demonstrate that a complex composed of activin type II receptors and TβRIII is both necessary and sufficient for high affinity inhibin binding. This study also illustrates the utility of this cell-free system for investigating hypotheses of receptor complex mechanisms resulting from crystal structure analyses.

In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

Transforming growth factor β (TGF-β) ligands exert their biological effects through type II (TβRII) and type I receptors (TβRI). Unlike TGF-β1 and -β3, TGF-β2 appears to require the co-receptor betaglycan (type III receptor, TβRIII) for high affinity binding and signaling. Recently, the TβRIII null mouse was generated and revealed significant non-overlapping phenotypes with the TGF-β2 null mouse, implying the existence of TβRIII independent mechanisms for TGF-β2 signaling. Because a variant of the type II receptor, the type II-B receptor (TβRII-B), has been suggested to mediate TGF-β2 signaling in the absence of TβRIII, we directly tested the ability of TβRII-B to bind TGF-β2. Here we show that the soluble extracellular domain of the type II-B receptor (sTβRII-B.Fc) bound TGF-β1 and TGF-β3 with high affinity (Kd values = 31.7 ± 22.8 and 74.6 ± 15.8 pm, respectively), but TGF-β2 binding was undetectable at corresponding doses. Similar results were obtained for the soluble type II receptor (sTβRII.Fc). However, sTβRII.Fc or sTβRII-B.Fc in combination with soluble type I receptor (sTβRI.Fc) formed a high affinity complex that bound TGF-β2, and this complex inhibited TGF-β2 in a biological inhibition assay. These results show that TGF-β2 has the potential to signal in the absence of TβRIII when sufficient TGF-β2, TβRI, and TβRII or TβRII-B are present. Our data also support a cooperative model for receptor-ligand interactions, as has been suggested by crystallization studies of TGF-β 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.

Differential actions of follistatin and follistatin-like 3.

Follistatin (FS) is an important physiological regulator of activin and other TGFbeta superfamily members. The recently discovered follistatin-like 3 (FSTL3; a.k.a. FLRG; FSRP) shares significant structural and functional homology with FS, but also has some interesting differences, including a prominent nuclear localization. The existence of these two related proteins allows detailed molecular and biochemical comparisons of the biologic roles of their individual structural elements. Current studies indicate that the heparin binding sequence is essential for the ability of FS to inhibit autocrine activin but is not sufficient to confer this activity on FSTL3. Preliminary analysis of FSTL3 transgenic mice suggests that FSTL3 regulates gonadal development and function through inhibition of the paracrine activity of activin and/or other related factors. These studies have identified important structural elements necessary for biological activity of FS and FSTL3 and potential roles for FSTL3 in vivo.

Interactions between mood and the structure of semantic memory: event-related potentials evidence

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.

Clinical high risk and first episode schizophrenia: Auditory event-related potentials

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.

Heritability of Neuropsychological Measures in Schizophrenia and Nonpsychiatric Populations: A Systematic Review and Meta-analysis

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.

A New MRI Masking Technique Based on Multi-Atlas Brain Segmentation in Controls and Schizophrenia: A Rapid and Viable Alternative to Manual Masking.

Brain masking of MRI images separates brain from surrounding tissue and its accuracy is important for further imaging analyses. We implemented a new brain masking technique based on multi‐atlas brain segmentation (MABS) and compared MABS to masks generated using FreeSurfer (FS; version 5.3), Brain Extraction Tool (BET), and Brainwash, using manually defined masks (MM) as the gold standard. We further determined the effect of different masking techniques on cortical and subcortical volumes generated by FreeSurfer.

Anterior commissural white matter fiber abnormalities in first-episode psychosis: A tractography study

Background The Anterior Commissure (AC) is an important interhemispheric pathway that connects contralateral temporal lobes and orbitofrontal areas. The role of the AC is not yet well understood, although abnormalities in this white matter tract have been reported in patients diagnosed with chronic schizophrenia. However, it is not known whether changes in the AC are present at earlier stages of the disease. Methods Diffusion Magnetic Resonance Images (dMRI) were acquired from 17 First Episode Schizophrenia Patients (FESZ) and 20 healthy controls. The AC was reconstructed using a streamline tractography approach. DMRI measures, including Fractional Anisotropy (FA), Trace, Axial Diffusivity (AD) and Radial Diffusivity (RD) were computed in order to assess microstructural changes in the AC. Results FA was reduced, while trace and RD showed increases in FESZ. AD did not show differences between groups. Conclusion The observed changes in these dMRI measures, namely reductions in FA and increases in trace and RD, without changes in AD, likely point to myelin abnormalities of this white matter tract, and provide evidence of white matter pathology extant in the early phases of schizophrenia.

Abnormal interactions between context, memory structure, and mood in schizophrenia: an ERP investigation.

This study used event-related potentials to examine interactions between mood, sentence context, and semantic memory structure in schizophrenia. Seventeen male chronic schizophrenia and 15 healthy control subjects read sentence pairs after positive, negative, or neutral mood induction. Sentences ended with expected words (EW), within-category violations (WCV), or between-category violations (BCV). Across all moods, patients showed sensitivity to context indexed by reduced N400 to EW relative to both WCV and BCV. However, they did not show sensitivity to the semantic memory structure. N400 abnormalities were particularly enhanced under a negative mood in schizophrenia. These findings suggest abnormal interactions between mood, context processing, and connections within semantic memory in schizophrenia, and a specific role of negative mood in modulating semantic processes in this disease.