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Author Affiliations: Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont (Drs Sheng, Subburaju, and Benes and Mr Demers), and Program in Neuroscience (Dr Benes) and Department of Psychiatry (Drs Sheng, Subburaju, and Benes), Harvard Medical School, Boston, Massachusetts.
Context GAD67 regulation involves a network of genes implicated in schizophrenia and bipolar disorder. We have studied the copy number intensities of these genes in specific hippocampal subregions to clarify whether abnormalities of genomic integrity covary with gene expression in a circuitry-based manner.
Objective To compare the copy number intensities of genes associated with GAD67 regulation in the stratum oriens of sectors CA3/2 and CA1 in patients with schizophrenia, patients with bipolar disorder, and healthy controls.
Design Samples of sectors CA3/2 and CA1 were obtained from patients with schizophrenia, patients with bipolar disorder, and healthy controls. Genomic integrity was analyzed using microarrays, and the copy number intensities identified were correlated with the gene expression profile from a subset of these cases previously reported.
Setting Harvard Brain Tissue Resource Center at McLean Hospital, Belmont, Massachusetts.
Patients A total of 15 patients with schizophrenia, 15 patients with bipolar disorder, and 15 healthy controls.
Main Outcome Measures The copy number intensities for 28 target genes were individually examined using single-nucleotide polymorphism microarrays and correlated with homologous messenger RNA (mRNA) fold changes.
Results The copy number intensities examined using both microarrays and quantitative real-time polymerase chain reaction for the GAD67 gene were significantly decreased in sector CA3/2 of patients with schizophrenia and patients with bipolar disorder. Other genes associated with GAD67 regulation also showed changes in copy number intensities, and these changes were similar in magnitude and direction to those previously reported for mRNA fold changes in sector CA3/2 but not sector CA1. Moreover, the copy number intensities and mRNA fold changes were significantly correlated for both patients with schizophrenia (r = 0.649; P = .0003) and patients with bipolar disorder (r = 0.772; P = .0002) in sector CA3/2 but not in sector CA1.
Conclusion Insertions and deletions of genomic DNA in γ-aminobutyric acid cells at a key locus of the hippocampal circuit are reflected in transcriptional changes in GAD67 regulation that are circuitry-based and diagnosis-specific.
Copy number abnormalities have been found in genomic material from patients with many different brain disorders.1- 11 However, their significance for understanding the heritability and/or pathophysiology of such illnesses is not understood. The present study has attempted to explore this question by analyzing copy number intensities in laser-microdissected samples of the hippocampus from patients with schizophrenia and patients with bipolar disorder. In both disorders, dysfunction of γ-aminobutyric acid (GABA)–ergic cells has been inferred from the finding of decreased expression of the glutamic acid decarboxylase 67 kD isoform (GAD67), a key marker for GABAergic function.12- 15 There is a network of genes associated with the regulation of GAD67.16 This network appears to interact with other functional gene clusters, such as neurogenesis, cell cycle regulation, and the DNA damage response.17 Together, the latter 3 clusters play a critical role in maintaining genomic integrity, by detecting and repairing insertions, deletions, or perhaps even sequence rearrangements. If not repaired, such changes could theoretically result in the abnormal transcriptional regulation of genes associated with the regulation of GAD67.
In our study, samples have been obtained from the stratum oriens of sectors CA3/2 and CA1 (eFigure 1), a layer of the hippocampus in which GABA cells are the exclusive neuronal cell type. A preponderance of postmortem abnormalities in patients with schizophrenia and in patients with bipolar disorder have been found in sector CA3/2.18,19 These samples have been subjected to a microarray-based analysis of copy number intensities for 28 candidate genes involved in GAD67 regulation, neurogenesis, cell cycle regulation, and the DNA damage response. The results presented demonstrate that there are highly significant changes in the magnitude and direction of copy number intensities for specific target genes associated with GAD67 regulation in patients with schizophrenia and patients with bipolar disorder. Additionally, these copy number intensities show parallel variations in the expression of the respective messenger RNAs (mRNAs) for these target genes. To our knowledge, this is the first demonstration that disturbances in genomic integrity may contribute to GABA cell dysfunction in schizophrenia and bipolar disorder. Changes in copy number intensities vary in accordance with the disturbances in the expression of mRNAs associated with GAD67 regulation, but the patterns seen are fundamentally different for patients with schizophrenia and patients with bipolar disorder, suggesting that these changes occur in a circuitry-based and diagnosis-specific manner.
For the analyses of copy number intensities, postmortem samples of hippocampi from 15 healthy controls, 15 patients with schizophrenia, and 15 patients with bipolar disorder were obtained from the Harvard Brain Tissue Resource Center at McLean Hospital in Belmont, Massachusetts. The cases were group-matched for age, postmortem disorder, hemisphere, sex, and tissue pH (eTable). A subset of these cases (7 in each group) were described in an earlier microarray-based study,16 and the data from these cases were used to associate gene expression changes for the target genes with the respective copy number intensities obtained in the present study. Psychiatric diagnoses were established using a retrospective review of medical records and an extensive family questionnaire that includes information about medical history, psychiatric condition, and social demographics. The diagnosis of schizophrenia was made using the criteria of Feighner et al,20 whereas the diagnosis of bipolar disorder was made according to DSM-III-R criteria.
Sections (20 μm) were cut from a paraffin block using with a Jung RM2025 microtome and mounted on Leica frame slides. The sections were then deparaffinized and rehydrated in a graded series of xylene and ethanol. Nissl-stained sections were examined microscopically to ensure that each was cut in a transverse plane through the hippocampus and that all of the typical cytoarchitectonic features were present. A laser-microdissected apparatus was used to sample the stratum oriens of sectors CA2/3 and CA1. Because of the hypothesis-driven design of our study, we chose to contrast the findings in the stratum oriens of CA3/2 with those of sector CA1, which is also a layer in which GABA cells are the exclusive neuronal cell type.21 This layer in CA1 is, however, uniquely different from its homologue in CA3/2 in terms of its cytoarchitectonic detail, connectivity,22 functional integration,23 and gene expression patterns.17,21,24 For these reasons, we chose the stratum oriens of sector CA1 as a comparison site for changes in genomic integrity and mRNA expression in hippocampal GABA cells. There are approximately 3 times as many glial nuclei than neuronal nuclei in the stratum oriens of both sectors. Neurons are readily distinguishable from glia by their Nissl-positive cytoplasm and dendrites, their euchromatin content, and the size of their cell bodies, which are typically much larger. Glial nuclei show a predominance of heterochromatin, which is associated with gene silencing.25 These observations, together with our in situ hybridization studies of this layer, have suggested that very little gene expression is occurring in the glial cells at this locus.
A QIAamp DNA FFPE Tissue Kit (Qiagen) was used to extract genomic DNA from formalin-fixed, paraffin-embedded tissue. After extraction, the whole genome was amplified with a REPLI-g kit (Qiagen). DNA digestion, labeling, and hybridization were performed according to the manufacturer's instructions. In brief, genomic DNA (500 ng) is digested with Nsp I and Sty I restriction enzymes and ligated to adaptors that recognize the cohesive 4–base pair (bp) overhangs. All fragments resulting from restriction enzyme digestion were substrates for adaptor ligation. A generic primer that recognizes the adaptor sequence was used to amplify adaptor-ligated DNA fragments. Polymerase chain reaction (PCR) conditions were optimized to preferentially amplify fragments in the 200- to 1100-bp size range. The PCR amplification products for each restriction enzyme digest were combined and purified using polystyrene beads. The amplified DNA was then fragmented, labeled, and hybridized to Affymetrix Genome-Wide Human SNP Array 6.0. After the arrays were washed and stained, the copy number intensities were analyzed.
The scanned images of single-nucleotide polymorphism (SNP) arrays were analyzed using the Affymetrix Genotyping Console 2.0 and the Affymetrix Genotyping Tools software. Although copy number variants are commonly used as an end point in genetic studies of large populations or in searches for risk genes, copy number intensities provide greater sensitivity and more robust findings than the rounded-off ratios that result from analyses of copy number variants. The copy number intensities were determined according to the hybridization intensity data generated from each SNP probe using dChip software.26 To calculate mean copy number values for selected regions, the output of the SNP probe intensities were exported to Excel (Microsoft). Copy number intensity changes were measured by comparing the hybridization intensities of healthy controls with those of the patients with schizophrenia or bipolar disorder.
To validate copy number intensity changes identified by SNP arrays, we performed quantitative real-time PCR for GAD67 using genomic DNA (gDNA) from 6 controls, 6 patients with schizophrenia, and 6 patients with bipolar disorder. GAD67 gene probes was purchased from Applied Biosystems (the probes' identification numbers are Hs 01242242_cn and Hs 01602806_cn). Each 20-μL assay contained 10 ng of gDNA, 900nM each of forward and reverse primers for the reference gene (RNaseP) and for the target gene, 250nM each of the VIC dye (reference)–labeled and FAM dye (target)–labeled gene-specific probe in 1× TaqMan Gene Expression Master Mix. Individual samples were run in triplicate. Real-time data were collected by the OPTICON software. Quantitative real-time PCR data were analyzed using the relative quantification or ΔΔCt method27 based on DNA copy number ratio of a target gene vs reference gene in a given patient sample relative to matched healthy control sample. Relative quantity (RQ) is 2−ΔΔCt, and the copy number is 2 × RQ.
GraphPad Prism version 4.0 software was used for statistical analysis. The Fisher exact test and the 1-way analysis of variance with the Tukey post hoc test were used to evaluate differences in copy number for each target gene in the healthy control, schizophrenia, and bipolar disorder groups. Copy number intensities were also correlated with microarray-based gene expression data obtained in an earlier study16 in which an identical subset of cases was included.
Genomic copy numbers were determined by calculating the median signal intensities of the healthy controls, the patients with schizophrenia, and the patients with bipolar disorder with respect to normal reference DNAs. As shown in Figure 1, the GAD67- containing segment at the 2q24.3-2q31.1 chromosomal locus spanned approximately 14.2 megabases. The mean copy number intensity at the GAD67 -containing locus was 28% lower in the patients with schizophrenia than in the healthy controls. Similarly, lower numbers (15%) also occurred in the CA1 sector of the patients with schizophrenia at the same locus. Patients with bipolar disorder did not show differences in copy number intensities at the 2q24.3-2q31.1 locus in either sector (Figure 1).
Figure 1. Analysis of DNA copy number changes at the GAD67 -encompassing segment of chromosome 2q in sectors CA3/2 and CA1 in 15 healthy controls (Control), 15 patients with bipolar disorder (BD), and patients with schizophrenia (SZ). A, Heat map of copy number intensity (CNI) changes in the stratum oriens of sector CA3/2. Each column represents 1 sample and each row represents a specific gene, according to their physical order in the chromosome. Red indicates copy gain, and blue indicates copy loss. Copy numbers are displayed in the log2 ratio in a color code from −2 to 2. The GAD67 -encompassing segment is highlighted by the dotted line. The upper arrow points to the close-up view of CNIs at the GAD67 - encompassing segment at chromosome 2q (B). C, The CNIs of each patient are represented as squares (Control), circles (SZ), and triangles (BD), respectively. The horizontal bars indicate the mean. Mean values were compared using 1-way analysis of variance with the Tukey post hoc test. The SZ group had less copy numbers than the control group (mean [SD], 1.74 [0.27] vs 1.99 [0.05]; P < .01) but not the BD group. D, Heat map of CNIs in the stratum oriens of sector CA1. The lower arrow points to the close-up view of CNIs at the GAD67 -encompassing segment at chromosome 2q (E). F, The CNIs of each patient are represented as squares (Control), circles (SZ), and triangles (BD), respectively. The horizontal bars indicate the mean. Similar to the findings in sector CA3/2, the SZ group in sector CA1 had less copy numbers than the control group (mean [SD], 1.84 [0.15] vs 2.04 [0.09]; P < .05) but not the BD group.
The analysis of copy number intensities for 28 different target genes associated with the GAD67 regulatory network (n = 14), neurogenesis (n = 4), cell cycle regulation (n = 5), and the DNA damage response (n = 5) for sectors CA3/2 and CA1 are shown in Table 1 and Table 2, respectively. The overall sequence and its specific chromosomal locus are indicated for each gene in Tables 1 and 2. The genes that were chosen as targets for our study satisfied 2 criteria: (1) they must have shown significant differences in gene expression (fold changes),17,21,24 and (2) the genes must be associated directly or indirectly with the GAD67 regulatory network that was derived from a network association analysis.21 Some of the genes that are associated with this network (such as DLX1 and DLX2)28 and that play an important role in the development and function of GABA cells were not included because they did not show expression changes, and fell below the level of detection because of their very low abundance in the stratum oriens of sectors CA3/2 and CA1 of the human hippocampus.
Significant changes in copy number intensity in GAD67 regulatory genes were observed in 9 of 14 patients with schizophrenia (64%) and in 7 of 14 patients with bipolar disorder (50%) (Tables 1 and 2). The mean CNI for this gene was also decreased by 22% and 25%, respectively, in patients with schizophrenia and patients with bipolar disorder. In sector CA1, however, 50% of patients with schizophrenia showed significant CNI changes in GAD67 regulatory genes, whereas the patients with bipolar disorder showed no changes (Tables 1 and 2).
Heat maps of copy number intensities for specific chromosomal loci were plotted for several genes in the GAD67 regulatory network (Figure 1). As suggested by our earlier gene expression profile (GEP) study,21GAD67 expression was significantly decreased in sector CA3/2 of patients with schizophrenia and patients with bipolar disorder (Table 1). As shown in Figure 2A, the SNP arrays for GAD67, HDAC11, DAXX, PAX5, RUNX2, and CCND2 showed changes in copy number intensities in patients with schizophrenia and patients with bipolar disorder that are remarkably similar to those previously reported for a GEP study21 at this same locus of CA3/2. For example, GAD67 expression is reduced in both patients with schizophrenia and patients with bipolar disorder, HDAC11 and DAXX expression increased only in patients with schizophrenia, and both PAX5 and RUNX2 expression significantly decreased in patients with bipolar disorder. Two exceptions are PAX5, for which expression was only significantly lower in patients with bipolar disorder, and CCND2, for which transcripts were increased in patients with schizophrenia at this locus (Figure 2A). In the CA1 sector, copy number intensities for GAD67 are significantly decreased only for patients with schizophrenia, not for patients with bipolar disorder (Figure 2B), but this pattern is virtually identical to that seen for the GEP findings previously reported for the same cases.16 Copy number intensities for HDAC11 increased by 78% (Table 2), but the copy number intensities for the other genes do not show significant changes.
Figure 2. Heat Maps of DNA copy number changes for GAD67 regulatory genes in the stratum oriens of sector CA3/2 (A) and sector CA1 (B). The copy number intensities of 6 critical GAD67 regulatory genes are compared by performing the Fisher exact test between 15 healthy controls (Controls), 15 patients with schizophrenia (SZ), and 15 patients with bipolar disorder (BD). In the heat maps, red represents copy gain, and blue represents copy loss, in units of log2. The blue curves in the middle graphs indicate the degree of gain (right) or loss (left) of each gene. The red vertical line indicates a copy number of 2. Also shown are the probabilities that changes are significant; the arrows indicate whether copy number intensities are increased (red arrows) or decreased (blue arrows).
Copy number intensities for GAD65 (GAD2), GRIK1, RUNX2, PAX5, and SMAD4 were also decreased in the CA3/2 sector of patients with schizophrenia, whereas GRIK2, GRIK3, HDAC11, and DAXX all had higher copy number intensities. As shown in Table 3, the copy number intensity changes for these target genes in the CA3/2 sector of patients with schizophrenia were similar in direction to those reported with a GEP.16,21 In the CA3/2 sector of patients with bipolar disorder (Table 1), the copy numbers of GRIK1, GRIK2, GAD65, LEF1, DAXX, RUNX2, and PAX5 were also decreased, and most showed a direction of change consistent with the earlier GEP data for these same genes21 (Table 3).
The 4 genes in the neurogenesis cluster were chosen because they had shown significant changes in their GEPs, and our modeling suggested that they are probably important to the regulation of the cell cycle.19FGF3,29FGF9,30,31VEGF,32 and NRG133 are key players in the growth and differentiation of a wide variety of cells and tissues, including the hippocampus,34 and are believed to increase the risk for schizophrenia.35,36 In CA3/2 sector of patients with bipolar disorder, these genes showed significant decreases in copy number intensity, and these changes occurred in the same direction as those observed when a GEP was undertaken (Table 3). In the patients with schizophrenia, VEGF showed increases of copy number intensity in the CA3/2 sector, and this direction of change is similar to that seen in the GEPs for the same genes. NRG1 showed significant reductions in copy number intensity; however, the transcripts for this gene were significantly changed in the opposite direction for the GEP data (Table 3).
Copy number intensities for cell cycle regulation and the DNA damage response showed significant changes in the CA3/2 sector of patients with schizophrenia and patients with bipolar disorder (Table 1). The copy number intensity of E2F3 in patients with schizophrenia was significantly reduced, and this change was in the same direction as that observed for transcripts in the GEP study.21 The patients with bipolar disorder showed only 1 gene (MBD4) with significant changes in copy number intensity and gene expression, both of which were increased; however, this similar change was seen for this gene in sectors CA3/2 and CA1 of both groups of patients. Overall, the changes observed for copy number intensities in the cell cycle and DNA damage response categories showed much less consistency when compared with the GEP data for these same genes.
To validate the copy number intensity changes identified by SNP array, we performed quantitative PCR analysis for the candidate gene GAD67 using gDNA from microdissected tissues (obtained from 6 patients with schizophrenia, 6 patients with bipolar disorder, and 6 healthy controls). In sector CA3/2, the copy number for the GAD67 gene also decreased by 34% and 37%, respectively, in patients with schizophrenia and patients with bipolar disorder, which is in complete agreement with the SNP data. In sector CA1, the copy number for the GAD67 gene decreased by 59% in patients with schizophrenia, although there was only a 10% decrease in patients with bipolar disorder (eFigure 2). These results have demonstrated the overall validity of the copy number status determined by SNP microarrays, and they also establish that GAD67 is the gene with one of the most frequent genetic alterations in schizophrenia and bipolar disorder.
Do DNA copy number intensities reflect gene expression patterns that we have identified in patients with schizophrenia and patients with bipolar disorder within the loci of interest? In sector CA3/2 of both the schizophrenia and bipolar disorder groups, the majority of target genes showed abnormally high or low levels of mRNA expression, whereas in sector CA1, both groups showed a paucity of significant expression changes (Table 3). When decreases or increases of copy numbers are observed, the changes seen could be related to either deletions or duplications, respectively, of chromatin material. The genes showing significant correlations between copy number intensities and gene expression for the GAD67 regulatory genes (Figure 3) were generally quite different for the schizophrenia and bipolar disorder groups. As shown in Table 3, the patients with bipolar disorder showed no expression changes for GRIK3, DAXX, HDAC11, TGFB2, and TGFBR1, whereas all of the other genes showed significant expression changes. In patients with schizophrenia, RUNX2, LEF1, PAX5, and SMAD4 did not show expression changes. Overall, there was a diagnostic selectivity for the target genes associated with decreased GAD67 expression in schizophrenia vs bipolar disorder.21
Figure 3. Association of fold changes as a measure of gene expression and DNA copy number intensity (CNI) changes in the stratum oriens of sectors CA3/2 and CA1.The x-axis shows CNI changes, and the y-axis displays fold changes, from microarray data. Individual data points are connected with a line using linear regression analysis performed with GraphPad Prism version 4.0. In the stratum oriens of sector CA3/2, significant associations between CNI changes and fold changes are evident in patients with schizophrenia (SZ), patients with bipolar disorder (BD), and combined patients (SZ+BD), respectively. There are no significant associations between CNI changes and fold changes in any patient groups in sector CA1.
When the GEP data and the copy number intensity data (Table 3) were analyzed using linear regression analyses (Figure 3), a robust correlation was observed when both groups of patients were combined (r = 0.692; P = .0001) or when the patients with schizophrenia (r = 0.649; P = .0003) and the patients with bipolar disorder (r = 0.772; P = .0002) were separately compared with the healthy controls (Figure 3). For a majority of the target genes, the changes in copy number intensities and the fold changes tended to occur in the same direction, although the magnitudes of the respective changes were, in some instances, dramatically different. For example, mRNA expression for FGF9 was decreased 11-fold in patients with bipolar disorder, whereas the loss of copy number intensity for this gene was only 20%. Disparities of this type contributed to the variance in the data and resulted in a reduction in the r correlation coefficient, even when the correlations were statistically significant.
As shown in Table 4 and Figure 4, when the target genes were separated according to those directly related to the GAD67 regulatory network and those not related to it (ie, genes associated with growth factors, cell cycle, and DNA repair), much higher correlations between copy number intensity changes and mRNA levels were observed in the former (r = 0.712; P = .0001) than in the latter (r = 0.492; P = .008) of sector CA3/2 but not sector CA1 (r = 0.067 and r = 0.225, respectively). These data suggest that the expression of genes in the GAD67 network in the CA3/2 sector is tightly linked to the status of genomic integrity at this locus.
Figure 4. Association of fold changes as a measure of gene expression and DNA copy number intensity (CNI) changes for GAD67 and non- GAD67 regulatory genes in the stratum oriens of sectors CA3/2 and CA1. The x-axis shows CNI changes, and the y-axis displays fold changes, from microarray data. Individual data points are connected with a line using linear regression analysis performed with GraphPad Prism version 4.0. In sector CA3/2, both clusters showed a significant association between CNI changes and fold changes, but the GAD67 regulatory network has a higher correlation efficiency than does the non- GAD67 regulatory network. However, there is no significant association between CNI changes and fold changes in any gene cluster in sector CA1.
The linear regression analyses of target genes in sector CA1 did not reveal any correlation between gene expression and copy number intensity changes. There are many genes showing notable expression changes but no copy number intensity changes, suggesting that a dissociation between copy number intensities and gene expression changes may occur in sector CA1. As with sector CA3/2, however, a subset of genes in sector CA1 not related to GAD67 regulation did not show correlations with copy number intensities (Figure 4). These results demonstrate a striking subregional difference in the association of copy number intensities with gene expression changes.
There is increasing evidence supporting the involvement of copy number variants in the etiology of schizophrenia,9,37- 39 although it is not clear what mechanisms may be related to these changes. Most of these reports have employed genome-wide screening for copy number variants, and only a few have concentrated on specific target genes.40 Although there have been preliminary attempts at linking copy number variants with expression data for specific genes in cancer research,41,42 to date, no study of the brain has attempted to associate the occurrence of copy number intensities for specific target genes with the expression of their respective mRNAs. The results described herein suggest that copy number intensity changes for specific target genes and their associated mRNAs vary not only in a diagnosis-specific way but also in a circuitry-based manner.
GAD67 plays an important role in the activity of GABA neurons and their dysfunction in schizophrenia. Although one association study37 concluded that there was a link between the GAD67 gene and childhood-onset schizophrenia, another study,43 using a Danish cohort, provides evidence that, in this sample, there is no link to schizophrenia but, possibly, a link to bipolar disorder. Another gene, neuregulin 1 (NRG1), may be functionally involved in the regulation of GAD67 activity.44 Interestingly, NRG1 also showed significant changes in both copy number intensity and gene expression, in patients with schizophrenia and patients with bipolar disorder. This gene appears to have a weak association with schizophrenia when haplotype-based P values were included in the analyses, and there was no evidence of between-study heterogeneity.45 These studies underscore the difficulties inherently present when attempting to relate copy number intensities derived from blood samples in population studies to copy number intensities obtained from brain tissue in studies of the molecular regulation of neural circuitry. Generally speaking, the genes included in the present study cannot be thought of as genetically transmitted risk factors, even when both copy number intensities and mRNA expression show robust changes, because the study design is fundamentally different from that used in association studies. The information gathered in our study is most useful in identifying the ways in which the molecular regulation of complex circuits may be abnormal, particularly when combined with parallel rodent modeling.46
The target genes examined in our study are involved in the functional maintenance of hippocampal GABA cells that show abnormal expression of GAD67 in schizophrenia and bipolar disorder.17,21 They include networks that regulate GAD67 expression, neurogenesis, the cell cycle, and the DNA damage response. In the present study, most of these genes showed significant increases or decreases of copy number intensities at their respective chromosomal loci. The largely robust nature of these copy number intensities and their correlation with the respective expression changes suggest that they may be linked to the regulation of functional differentiation and genomic integrity in hippocampal GABA cells. Widespread deletions along the GAD67 -encompassing segment of chromosome 2q (ie, 2q24.3-2q31.1), where GAD67 is encoded,47 have been identified in patients with schizophrenia but not in patients with bipolar disorder. The fact that GAD67 expression is significantly reduced in sector CA3/2 of both disorders suggests that these broad-based deletions on the 2q chromosome may be only one of the many mechanisms involved in the decrease of GAD67 expression.
The results from quantitative PCR showed a decreased copy number intensity of GAD67 in patients with schizophrenia or bipolar disorder, which was consistent with the results from SNP arrays. These findings demonstrate that a decreased copy number intensity of GAD67 in the hippocampus could be a prevalent genetic change in the majority of patients with schizophrenia or bipolar disorder. More importantly, there was a significant correlation between DNA loss and RNA underexpression of the GAD67 gene, suggesting that the transcript level of this gene may be regulated by its DNA copy number.
In sector CA3/2, the direction of change for copy number intensities showed a high degree of correspondence with the expression changes for the respective target genes. For example, in patients with schizophrenia, HDAC11 and DAXX both showed increased copy number intensities and expression changes. In patients with bipolar disorder, however, these parameters for PAX5 and RUNX2 were both decreased. Indeed, the regression analyses provide compelling evidence to support the idea that these 2 variables are interrelated. The relationship between copy number intensities and gene expression changes was most striking for the genes directly involved in GAD67 regulation compared with the genes more indirectly involved in neurogenesis, cell cycle regulation, and the DNA damage response.
The fact that the nature of the changes in copy number intensity and gene expression for the target genes was quite different for the 2 disorders may reflect the fundamentally different nature of the molecular abnormalities found in the GABA cells of sector CA3/2 for each disorder. It seems unlikely that psychotropic medications are responsible for these differences because the 2 groups showed similar drug exposure histories (eTable). It seems more likely that the unique changes in copy number intensity and gene expression in sector CA3/2 might be related to differences in "risk genes" for the 2 respective disorders.
Unlike the copy number intensities in sector CA3/2, those in sector CA1 of patients with schizophrenia or bipolar disorder did not show any correlation with gene expression changes. Only 20% to 30% of the target genes associated with cell cycle regulation and DNA repair in sector CA1 of patients with schizophrenia or bipolar disorder showed significant changes in expression (Table 3).
This obvious difference between the findings in sector CA3/2 and the findings in sector CA1 is consistent with the idea that the local tissue environment surrounding a cell may play a critical role in influencing its profile of transcriptional activity. In the hippocampus of patients with schizophrenia or bipolar disorder, the concentration of significant findings in the stratum oriens of sector CA3/2, but not sector CA1, can potentially be explained by differences in the molecular activity within neurons that comprise the microcircuitry at these 2 respective sites.24 For example, the stratum oriens of sector CA3/2, but not sector CA1, receives a rich glutamatergic projection from the basolateral amygdala, and these fibers are believed to play an important role in the integration of emotion and cognition, particularly in relation to stressful events.48 Other systems that are unique to this locus include GABAergic fibers that originate in the septal nuclei49 and contribute to the regulation of oscillatory rhythms.50
The stratum oriens is unique because the exclusive neuronal cell type in this layer is the GABAergic interneuron. These latter cells receive a robust and specific projection from the basolateral amygdala,51 which exerts an important influence on membrane properties and the action potential firing rate in fast-spiking inhibitory cells.46 Based on the present findings, basolateral amygdala projections to the stratum oriens of the CA3/2 locus may contribute to the functional and genomic integrity of GABAergic interneurons at this locus, presumably through synaptic or modulatory mechanisms. The GAD67 regulatory network includes 3 kainate-sensitive glutamate receptor (KAR) genes (GRIK1, GRIK2, and GRIK3) that encode the GluR5, 6, and 7 subunits, respectively, for this receptor. Abnormal expression and activity of KAR in the hippocampus are believed to play an important role in schizophrenia.52,53 Because the GAD67 regulatory network is linked to the canonical clusters associated with the cell cycle and the DNA damage response, the synaptically mediated influence of electrical activity generated within the trisynaptic pathway could contribute, at least theoretically, to parallel changes in copy number intensity and gene expression for the target genes associated with the regulation of GAD67 in GABA cells at this locus. These changes could include either deletions or duplications of genomic sequences in these target genes.
Most of our knowledge regarding the relationship between the sensing and repair of DNA has come from proliferating cell populations, like those active during embryogenesis.54 Little or nothing is known about the regulation of the cell cycle or the DNA damage response in postmitotic cells in the adult brain. Many believe that terminal differentiation involves an extensive reprogramming of the genome, so that genes that are relevant to interneuron function, like those associated with GAD67 regulation, are transcribed, while other genes are permanently silenced.55
The mechanisms associated with the repair of damaged DNA include pivotal target genes, such as CCND2, E2F3, MBD4, and HDAC, that may help to link the differentiation of mature GABA cells to their ability (or inability) to repair damaged DNA and preserve their genomic and functional integrity. To our knowledge, the present study provides the first evidence that deletions and/or duplications are present in terminally differentiated neurons in the adult hippocampus and that such changes may also contribute to the aberrant expression of key genes involved in the normal and abnormal functioning of hippocampal GABA cells.
In summary, the analyses reported herein demonstrate that there is considerable overlap between copy number intensities and mRNA expression for target genes associated with GAD67 regulation at a key locus within the hippocampi of patients with schizophrenia or bipolar disorder. Elucidating cell type–specific and locus-specific associations of genes comprising the GAD67 regulatory network in hippocampal GABA cells with those associated with the cell cycle and DNA repair could help to explain the presence of unique cellular endophenotypes in each of these 2 disorders.56 The genomic integrity and differentiation of tissue-specific functions in postmitotic GABA cells, and their potential relationship with age-related changes in health and disease,54 are issues that will require further study in many different forms of neuropsychiatric disease.
Correspondence: Francine M. Benes, MD, PhD, McLean Hospital, 115 Mill St, Belmont, MA 02478 (email@example.com).
Submitted for Publication: July 15, 2011; final revision received November 3, 2011; accepted November 15, 2011.
Published Online: February 6, 2012. doi:10.1001/archgenpsychiatry.2011.1882
Financial Disclosure: None reported.
Funding/Support: This study was supported by National Institutes of Health grants MH077175, MH42261-08, and MH/NS 077550 and the William P. and Henry B. Test Endowment (Harvard University).
Additional Contributions: We thank Cheng Li, PhD, Associate Professor of Biostatistics and Computational Biology, Harvard Medical School, for his extraordinary generosity and patience in helping us to organize our SNP database for copy number intensities and their analyses using the most appropriate statistics. We also thank Deborah L. Levy, PhD, for her expertise in genetics studies of blood samples from live subjects and her insights into how copy number variants and risk genes may interact in psychiatric disorders.
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Sheng G, Demers M, Subburaju S, Benes FM. Differences in the circuitry-based
association of copy numbers and gene expression between the hippocampi of
patients with schizophrenia and the hippocampi of patients with bipolar disorder.Arch Gen Psychiatry. Published online February 6, 2012.
eTable 1. Demographics of subjects.
eFigure 1. Laser microdissection.
eFigure 2. Relative copy number of the GAD67 gene in genomic DNA from SZ,
BD, and healthy controls.
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text:
Web Camp Belgium: Interview with Scott Hanselman
- Posted: Feb 01, 2011 at 7:41AM
Right click "Save as…"
On January 24th Scott Hanselman joined us in Brussels for the first Web Camp Belgium.
In this short interview Scott talks about his sessions and the Microsoft 'January Web Release' which is the umbrella name for new released products ASP.NET MVC 3, NuGet, IIS Express, SQL Compact Edition and WebMatrix.
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subset: commoncrawl


text:
Source: Ford
quote: i really don't understand manufactures' reluctancy to at least offer a diesel option in these to test the waters of demand.
quote: you can't compare apples to oranges here. no matter what you do to a petrol engine (even implementing diesel technologies such as direct injection and turbo charging) it will never beat a diesel.


text:
Top Definition
a close buddy, compadre, smoking and/drinking buddy. a term of endearment between men to reaffirm heterosexuality
hey broham, throw me a cold one.
von Krisana 24. Februar 2004
Trending Now
Can you define these popular missing words?
Friend. Compatriot. Brother. Bastardized form of BROTHER. Short for BROHAMULUS.
"Sup, brohamulus, where the chickens is at?"
von ready2ruck 10. März 2003
Broham is actually pronounced brohym, its an irish slang turm for brother or friend, made popular by the irish mob.
Hey, whats up broham wanna knock-over a 7/11?
von patrick "big dirty" shane 28. September 2007
A title for a male figure, whose familiarity is that of a brother.
What's up bro-ham?
von KuriKuri 9. September 2008
A "Broham" is the ebonic pronunciation of Brougham. A Broham is consistently attributed to the large rear wheel drive Cadillac Fleetwoods of the 1970s and 80s. The word Broham is commonly used within the African American community regarding people who drive these Caddy "Wips" , "Ghetto Cruisers", or "Hoopties". Most Urban youths across the country dream of one day owning a Broham.
von Fleetwood Broham 28. Februar 2011
A secret handshake among bros, usually a high five or something similar to daps. Bro ham is given when a certain type of "brohood" is expressed, or when some type of "brohood" is experienced or seen with the Bro.
Travis- "Dude yesterday, I totally showed up the fertility god in a game of connect four."
Perrin- "Dude, give me some BRO HAM!"
Perrin- "Dude, give me some BRO HAM!"
von Perrin Hawver 2. Februar 2008
Jewish brother
He is my broham
von Coesan 6. Juli 2011


text:
From SOSwiki
Laboratory Methods in Synthetic Biology
- Offered as BIOE 425C, CSE 488C, EE 425C
- Winter 2012
- Instructor: Eric Klavins
- Teaching Assistant: Robert Egbert
- Weekly meeting time: Mondays 3:30-4:20 (except for the first two weeks -- schedule TBA)
- Lab: EEB 031
Description: In this course we design and build synthetic gene regulatory circuits for bacteria that can perform simple functions. This quarter we will focus on two applications: diagnostics and biofuels. Students will learn gene regulatory network design, specification, gene synthesis, cloning, experiment design, microscopy, cytometry, and other fundamental methods in synthetic biology. The course is organized around projects, with small teams, weekly meetings to present progress, and open scheduling for lab work. Pre-requisite: Introduction to Synthetic Biology or a similar course, or permission from the instructor.


text:
The BCS standings announcement is always a fun time every Sunday evening, and we're happy to take you through the fifth BCS standings after Week 12 of college football.
Good evening everybody, Rich Thomaselli, Deputy College Football Editor for Bleacher Report here, and I'm happy to guide you through the announcement on ESPN in about 45 minutes (8:15 EST).
We'll see if anything has changed from last week, even though all four unbeaten teams stayed that way, and whether or not any bowl projections have changed.


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QUOTE (wingsdiehard13 @ June 28, 2009 - 03:23PM) <{POST_SNAPBACK}>
Okay... They aquired his rights yesterday. Have they signed him?
Nope and I would bet they won't sign him. Wouldn't it mean dumping one of their other big names? Like say Phaneuf??
I like Jay but I don't see them dumping Phaneuf.


text:
Quality Education in the Benedictine Tradition
May 3, 2013
Eight Saint Vincent College seniors who have been accepted to law schools were recognized at the third annual Saint Vincent Law Society Send-Off Luncheon at the college on May 1. Seated, left to right, are Thomas Cocchi of Pittsburgh, a finance major who will attend Duquesne University Law School; Nick Corletti of Pittsburgh, an accounting major, Duquesne University Law School; Alexandria Correa of Glen Rock, N.J., a sociology major, City University of New York Law School; Bridget Fitzpatrick of Pittsburgh, a political science major, Villanova University Law School; and Anthony Weisenburger of Pemberville, Ohio, an economics major, University of Pittsburgh Law School. College officials and alumni leaders of the Law Society, standing from left, are Dr. Bruce Antkowiak, professor of law and chair of the Criminology, Law and Society program; Dennis Gilbert, associate director of the career center; Dr. Gabriel Pellathy, professor emeritus of political science; Attorney Ned J. Nakles, Jr., SVC'79, of Latrobe; Attorney Gino F. Peluso, SVC'77, vice president of the Law Society; and Attorney Francis E. Pipak, Jr., SVC'71, president of the Law Society and a partner with Pietragrallo Gordon Alfano Bosick and Raspanti, Pittsburgh. Missing from photo are Paige Holderbaum of Latrobe, an English major, Duquesne University School of Law; Alex Walsh of Overland Park, Kansas, a history major, University of New Hampshire School of Law; and Del Nolfi of Trafford, an accounting major, University of Pittsburgh Law School.
Follow us on Twitter: @MySaintVincent Like us on Facebook:


text:
Serves 4 |
Prep Time 10 minutes |
Cook Time 25 minutes
1 tsp Eden Toasted Sesame Oil
2 tsp Eden Extra Virgin Olive Oil
1 cup diced red onion
1 cup sliced mushrooms
1 tsp Eden Shoyu Soy Sauce, optional
1 cup Eden Hulled Buckwheat, rinsed and drained
2 cups boiling water
1 cup chopped green cabbage
1/2 cup thickly sliced carrotsor rutabaga
1/2 cup Eden Sauerkraut, or to taste
2 Tbsp minced chives, for garnishscallions or parsley
Heat oils in a medium saucepan and sauté onion for 2 to 3 minutes. Add mushrooms and shoyu and sauté 2 to 3 minutes. Add buckwheat and sauté 3 minutes. Add all remaining ingredients except parsley. Cover and simmer on low for 20 minutes. Place in a serving dish and garnish with chives. Add more sauerkraut if desired.
American, Condiments, European, Good/High Fiber, Good/High Protein, Japanese Food, Macrobiotic, Main Course, No Sweetener Added, Oils, Sauerkraut, Vegan, Whole Grain, Whole Grain


text:
If the squirrels
were to devour your eyes
Modigliani would
bring you to life
in one of his paintings.
For the next poem in this sequence, click here.
Poetry From the October 2005 issue: Jaguar Tongues
Humberto Ak abalHumberto Ak abal
Humberto Ak abal writes in Kichè (Maya) at his home far from his birthplace (1952) in Momostenango, Totonicapán, Guatemala. He is one of the most widely translated poets writing in an indigenous language in the Americas, his work having appeared in the U.S., as well as Austria, France, Switzerland, and Germany and in a large hardcover edition sponsored by the United Nations. He reads easily in a very deep voice that somehow reminds one of the sound a great tree would make, if trees spoke Kiché. Some of his work has been translated into English by Robert Bly, other poems by Dennis Tedlock. He has received the Blaise Cendras Prize from Switzerland, as well as many prizes and honorary degrees in Latin America.
Translated from SpanishSpanish by Earl ShorrisEarl Shorris and by Sylvia Sasson ShorrisSylvia Sasson Shorris
Earl Shorris was a prominent social critic and author. His works include Ofay; The Boots of the Virgin; A Novel of Pancho Villa; The Death of the Great Spirit; The Oppressed Middle: Scenes From Corporate Life; Latinos: A Biography of the People; and New American Blues: A Journey Through Poverty to Democracy among others. He was the coeditor of In the Language of Kings: An Anthology of Mesoamerican Literature, Pre-Columbian to the Present; The Life and Times of Mexico; and While Someone Else Is Eating: Poets and Novelists on Reaganism. He was a contributing editor to Harper's, and his essays and articles appeared in the Nation, the Atlantic Monthly, the New York Times, the Los Angeles Times, American Educator, the Antioch Review, and many more publications. He founded and chaired the advisory board of The Clemente Course in the Humanities; and cofounded—with Howard Meredith and members of the Kiowa, Cherokee, Chickashaw, Maya, Nahua, Lakota, CYup'ik, and other tribes and nations—the Pan-American Indian Humanities Center at the University of Science and Arts of Oklahoma. He died in May of 2012.
Sylvia Sasson Shorris is the author of Talking Pictures: With the People Who Made Them and co-editor of While Someone Else Is Eating: Poets and Novelists on Reaganism and In the Language of Kings: An Anthology of Mesoamerican Literature Pre-Columbian to the Present. She has published articles in The Nation, Chicago Tribune, Fork Roads, and Review (a publication of the Center for Inter-American Relations), and has been a translator in Mexico for Luis Montes Film Distribution, and in New York for 20th Century-Fox Film Corporation.
This copy is for your personal, noncommercial use only. You can order presentation-ready copies for distribution by contacting us at firstname.lastname@example.com.


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After he shot to fame at age 17 after starring as squeaky-clean basketball star Troy Bolton on Disney Channel's High School Musical franchise, it appeared the heartthrob had avoided the pitfalls of youthful stardom.
But after it was revealed Monday that Efron, now 25, had checked into rehab earlier this year, sources tell PEOPLE the seemingly straight-arrow actor – who has never run into trouble with the law and has a sterling reputation as a professional on set – partied much harder than his public image let on.
"He surrounds himself with a group that enjoys partying," an Efron insider tells PEOPLE. "He got caught up in the partying lifestyle the past few years."
Says another source who has socialized with Efron: "Like most people at clubs, he liked to drink and have a good time. He definitely liked to party."
Trying to Avoid the Wrong PathJust a year ago, the California native – who grew up in a non-Hollywood family (his father is an electrical engineer and his mother a secretary) – told PEOPLE he avoided going down the wrong path by "appreciat[ing] the work I've done."
"The stakes are very high," he said at the time. "I care too much about those around me and everything I've worked for to just go out and blow it. It's just a personal integrity."
While acknowledging he does "like to have fun," the actor pointed out that "some people can handle it and some people can't."
Though he was struggling in private, several nightlife sources say he didn't appear out of control while clubbing and in fact tried to keep a low profile.
"He would make sure that his friends surrounded him and was clearly concerned with his privacy … almost to a paranoid level," says one insider who has seen him frequently at L.A. hotspot Bootsy Bellows drinking vodka soda.
After-Hours PartiesEfron also often turned up at after-hours parties at friends' homes, sources say.
Enablers are often crippling for those with addiction issues, says William Oswald, director of Summit Malibu Treatment Center, who has not treated Efron.
"Codependents who are living off of [a star] and keeping the party going can really hinder things," says Oswald, whose treatment center provides "hand-carved treatment in a non-institutionalized" environment. "There are lots of predators who would feed off of someone like him because they're getting the party with it."
What a recovering addict needs is people who will "stand up and say, 'This is not a good idea. You're going down the wrong path,'" he adds. "[Someone like Zac] is in a pretty vicious business. … Friends make you feel better and drugs and alcohol make you feel better."
Additional reporting by JENNIFER GARCIA, RAHA LEWIS and PATRICK GOMEZ


text:
Completing Claims Forms, Critical Stage of Dean Foods Settlement Claims Process
Completing Claims Forms, Critical Stage of Dean Foods Settlement Claims Process
Attached you will find a news release containing the following: 4 pages, easy read, large print, pdf format. If you cannot open attachment, please contact me and I will resend in another email format.
A.) A Farmer's Guide to Determining Pounds Claimed in Dean Foods/SMA Settlement, [may be used as a take-out with proper referencing to AgriVoice, in any other media print publications or 'shared email news' form]
B.) A FAQ's Section based on repeated producer phone calls and questions in recent days and weeks
C.) News release is designed to used in its entirety or as segments per an editor's space; proper referencing should be noted
D.) Producers receiving this are asked to read carefully - this is a process of details, that count. Simple might be the wish, but simple is not the answer. The most common issues and questions are summarized and addressed that have come to my attention per many producer phone calls in recent days as farmer/claimants complete these claims forms for mailing in the next week.
E.) If a recipient has further questions, feel free to contact me.
Any updates will follow accordingly.
There will be a Motions Hearing tomorrow prior to July 10th trial date - Oral Arguments by the Attorneys for Plaintiffs and Defendants will be heard on why DFA rank-and-file members should be recertified back into litigation class. DFA Board Members have previously been excluded. Reports will follow in next couple of days.
Julie Walker


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AMT Cast Back On Stage for Another Season
March 8, 2008 - By WAYNE SHEETS, Contributing Business Writer
The American Mountain Theater kicked off its 2008 season a week ago. After last year's performances, I wondered how the program could be improved....
No comments posted for this article.
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text:
Governor, legislature approve major I-4 improvement project
UPDATED 6:40 PM EST Feb 01, 2013
Gov. Rick Scott and the Florida legislature have given the go-ahead to get the money for a $2.1 billion improvement project for Interstate 4.
The project would cover 21 miles from west of Kirkman Road to east of State Road 434.
The project would include 56 new bridges and could add four managed lanes or tolled express lanes.
It would take five to six years to complete, according to the governor's office.
The Florida Department of Transportation is holding a forum in Orlando on March 4 to get private sector feedback on the project.
FDOT hopes to start the project in 2015.
Copyright 2013 by WESH.com All rights reserved. This material may not be published, broadcast, rewritten or redistributed.


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Top Definition
Someone who cant see the lighter side of life. Glass half empty kind of person who's whole goal in life is to suck the morale out of every person they meet. Usually the one finding a problem when there isnt one....
Shit dude, stop complaining, you're a flippin morale vortex you are.
Por mikeythatsme 13 de abril de 2010
Trending Now
Can you define these popular missing words?


text:
It's a bad idea for me to read good books. I love to read. In fact, I would rather read than do just about anything; therefore, I have to ration my input so I can be a productive member of society.
Unfortunately, for me, reading is the antithesis of writing. Reading the work of a talented author inspires me, however, it also consumes me and steals time that I might otherwise spend writing. You may have deduced by now that I have been reading a lot this week, which is why that is all I have to talk about.
My recent reading binge began last week when I went to visit a friend. I always give myself permission to read while flying since it passes the time in airports and on planes. There is the added bonus that, if my nose is buried in a book, I don't have to feel guilty about not talking to the person next to me. I also feel very self-righteous when I read while traveling because I think it makes me appear smarter than those who are watching TV or playing games on their phone. They maybe be watching the History Channel or beating the computer at chess while I am knee-deep in chick-lit, but hey, I'm holding a book – so there.
Regrettably, I didn't finish my book on the plane home. This is a problem because reading and parenting aren't compatible in my world.
I have a hard time tearing myself away from a compelling story in order to do basic mom things.
Like cook dinner.
Or check homework.
My kids quite enjoy my tunnel vision while I'm reading a good book and often take advantage of how agreeable I am when my brain is otherwise engaged.
"Can I have ice cream?"
"Yes. Get it yourself, though."
"Can I go play next door?"
"Sure, whatever."
"I need new dress-code pants, can you get me some?"
"Maybe tomorrow, OK?"
Since I got home at midnight from my trip, I was able to make a clean break from my book for a while and was busy enough that I didn't pick it up again until last weekend. And then I stayed up until 11:30 p.m. one night to finish it.
But that's not the worst part.
I did a crazy thing and got another book, "Gone Girl" by Gillian Flynn. It's what we're reading this month for the Greeley Moms book club. It's a page-turner, to say the least. Straight-up totally-ignore-your-family good.
I'm to the point now that I actually hope to finish the book just so my life can get back to its regularly scheduled programming.
I may complete it today.
I have to, really - before I agree to get another dog.
Besides, I need time to go shopping for pants.
Jaymi Anderson is married with two daughters. Read her Fridays on Greeley Moms.
My recent reading binge began last week when I went to visit a friend.


text:
Name: Zach Helsel
School: Claysburg-Kimmel
Age: 18
Article Photos
Grade: Senior
Sport: Football
Athlete of the week achievement: Helsel rushed for 257 yards on 25 carries, scored four touchdowns and added a two-point conversion in the Bulldogs' 48-12 season-ending rout of Southern Huntingdon.
Season update: Helsel finished the season with 1,531 rushing yards for Claysburg, which finished the season 4-6.
Coach Joe Kitt's quote: "He's meant a lot to our team. All year, we looked to him to make the big plays. He's just a tough kid, runs very hard. His performance this weekend was just outstanding. He's a tremendous kid and I can't say enough good things about him."
Favorite teacher: Mr. Woodring
Favorite subject: Gym
Favorite movie: "That's My Boy"
Favorite food: Eggs
Favorite song: "Remember the Name" by Fort Minor
Outside interests: Snowboarding and riding dirt bikes
Favorite professional team: Philadelphia Eagles
Favorite college team: Penn State
Pro athlete most admired: Paul Posluszny
Best athlete I ever played with: Claysburg-Kimmel graduate Tyler Ickes
Best athlete I ever competed against: Glendale graduate Tyler Jenny
Most influential person on my athletic career: My parents
Proudest athletic achievement: Getting my 1,500 yards and 25 touchdowns
How I got my start in football: Youth football
Future goal: To go to college


text:
Great day for racing - almost too nice for 'cross. They did a nice job with the course. The had a short spot going across a sidehill in dirt that caused more folks problems than I would have imagined. And then threw in a big dirt bump that was kind of fun. The atmosphere was really good, they had a ton of tents up and cards for the poker game. One thing that we might want to add is the paper and markers to make posters to cheer with! I also like that they raised a bit of cash for charity.
Ladd and I did this one! More on that epic battle soon. For now, enjoy and comment.
Ok, I admit this is part report and part shameless plug to get people to do this with me next year.
Okay, this is gonna be a cool toy!
Let me know what you think.
I'm just going to start off with this challenge - let's get a group and sign up for 2014! (Yeah, it was really fun and we need to do this again soon.) Dan and I are working on a scheme that will make you all want to join, there will be more details later!
Big thanks to Aaron's friend for letting us crash in his basement (which was close to Husky Stadium) and Jon for driving support and a place to crash in Portland.
We arrived in Seattle late - only 4 hours sleep! Probably not the best way to prepare for a day on the bike, but we rolled with it.


text:
No tax dollars used for federal judges' portraits
June 21, 2013
The federal government often is painted as being wasteful with taxpayer dollars. That's not the case with oil-based painted portraits of two late senior U.S. Middle District Court judges....
Should we replace all art with technology? How about making the statues in churches, parks, etc. from the new 3d plastic printers? Why do we care? We aren't paying for it and the attorneys who practice before the Courts are.
1 Agrees | 0 Disagrees | Report Abuse »
With modern technology, they could probably take a high resolution digital picture, do some photoshop work, and then print it on a canvas giclee for a fraction of the cost.
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text:
TCR Friday Notes
I realized my Cubs apathy reached a new height when I had no idea who the Cubs are playing today and don't really care to look it up.
- In the news, Kaplan's impeccable, most-excellent sources told him that the Cubs and Starlin Castro are working on an extension that would take him up to free agency and beyond. Rosenthal piggybacks on it with a tweet today saying that it should be a 6 to 7 year deal possibly with a club option and that it could be completed by next week. If my math is right, that should take him through 2018 and possibly 2019 which would be through his age 29 season. The numbers on this should be fascinating. My prediction yesterday was something in the 6/60 range, but I wouldn't be surprised if it's higher considering inflation and factoring in the usual rise in salary numbers.
Theo is already saying nice things about Castro in the media, so looks like this is just crossing the t's and dotting the i's, and hopefully doing it a lot better than Jim Bowden did during the trade deadline.
Dodgers getting Dempster.....final dotting of i's and crossing of t's being worked on......
— JIM BOWDEN (@JimBowdenESPNxm) July 31, 2012
- Filed under "You Can't Make This Stuff Up", Ryan Dempster was put on the Rangers restricted list for personal reasons and won't make his start for Saturday in Toronto. Sounds terrible, until you find out that the personal reason is that Canadian-born Ryan Dempster can't find his Canadian passport.
- And in "Sad Trombone" news, Mark Prior has been released by the Boston Red Sox. The 31-year old had a 3.96 ERA in Pawtucket in 25 innings with 38 K's, but 23 walks.
Re: TCR Friday Notes
"I realized my Cubs apathy reached a new height when I had no idea who the Cubs are playing today and don't really care to look it up."
we don't even have many game threads anymore and no one seems to care/notice.
also, last i checked, the topic in Parachat was welcoming Rizzo's 2nd day on the team or something.
Re: TCR Friday Notes
after this 4th inning i realize why people aren't watching...
t.wood is making volstad look like an ace tonight.
Re: TCR Friday Notes
Will Ryne Sandberg return to the big league with the Phillies?
"Confidently professional" is how Phillies catcher Erik Kratz describes his former manager. "He thinks he was just a regular player who just grinded it out and tried harder than everybody else, and it just so happens he ended up in the Hall of Fame."
Told of Kratz's description, Sandberg smiled.
"I was," he said. "That's true. I felt like I was an average player. I was told when I won the MVP in 1984 that Pete Rose said, 'This guy did not necessarily have the best tools, but he outworked everybody else.' I think that hit the nail on the head then. That's what I did, and that's what I have always done. That's what I continue to do."
Re: TCR Friday Notes
It's easy to get a Canadian passport quick. My friend was coming to the states in January, eh. He realized 5 days before he was coming that his passport was expired. He went to the passport joint and got one in 3 days. Governmental shit moves a lot faster when you only have 10% of the population of our dumb asses. Say what you want about their floppy heads and beady eyes, the goofy bastards are pretty good at life.
Alas, Dumpster is in the states, so it will probably take him like 3 months to get a passport. Hoser.
Re: TCR Friday Notes
Link from the twitter feed...article on #22's release with an interview of his Pawtucket room mate.
His K rate is still good. Why not Iowa, Mike W. needs a reason to go to the park these days.
Re: TCR Friday Notes
before he got his latest injury (shocking) he was doing well enough to eventually get a call-up, even if it took until Sept.
...after he came back from injury he forgot how to locate his pitches...dunno about velocity change. either way it got ugly, quick.
Re: TCR Friday Notes
Vogelbomb 3-5 with a TRIPLE
Almora 2-4 and a double
7-6 win for Hawks over Dust Devils
Re: TCR Friday Notes
A triple?? Wowowowow! I'll resist all the earthquake and respirator jokes and just say: Go get'em Don, errrr Dan!
Re: TCR Friday Notes
I think that's his third triple, actually. It's part of his weight loss program.
Re: TCR Friday Notes
Dudes: pretty impressive Soriano homer off Cueto! ... and just became like the 6th guy in HISTORY with 1000 RBI, 400 2B, 350 HR, and 250 SB. That said, the best part about the homer is watching Reds Catcher, Hanigan's immediate reaction to contact: priceless!
Re: TCR Friday Notes
BTW - Glanville article front page of NYT. Nicely done, Dan...er Doug!
Re: TCR Friday Notes
ESPN Deportes reporting that Castro has signed a 7 yr/$60M extension.
Re: TCR Friday Notes
via rotowurld:
"The contract covers four years of arbitration eligibility and three years of free agency, including a $16 million option for 2020. Castro, 22, was expected to qualify for "Super Two" status, so the Cubs were able to lock up one of their core players for a reasonable $8.57 million in Average Annual Value (AAV). It's hard to see this as anything but a positive for a rebuilding franchise.?
Re: TCR Friday Notes
starlin castro...you gotta pay attention to your 3rd base coach rather than watching the OF'rs.
sigh....another mental blowup.
Re: TCR Friday Notes
Like I have been saying. Most minor leaguers learn the craft without the prying eyes of an MLB audience. Castro is learning on the job, and theocorp still thinks enough of him to tie him up for 7 years.
This is a good year for these kinds of mistakes. Team isn't doing shit anyway.
Re: TCR Friday Notes
I can't go back and doublecheck--the game is in mlb.com quarantine for a while--but during the live broadcast, the replay showed Listach giving Castro the stop sign. Brantley had already accused Castro of not watching his coach, and should have corrected himself, but why bother--right, Cowboy?
Re: TCR Friday Notes
Virginia Phil has it 100% right. Went back and just watched it. Listach has the stop sign on and pointed at the bag. Castro was perfect.
Also as correctly called on the Cubs broadcast, Castro's run was not the problem as it would have brought the Cubs within 1 run. Wellington Castillo COMPLETELY BLEW his job watching a popup drop with two out, representing the tying run, and never reaching 1/2 a jog, and somehow avoiding ending up at 2nd base and in scoring position. So yeah, Cowboy owes Starlin an apology as he apparently can't watch a replay very well. And Wellington needs an ass-whoopin' and likely will get one.
Re: TCR Friday Notes
the announce team was going on about how listach was giving the run sign. go figure...
Re: TCR Friday Notes
Yeah he was, but the advantage of watching the replay showed it was while Soriano was running, then as Castro approached the base Listach had a stop sign up and pointed at the bag. Actually just showed crappy overall awareness by Brantley, since Casro's run was meaningless as far as possibly getting thrown out at home with two outs in the ninth and down two.
Re: TCR Friday Notes
yup...i was only going on the broadcasters...never followed up and just assumed.
Re: TCR Friday Notes
@ESPNChiCubs: Theo says nothing finalized on Castro contract. Beyond that no comment.
Proverbially putting horses on hold.
Re: TCR Friday Notes
I'd suggest Adderal for young Mr. Castro but that just brings in another host of problems. How about using a clicker?
Re: TCR Friday Notes
Game 2 lineup, omg...
@CarrieMuskat: Cubs lineup for G2...
Valbuena 3b, Mather lf, Rizzo 1b, Castro ss, LaHair rf, Clevenger c, Jackson cf, Cardenas 2b, Raley p
Re: TCR Friday Notes
Wow... that is beyond awful. This is a big league game, right?
Re: TCR Friday Notes
And in Welington's defense...
@ESPNChiCubs: Sveum not down on W Castillo for not advancing to second in ninth. Castillo playing on sore right foot that nearly kept him out of lineup.
Re: TCR Friday Notes
Well Sveum needs to watch the play again, because baseball awareness says, quit watching your damn ball, drop the frickin' bat, and proceed at your top speed (however gimpy it might be) if there are two outs in the ninth and you are the tying run. Anyone who watches it will see he wasn't hustling or aware of the situation (and there was no limp, he moved well when he realized the ball was kicked, sped up around first, and stopped). Sveum is probably just covering Castillo's ass for some reason.
Re: TCR Friday Notes
b.jackson not only didn't K in the first game...he just hit his 1st HR (solo) to RF in the second game.
Re: TCR Friday Notes
3 innings, 4 hits, 4 bb, and 1 run to show for it....which was, of course, a solo HR.
Re: TCR Friday Notes
Jackson got completely f&cked on his second at bat. Called strike three on a pitch at the shoulders. Ump let's a wild pitcher off the hook for no reason with one of the highest strikes I've ever seen called. Two men on of course. Cubs dugout got in a shouting match with the ump . . . He pulled off his mask and yelled "blah blah blah I didn't have it up!". Ridiculous call. NO one booted from game tho. No fun being a rookie sometimes mr jackson... Nice hr though!
Re: TCR Friday Notes
he's got such great tools under the whole lack-of-mental-game or ability to actually see the ball....whatever is causing him to be so jumpy about everything thrown at him.
Re: TCR Friday Notes
i can't believe there's no castro post yet...or more "OH FUCK YEAH! WOO!" posts.
down year for him, but in a world where a guy who hits like castro this year can easily get $3-6m...great gamble, imo...especially when the contract is supposedly through 2019 and castro projects to do better than what he's doing in 2012.
Re: TCR Friday Notes
I expected to see something, too. This is the new model, of course, as it's been since I guess the Evan Longoria contract. Rizzo's next, I guess next year?
Overall I'm content with the Castro deal. I think he's going to hit no matter what. His defense has improved.
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FYI: Randall Delgado has been getting lit up regularly in AAA. (tonight already 4 ER 2 HR in 4 innings so far). Cubs AND Braves may end up happy with the deal that wasn't made.
I know that's oversimplifying things but Delgado has pretty much sucked at all levels this year. Might not be an accident that they were dealing him.
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@CarrieMuskat: Jorge Soler homers to straightaway center in 3rd at bat, 3rd hit of game for Peoria. Very impressive.
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ryan ludwick seems to have a hot bat...
8-6, bottom 7.
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8-7, bottom 8...sigh.
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9-7, top 9...dejesus solo shot
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cubs win...fun game. CIN was down 8-2 early...
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b.hamilton (AA, CIN) is 2/2 with a SB tonight (in progress).
143...2 away from sharing the record.
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We're allocated 1 fun win a month. On to September.
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Angels are looking like the bust of 2012. Tonight they were up 8-0 on Rays and Carlos Pena just jacked a 2-run pinch homer in top of 8th to take 10-8 lead. Farnsworth, Fuld and Pena having great games tonight btw.
Frickin' Angels about to fall 8 back of Texas in a real ugly way, if they can't come back in the last 6 outs. This could be a nail in coffin type game.
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Yes I guess last year proved a LOT can happen in September!
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We need a bears site
soler interview
Maybe Soler can spare some loose change and get mr capie a toothbrush and some tooth whitener... Yikes!
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1.) Unbelievable! ... if this is at all representative of the amount of dishonesty in the doping practice, we are all in for a rude awakening when as Bud said last week at the owners meeting in Denver, "this all comes out."
2.) I'm shocked that it was only 50 games, if they knew about this deception, and all it indicates about premeditation etc. And if it wasn't fully known I wonder if the suspension can be increased in severity?
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at least his agent is trying to earn his pay.
i wouldn't worry about only having a 50-game suspension. in this era his career is practically over...tainted player, bad example to the kids...a horrible career-ending gamble. if history is any lesson...he's screwed.
lol...not...he'll get $10m+ multi-year next season. that will teach kids not to roid. ain't that right STL's hitting -coach-?
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The guy just turned 28 this month. No way that his career is OVER.
He did hurt his pocketbook in what should have been a big offseason payday. He will still be in MLB during the 2013 season.
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Yeah, I took it as crunch saying it won't effect him AT ALL in the long run. Sad either way ...
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pretty much...
i'm not worried about the impact on the records/stats as much as the players and those not on the mlb level yet.
things are a lot better than they were.
i'm satisfied with what's been done to address PEDs, even if it took a long time to get there.
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it's been weird (though it shouldn't be, imo) watching joe sheehan "evolve" to hybridizing numbers + "eyes on the ground" type scouting when evaluating players. he's been finding a good middle-ground between those two allegedly waring camps of thought the past couple of years. there's a lot more hybrid evaluators these days...a lot less "side picking."
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Can I just say, as a fan of the new regime, and a fan of Dale Sveum's, that the Cubs' baserunning is f%cking ATROCIOUS! Its a disaster. I mean these are the things we can supposedly control (as opposed to talent): The fundamentals! Soriano thrown out at second stealing before pitcher delivers, Valbuena's game changing out overrunning third, Volstad jogging to first, partway with bat and turning back to watch the play today when a reasonable sprint to first would have been safe, Castillo's space cadet romp to first yesterday. I'd be embarrassed if I was Sveum right now -- aggressive and smart is harder than it looks apparently.
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they're being very aggressive with their running game...very very aggressive...with players you probably shouldn't be aggressive with.
the 2nd game last night...that's a perfect time to be aggressive. dude's leg kick was so high (didn't pitch out of the stretch without a high lift to the leg) and his velocity low enough that even b.lahair made the battery seem like j.moyer throwing to m.piazza.
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to the 17th...PIT/STL
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PIT takes the lead in the top 17th...and STL ties in the bottom 17th...
...and now on to the 19th...
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PIT takes a 4-3 lead ... on pitch #553.
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6-3 now...wheels coming off...to the bottom of the 19th...
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Cubs claimed LHP Alex Hinshaw off waivers from the Padres.
Cubs transferred RHP Arodys Vizcaino to the 60-day disabled list.
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Would be a serviceable lefty in the pen but he walks way too many.
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astros have lost 40 out of their last 47.
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It's like beating a dead horse but were gonna call up someone awesome to pitch soon....
Cubs manager Dale Sveum mentioned Chris Rusin as a good candidate to be called up to start Tuesday at Milwaukee.
The 25-year-old left-hander has never pitched in the big leagues. He's 8-8 with a 4.59 ERA over 24 starts at Triple-A Iowa to go with a 87/52 K/BB rate over 133-plus innings. Chicago needs a Tuesday starter because of Saturday's doubleheader.
Yikes, Hendry left a lot of good talent behind.
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I'd rather see Rusin...Nick Struck, or even Eric Jockisch rather than Casey Coleman or Rodrigo Lopez again.. oof..
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What really sucks is that I really got duped into thinking Hendry was good for at least pitching even if not so much position talent. I don't know how much of it was Hendry because I'm not a walking encyclopedia like others here, but at one time the Cubs had going through their system and to the parent club or other teams, Z, Wood, Prior, Dontrelle (who imploded as expected but was still good for a few years), Sergio Mitre, Ricky Nolasco, and I'm pretty sure there were others. He even did some good stuff roster-wise early on, like the Miracle at Home Plate (getting rid of Todd Hundley for Eric Karros and Grudz if I remember right), and getting Ramirez.
Then it's like he turned into a semi truck on a hot Texas highway blowing out his tires and crashing into flames.
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Juan Cruz, Renyel Pinto, Rich Hill, Todd Wellemeyer, Scott Downs and Kyle Lohse all had some MLB success.
We also had a lot of really highly hyped Pitching prospects (suspects) that never panned out due to injury.
Bobby Brownlie
Ben Christiansen
Chadd Blasko
Luke Haggerty
Matt Clanton
Mark Pawelek
Were all 1st round picks over a 5-6 year period that were felled by a combo of injury/cubbery.
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Thanks, Dr. A. I guess I sort of attribute the list of busts as really pretty typical for an MLB team, rather than Cubbery. Although it's safe to assume at least one of them had some sort of freak injury.
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Losing 6 first round picks in 6 year to injury is REALLY unlucky. Not even counting Mark Prior who was a 7th 1st round pick of that same 6 year time span.
Not even counting guys like Grant Johnson and Donnie Veal who were 2nd rounders.
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Unlucky? Cubbery? Stockstillery, you mean.
Did Lou Mantanez and Ryan Harvey have sore arms, too? They were Stockstill's non-pitcher first-rounders. Not late first round, either: Montanez was 3, Harvey 6.
A lot of recent Cub pitchers have had arm problems and are still standing. We traded one of them for Rizzo, and another for Epstein.
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I think Montanez was a Hendry as scouting director pick? Harvey might have been Stockstill's first pick.
In particular were thought of as "can't miss" types. Tough to fault a Scouting Directer completely for injury problems.
The training and development people employed by the Cubs share much of this blame.
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There are conflicting stories around the web about who was scouting director in 1999-2000, like this one from baseballanalysts.com:
Cubs: John Stockstill (1999)
First-round picks under Stockstill: Ben Christensen (99), Luis Montanez (00), Mark Prior (01), Bobby Brownlie (02), Luke Hagerty (02), Chadd Blasko (02), Matt Clanton (02), Ryan Harvey (03)
Best pre-2004 players drafted: Steve Smyth (99-4), Dontrelle Willis (00-8), Mark Prior (01-1), Brian Dopirak (02-2), Ryan Harvey (03-1)
Steals: no 1999 steal, Dontrelle Willis (00-8), Brendan Harris (01-5), Adam Greenberg (02-9), Sean Marshall (03-6)
The longest tenured NL scouting director, John Stockstill has both success stories and blemishes on his resume. Most consistent in his ideology is the tendency to draft players that have slipped due to economic concerns, using the Chicago market to his advantage. Stockstill also tends to spend late-round picks on players generally seen as hard to sign, and many are names that tend to pop up again: Khalil Greene, Taylor Teagarden, Jeff Larish, etc. Stockstill was unfortunate to come right before the Corey Pattersons and Kerry Woods were drafted, and also is likely bummed that Jim Hendry chose to include Dontrelle Willis in the Matt Clement trade. I'm not sure that Stockstill will have a lot more drafts with the Cubs at this pace, but expect more of the draft-the-undraftable strategy to continue in 2005.
But I think you're right about Hendry. This quote from Phil Rogers in 2000 clinches it for me:
"We thought Montanez was the best player for us in the country," Cubs scouting director Jim Hendry said. "He's a lot like the [Alex] Gonzalez kid who plays for Toronto. His bat at 18 is probably farther along."
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The best part about that quote is that they drafted a kid 3rd overall WITH THE HOPE that he might be Alex Gonzalez at some point.
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You mean a long-term starting ss in the big leagues? That is a pretty high ceiling.
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Alex Gonzalez of the Toronto Blue Jays, aka, the Cubs starting shortstop in 2003, he of the NLCS error and .220-ish batting average. (I really liked watching him play and rooting for him, but you never hope a 1st round pick turns into him.) The Alex Gonzalez you're thinking of was with the Marlins.
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Nope- I knew exactly who he was talking about.
Again, he started at SS in the big leagues for several years. He wasn't great, and arguably wasn't even good. But not many prospects, even those drafted in the first round, become everyday starters for several years in the big leagues.
Not quite sure when the Hendry quote was said, but Gonzalez was also a top ten prospect by BA in 1994 and 1995.
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Yikes....well the Cubs sure set the bar low. Our #3 pick in the whole draft can become as good as a 13th round pick that cracked an OPS+ of 100 or greater exactly 1 time.
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Apologies. Your description sounded to me a lot more like the other, more successful Alex Gonzalez.
I guess as realistic projections for first rounders, that makes sense. But usually when we talk about first-rounder ceilings we compare them to Gary Sheffield or Jose Reyes or Chris Carpenter or something. A draft selection with a ceiling of Alex Gonzalez the lesser shouldn't go in the first round, if that's really what you think of him as a scouting director. But Hendry obviously thought pretty highly of that Alex Gonzalez.
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"the other, more successful Alex Gonzalez."
You made me look up for on B-R.
Cub A-Gonz played 13 seasons and amassed 8.7 WAR for his career, topping out with 2.0 WAR twice. (over $30M career earnings)
Marlin A-Gonz in in his 14th season and has 8.1 WAR for his career, with his two best seasons being 3.3 and 2.0 WAR. (over $27M career earnings)
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Point was more the projecting the Ceiling of your 3rd overall draft pick to be a replacement level big league player.
I'd be akin to hoping Mark Prior would have the ceiling of Jason Marquis.
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Well Christensen, Brownlie, and Pawelek also just sucked. That was part of the issue too. Clanton? Oof....
Recent comments
J-Hey not finishing with an offensive onslaught.
If Geoff Blum could be a Playoff hero, there is hope still...
Giants scare me. I think you're wrong about Bumgarner, he would pitch on short rest for Game 2 and then full rest for Game 5. Cueto would go Game 1, then short rest in game 4. Add in some really tough outs in that lineup and I want nothing to do with them. With that rotation they can easily steal a series.
Cards are a tough matchup. The rivalry evens out their comparable lack of talent. And like someone said, they love HRs, which is how to beat the Cubs. The upside is that I would feel really good about Lester twice against STL.
j.buchanan with a nice start...5ip 2h 1bb 3k, 0r/er
zobrist with 2HR and a double through 8
heyward 0-4 :(
Mark Gonzales @MDGonzales
Soler likely to return Sunday, Maddon says
Right now, I'd like to see the Mets first, Giants 2nd.
I believe that since most of the team from last years' NLCS is on the squad this year, they will really amp their game up even more to kick their ass in payback for 2015.
The Giants just do not have the depth in years past, and I think all things equal - and at Wrigley - they could handle them.
I do not want to see the Cards, period. Or their fans, media, or Joe Buck.
I don't want to play Braves in the first round. Any friggin team in the league can win 3 of 5..I hate the first round. Furthermore, I wanted to play the Marlins in 2003 and the Mets over Dodgers last year.
With that said in reverse order:
3. Cardinals: It will be devastating to lose in the first round, but even worse to their main rival. It is increased incentive for the Cardinals, especially after last year. Cards would have nothing to lose, Cubs have everything to lose.
2. Giants: Rotation in the playoffs scare me a bit, but what a lousy team.
1. Mets--because of the losses in the rotation
2. Giants--because they're not the team they were BUT they maybe have bullshit even-year magic?
3. Cardinals--because rivalry and not making the playoffs hurts them more than losing in the NLDS plus getting eliminated by them in the playoffs would make for horrible sports commentary next throughout next season.
Who's asking?
CLE/DET rained out last night already, possible rain-outs in New York (vs. Baltimore), Boston(vs. Toronto) and Philly(vs. Mets) this weekend too.
Not only games involving playoff spots that would need to be played, but any that involve home field advantage.
I got the first one! Second one I'm not even sure what even/odd betting is.
any opponent preference for NLDS?
Mets are down to 1 great pitcher instead of 4. Syndegaard may pitch Sunday which means if Mets win the WC game, he'd be set up for Game 1. There's a chance they clinch a spot by Sunday so he'd pitch the WC and then we'd probably get Colon for Game 1. They've certainly had the hottest bats over the last week and month out of the WC options.
A couple of Cub related puzzles.
Can't teach height and thinness
Hopefully Pirates don't call up A. Lincoln.
j.buchanan going friday...should be...baseball...or something like it.
Wow. I didn't know they could do that.
Nice for Willson, not so much for Addy.