A comparison of FreeSurfer-generated data with and without manual intervention

This paper examined whether FreeSurfer - generated data differed between a fully – automated, unedited pipeline and an edited pipeline that included the application of control points to correct errors in white matter segmentation. In a sample of 30 individuals, we compared the summary statistics of surface area, white matter volumes, and cortical thickness derived from edited and unedited datasets for the 34 regions of interest (ROIs) that FreeSurfer (FS) generates. To determine whether applying control points would alter the detection of significant differences between patient and typical groups, effect sizes between edited and unedited conditions in individuals with the genetic disorder, 22q11.2 deletion syndrome (22q11DS) were compared to neurotypical controls. Analyses were conducted with data that were generated from both a 1.5 tesla and a 3 tesla scanner. For 1.5 tesla data, mean area, volume, and thickness measures did not differ significantly between edited and unedited regions, with the exception of rostral anterior cingulate thickness, lateral orbitofrontal white matter, superior parietal white matter, and precentral gyral thickness. Results were similar for surface area and white matter volumes generated from the 3 tesla scanner. For cortical thickness measures however, seven edited ROI measures, primarily in frontal and temporal regions, differed significantly from their unedited counterparts, and three additional ROI measures approached significance. Mean effect sizes for edited ROIs did not differ from most unedited ROIs for either 1.5 or 3 tesla data. Taken together, these results suggest that although the application of control points may increase the validity of intensity normalization and, ultimately, segmentation, it may not affect the final, extracted metrics that FS generates. Potential exceptions to and limitations of these conclusions are discussed

A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression.

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response

Assessment of High-Sensitivity C-Reactive Protein Levels as Diagnostic Discriminator of Maturity-Onset Diabetes of the Young Due to HNF1A Mutations

OBJECTIVE: Despite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A (HNF1A) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high-sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY). RESEARCH DESIGN AND METHODS: Serum hs-CRP was measured in subjects with HNF1A-MODY (n = 31), autoimmune diabetes (n = 316), type 2 diabetes (n = 240), and glucokinase (GCK) MODY (n = 24) and in nondiabetic individuals (n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded approximately 11% of subjects in whom the single available hs-CRP measurement was >10 mg/l. RESULTS: Geometric mean (SD range) hs-CRP levels were significantly lower (

Low Frequency Variants in the Exons Only Encoding Isoform A of HNF1A Do Not Contribute to Susceptibility to Type 2 Diabetes

Background: There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8-10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1-7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8-10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D. Methodology and principal findings: We performed targeted capillary resequencing of HNF1A exons 8-10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (≤ 45 years) and/or family history of T2D (≥ 1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9-24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rd61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected. Conclusions and significance: We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion

The Importance of Satellite Quenching for the Build-Up of the Red Sequence of Present Day Galaxies

In the current paradigm, red sequence galaxies are believed to have formed as blue disk galaxies that subsequently had their star formation quenched. Since red-sequence galaxies typically have an early-type morphology, the transition from the blue to the red sequence also involves a morphological transformation. In this paper we study the impact of transformation mechanisms that operate only on satellite galaxies, such as strangulation, ram-pressure stripping and galaxy harassment. Using a large galaxy group catalogue constructed from the SDSS, we compare the colors and concentrations of satellites galaxies to those of central galaxies of the same stellar mass, adopting the hypothesis that the latter are the progenitors of the former. On average, satellites are redder and more concentrated than central galaxies of the same stellar mass. Central-satellite pairs that are matched in both stellar mass and color, however, show no average concentration difference, indicating that the transformation mechanisms affect color more than morphology. The color and concentration differences of matched central-satellite pairs are completely independent of the halo mass of the satellite galaxy, indicating that satellite-specific transformation mechanisms are equally efficient in haloes of all masses. This strongly favors strangulation as the main quenching mechanism for satellite galaxies. Finally, we determine the relative importance of satellite quenching for the build-up of the red sequence. We find that roughly 70 percent of red sequence satellite galaxies with a stellar mass of 10^9 Msun had their star formation quenched as satellites. This drops rapidly to zero with increasing stellar mass, indicating that a significant fraction of red satellites were already quenched before they became a satellite.Comment: 14 pages, 10 figures. Submitted for publication in MNRA

Neuroanatomic Predictors to Prodromal Psychosis in Velocardiofacial Syndrome (22q11.2 Deletion Syndrome): A Longitudinal Study

Background: Up to 30% of young adults with velocardiofacial syndrome (VCFS; 22q11.2 deletion syndrome) develop schizophrenia or psychosis. Identifying the neuroanatomic trajectories that increase risk for psychosis in youth with this genetic disorder is of great interest. Methods: We acquired high-resolution anatomic MR images and measures of psychiatric function on 72 youth with VCFS, 26 unaffected siblings and 24 age-matched community controls at two timepoints, between late childhood (mean age, 11.9 years) and mid-adolescence (mean age, 15.1 years). Results: With the exception of cranial gray matter and orbitofrontal prefrontal cortex, neuroanatomic trajectories in youth with VCFS were comparable to unaffected siblings and community controls during this developmental window. However, in youth with VCFS, longitudinal decreases in the volumes of cranial gray and white matter, prefrontal cortex, mesial temporal lobe, and cerebellum were associated with increased combined prodromal symptoms at Time 2. In contrast, only decreases in temporal lobe gray matter volumes (p \u3c .002) and verbal IQ (p \u3c .002) predicted specifically to positive prodromal symptoms of psychosis at Time 2. Conclusions: These findings are in line with studies of non-VCFS individuals at risk for schizophrenia, and suggest that early decrements in temporal lobe gray matter may be predictive of increased risk of prodromal psychotic symptoms in youth with VCFS

The Pittsburgh Sloan Digital Sky Survey MgII Quasar Absorption-Line Survey Catalog

We present a catalog of intervening MgII quasar absorption-line systems in the redshift interval 0.36 <= z <= 2.28. The catalog was built from Sloan Digital Sky Survey Data Release Four (SDSS DR4) quasar spectra. Currently, the catalog contains > 17,000 measured MgII doublets. We also present data on the ~44,600 quasar spectra which were searched to construct the catalog, including redshift and magnitude information, continuum-normalized spectra, and corresponding arrays of redshift-dependent minimum rest equivalent widths detectable at our confidence threshold. The catalog is available on the web. A careful second search of 500 random spectra indicated that, for every 100 spectra searched, approximately one significant MgII system was accidentally rejected. Current plans to expand the catalog beyond DR4 quasars are discussed. Many MgII absorbers are known to be associated with galaxies. Therefore, the combination of large size and well understood statistics makes this catalog ideal for precision studies of the low-ionization and neutral gas regions associated with galaxies at low to moderate redshift. An analysis of the statistics of MgII absorbers using this catalog will be presented in a subsequent paper.Comment: AJ, in pres

New onshore insights into the role of structural inheritance during Mesozoic opening of the Inner Moray Firth Basin, Scotland

The Inner Moray Firth Basin (IMFB) forms the western arm of the North Sea trilete rift system that initiated mainly during the Late Jurassic–Early Cretaceous with the widespread development of major NE–SW-trending dip-slip growth faults. The IMFB is superimposed over the southern part of the older Devonian Orcadian Basin. The potential influence of older rift-related faults on the kinematics of later Mesozoic basin opening has received little attention, partly owing to the poor resolution of offshore seismic reflection data at depth. New field observations augmented by drone photography and photogrammetry, coupled with U–Pb geochronology, have been used to explore the kinematic history of faulting in onshore exposures along the southern IMFB margin. Dip-slip north–south- to NNE–SSW-striking Devonian growth faults are recognized that have undergone later dextral reactivation during NNW–SSE extension. The U–Pb calcite dating of a sample from the synkinematic calcite veins associated with this later episode shows that the age of fault reactivation is 130.99  ±  4.60 Ma (Hauterivian). The recognition of dextral-oblique Early Cretaceous reactivation of faults related to the underlying and older Orcadian Basin highlights the importance of structural inheritance in controlling basin- to sub-basin-scale architectures and how this influences the kinematics of IMFB rifting

New onshore insights into the role of structural inheritance during Mesozoic opening of the Inner Moray Firth Basin, Scotland

The Inner Moray Firth Basin (IMFB) forms the western arm of the North Sea trilete rift system that initiated mainly during the Late Jurassic–Early Cretaceous with the widespread development of major NE–SW-trending dip-slip growth faults. The IMFB is superimposed over the southern part of the older Devonian Orcadian Basin. The potential influence of older rift-related faults on the kinematics of later Mesozoic basin opening has received little attention, partly owing to the poor resolution of offshore seismic reflection data at depth. New field observations augmented by drone photography and photogrammetry, coupled with U–Pb geochronology, have been used to explore the kinematic history of faulting in onshore exposures along the southern IMFB margin. Dip-slip north–south- to NNE–SSW-striking Devonian growth faults are recognized that have undergone later dextral reactivation during NNW–SSE extension. The U–Pb calcite dating of a sample from the synkinematic calcite veins associated with this later episode shows that the age of fault reactivation is 130.99  ±  4.60 Ma (Hauterivian). The recognition of dextral-oblique Early Cretaceous reactivation of faults related to the underlying and older Orcadian Basin highlights the importance of structural inheritance in controlling basin- to sub-basin-scale architectures and how this influences the kinematics of IMFB rifting