Zebrafish orthologs of human muscular dystrophy genes

BACKGROUND: Human muscular dystrophies are a heterogeneous group of genetic disorders which cause decreased muscle strength and often result in premature death. There is no known cure for muscular dystrophy, nor have all causative genes been identified. Recent work in the small vertebrate zebrafish Danio rerio suggests that mutation or misregulation of zebrafish dystrophy orthologs can also cause muscular degeneration phenotypes in fish. To aid in the identification of new causative genes, this study identifies and maps zebrafish orthologs for all known human muscular dystrophy genes. RESULTS: Zebrafish sequence databases were queried for transcripts orthologous to human dystrophy-causing genes, identifying transcripts for 28 out of 29 genes of interest. In addition, the genomic locations of all 29 genes have been found, allowing rapid candidate gene discovery during genetic mapping of zebrafish dystrophy mutants. 19 genes show conservation of syntenic relationships with humans and at least two genes appear to be duplicated in zebrafish. Significant sequence coverage on one or more BAC clone(s) was also identified for 24 of the genes to provide better local sequence information and easy updating of genomic locations as the zebrafish genome assembly continues to evolve. CONCLUSION: This resource supports zebrafish as a dystrophy model, suggesting maintenance of all known dystrophy-associated genes in the zebrafish genome. Coupled with the ability to conduct genetic screens and small molecule screens, zebrafish are thus an attractive model organism for isolating new dystrophy-causing genes/pathways and for use in high-throughput therapeutic discovery

Growth of white matter in the adolescent brain: role of testosterone and androgen receptor

The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n = 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath

BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals

Berkeley Supernova Ia Program I: Observations, Data Reduction, and Spectroscopic Sample of 582 Low-Redshift Type Ia Supernovae

In this first paper in a series we present 1298 low-redshift (z\leq0.2) optical spectra of 582 Type Ia supernovae (SNe Ia) observed from 1989 through 2008 as part of the Berkeley SN Ia Program (BSNIP). 584 spectra of 199 SNe Ia have well-calibrated light curves with measured distance moduli, and many of the spectra have been corrected for host-galaxy contamination. Most of the data were obtained using the Kast double spectrograph mounted on the Shane 3 m telescope at Lick Observatory and have a typical wavelength range of 3300-10,400 Ang., roughly twice as wide as spectra from most previously published datasets. We present our observing and reduction procedures, and we describe the resulting SN Database (SNDB), which will be an online, public, searchable database containing all of our fully reduced spectra and companion photometry. In addition, we discuss our spectral classification scheme (using the SuperNova IDentification code, SNID; Blondin & Tonry 2007), utilising our newly constructed set of SNID spectral templates. These templates allow us to accurately classify our entire dataset, and by doing so we are able to reclassify a handful of objects as bona fide SNe Ia and a few other objects as members of some of the peculiar SN Ia subtypes. In fact, our dataset includes spectra of nearly 90 spectroscopically peculiar SNe Ia. We also present spectroscopic host-galaxy redshifts of some SNe Ia where these values were previously unknown. [Abridged]Comment: 34 pages, 11 figures, 11 tables, revised version, re-submitted to MNRAS. Spectra will be released in January 2013. The SN Database homepage (http://hercules.berkeley.edu/database/index_public.html) contains the full tables, plots of all spectra, and our new SNID template

SN 2011hw: Helium-Rich Circumstellar Gas and the Luminous Blue Variable to Wolf-Rayet Transition in Supernova Progenitors

We present optical photometry and spectroscopy of the peculiar Type IIn/Ibn supernova SN2011hw. Its light curve exhibits a slower decline rate than normal SNeIbc, with a peak absolute magnitude of -19.5 (unfiltered) and a secondary peak of -18.3 mag (R). Spectra of SN2011hw are unusual compared to normal SN types, most closely resembling the spectra of SNeIbn. We center our analysis on comparing SN 2011hw to the well-studied TypeIbn SN2006jc. While the two SNe have many important similarities, the differences are quite telling: compared to SN2006jc, SN2011hw has weaker HeI and CaII lines and relatively stronger H lines, its light curve has a higher luminosity and slower decline rate, and emission lines associated with the progenitor's CSM are narrower. One can reproduce the unusual continuum shape of SN2011hw with equal contributions of a 6000K blackbody and a spectrum of SN2006jc. We attribute this emission component and many other differences between the two SNe to extra opacity from a small amount of additional H in SN2011hw, analogous to the small H mass that makes SNeIIb differ from SNeIb. Slower speeds in the CSM and elevated H content suggest a connection between the progenitor of SN2011hw and the class of Ofpe/WN9 stars, which have been associated with LBVs in their hot quiescent phases between outbursts, and are H-poor - but not H-free like classical Wolf-Rayet (WR) stars. We conclude that the similarities and differences between SN2011hw and SN2006jc can be largely understood if their progenitors exploded at different points in the transitional evolution from an LBV to a WR star.Comment: 11 pages, 7 figures, submitted to MNRA

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n = 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath

RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106

Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto-HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwesterm Oncology Group S1106 trial was designed to assess rituximab plushyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre-transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto-HCT. Fifty-three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2-year progression-free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi-centre transplant trials in MCL. RB achieved a 2-year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL

RB but not R‐HCVAD is a feasible induction regimen prior to auto‐HCT in frontline MCL: results of SWOG Study S1106

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136294/1/bjh14480_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136294/2/bjh14480.pd

Characteristics and Predictive Value of Blood Transcriptome Signature in Males with Autism Spectrum Disorders

Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62–0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65–0.82), but not for female samples (AUC 0.51, 95% CI 0.36–0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58–0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified