The SEGUE Stellar Parameter Pipeline. III. Comparison with High-Resolution Spectroscopy of SDSS/SEGUE Field Stars

We report high-resolution spectroscopy of 125 field stars previously observed as part of the Sloan Digital Sky Survey and its program for Galactic studies, the Sloan Extension for Galactic Understanding and Exploration (SEGUE). These spectra are used to measure radial velocities and to derive atmospheric parameters, which we compare with those reported by the SEGUE Stellar Parameter Pipeline (SSPP). The SSPP obtains estimates of these quantities based on SDSS ugriz photometry and low-resolution (R = 2000) spectroscopy. For F- and G-type stars observed with high signal-to-noise ratios (S/N), we empirically determine the typical random uncertainties in the radial velocities, effective temperatures, surface gravities, and metallicities delivered by the SSPP to be 2.4 km/s, 130 K (2.2%), 0.21 dex, and 0.11 dex, respectively, with systematic uncertainties of a similar magnitude in the effective temperatures and metallicities. We estimate random errors for lower S/N spectra based on numerical simulations.Comment: 37 pages, 6 tables, 6 figures, submitted to the Astronomical Journa

Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function

Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (P = 0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered

Predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome

Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36months read in the core laboratory of 608 trial subjects, aged 6months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz)>3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year>90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R-2=0.01) or by change in AoR diameter (AoRd)/year>90th percentile with higher sinotubular junction z-score and non-white race (R-2=0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R-2=0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364

Subgrouping the autism "spectrum": reflections on DSM-5

DSM-5 has moved autism from the level of subgroups ("apples and oranges") to the prototypical level ("fruit"). But making progress in research, and ultimately improving clinical practice, will require identifying subgroups within the autism spectrum

Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow

Blood neutrophil homeostasis is essential for successful host defense against invading pathogens. Circulating neutrophil counts are positively regulated by CXCR2 signaling and negatively regulated by the CXCR4-CXCL12 axis. In particular, G-CSF, a known CXCR2 signaler, and plerixafor, a CXCR4 antagonist, have both been shown to correct neutropenia in human patients. G-CSF directly induces neutrophil mobilization from the bone marrow (BM) into the blood, but the mechanisms underlying plerixafor-induced neutrophilia remain poorly defined. Using a combination of intravital multiphoton microscopy, genetically modified mice and novel in vivo homing assays, we demonstrate that G-CSF and plerixafor work through distinct mechanisms. In contrast to G-CSF, CXCR4 inhibition via plerixafor does not result in neutrophil mobilization from the BM. Instead, plerixafor augments the frequency of circulating neutrophils through their release from the marginated pool present in the lung, while simultaneously preventing neutrophil return to the BM. Our study demonstrates for the first time that drastic changes in blood neutrophils can originate from alternative reservoirs other than the BM, while implicating a role for CXCR4-CXCL12 interactions in regulating lung neutrophil margination. Collectively, our data provides valuable insights into the fundamental regulation of neutrophil homeostasis, which may lead to the development of improved treatment regimens for neutropenic patients.This research was funded by SIgN, A*STAR, Singapore. C.N.Z. Mattar and J.K.Y. Chan received salary support from the National Medical Research Council of Singapore (NMRC/TA/003/2012 and NMRC/CSA/012/2009, respectively).S

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Evaluating Sex and Age Differences in ADI-R and ADOS Scores in a Large European Multi-site Sample of Individuals with Autism Spectrum Disorder

Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology