Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable ...biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD.
Studies of excised lungs show that significant airway attrition in the "quiet" zone occurs early in chronic obstructive pulmonary disease (COPD).
To determine if the total number of airways ...quantified in vivo using computed tomography (CT) reflects early airway-related disease changes and is associated with lung function decline independent of emphysema in COPD.
Participants in the multicenter, population-based, longitudinal CanCOLD (Canadian Chronic Obstructive Lung Disease) study underwent inspiratory/expiratory CT at visit 1; spirometry was performed at four visits over 6 years. Emphysema was quantified as the CT inspiratory low-attenuation areas below -950 Hounsfield units. CT total airway count (TAC) was measured as well as airway inner diameter and wall area using anatomically equivalent airways.
Participants included never-smokers (n = 286), smokers with normal spirometry at risk for COPD (n = 298), Global Initiative for Chronic Obstructive Lung Disease (GOLD) I COPD (n = 361), and GOLD II COPD (n = 239). TAC was significantly reduced by 19% in both GOLD I and GOLD II compared with never-smokers (P < 0.0001) and by 17% in both GOLD I and GOLD II compared with at-risk participants (P < 0.0001) after adjusting for low-attenuation areas below -950 Hounsfield units. Further analysis revealed parent airways with missing daughter branches had reduced inner diameters (P < 0.0001) and thinner walls (P < 0.0001) compared with those without missing daughter branches. Among all CT measures, TAC had the greatest influence on FEV
(P < 0.0001), FEV
/FVC (P < 0.0001), and bronchodilator responsiveness (P < 0.0001). TAC was independently associated with lung function decline (FEV
, P = 0.02; FEV
/FVC, P = 0.01).
TAC may reflect the airway-related disease changes that accumulate in the "quiet" zone in early/mild COPD, indicating that TAC acquired with commercially available software across various CT platforms may be a biomarker to predict accelerated COPD progression.
The apoptotic actions of p53 require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT ...(Tel2, Tti1, Tti2) cochaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in p53-associated cell death. In the present study we report an apoptotic signaling cascade linking CK2, TTT, the PIKKs, and p53. We demonstrate that IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the TTT complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program in human cancer cells and in murine B cells.
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•IP7 binds with high affinity to CK2•IP7 binding enhances CK2-mediated phosphorylation of Tel2/Tti1•IP6K2 binds Tti1 to facilitate stabilization of DNA-PKcs/ATM•The IP7/CK2/TTT cascade activates the DNA-PKcs/ATM-p53 apoptotic program
Human IP6K2 mediates p53-dependent cell death. Rao et al. show that IP6K2 functions by promoting p53 phosphorylation by DNA-PKcs/ATM. IP6K2 acts on DNA-PKcs/ATM indirectly by generating an inositol pyrophosphate (IP7) that binds to CK2 and mediates CK2-dependent phosphorylation of a chaperone complex (Tel2/Tti1/Tti2) known to control the stability and activity of DNA-PKcs/ATM.
We report the discovery of a candidate stellar-mass black hole in the Milky Way globular cluster M62. We detected the black hole candidate, which we call M62-VLA1, in the core of the cluster using ...deep radio continuum imaging from the Karl G. Jansky Very Large Array. M62-VLA1 is a faint source with a flux density of 18.7 + or - 1.9 mu Jy at 6.2 GHz and a flat radio spectrum ( alpha = -0.24 + or - 0.42, for S sub(nu) = nu super( alpha )). M62 is the second Milky Way cluster with a candidate stellar-mass black hole; unlike the two candidate black holes previously found in the cluster M22, M62-VLA1 is associated with a Chandra X-ray source, supporting its identification as a black hole X-ray binary. Measurements of its radio and X-ray luminosity, while not simultaneous, place M62-VLA1 squarely on the well-established radio-X-ray correlation for stellar-mass black holes. In archival Hubble Space Telescope imaging, M62-VLA1 is coincident with a star near the lower red giant branch. This possible optical counterpart shows a blue excess, H alpha emission, and optical variability. The radio, X-ray, and optical properties of M62-VLA1 are very similar to those for V404 Cyg, one of the best-studied quiescent stellar-mass black holes. We cannot yet rule out alternative scenarios for the radio source, such as a flaring neutron star or background galaxy; future observations are necessary to determine whether M62-VLA1 is indeed an accreting stellar-mass black hole.
The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation; however, instances of CD133
− cells exhibiting ...similar properties have also been reported. Here, we show that some
PTEN-deficient GBM tumors produce a series of CD133
+ and CD133
− self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stemlike cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage.
► GBM PTEN deficiency correlates with successfully expandable neurosphere culture ► Identification of self-renewing CD133
− cell type generating CD133
+ and CD133
− progeny ► Evidence for lineage hierarchy of self-renewing, tumor-initiating cells in GBM ► GBM cell lineage with graded spectrum of cancer stem cell competencies
Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions
...(for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping
(the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain-behavioural phenotype associations
. Here we used three of the largest neuroimaging datasets currently available-with a total sample size of around 50,000 individuals-to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain-phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals.
Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.
We sought to ...identify donor, recipient, and perioperative risk factors for PGD.
We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression.
A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio OR, 1.8; 95% confidence interval CI, 1.2-2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% increase in FiO2; 95% CI, 1.0-1.2; P = 0.01); single lung transplant (OR, 2; 95% CI, 1.2-3.3; P = 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2-5.3; P < 0.001); overweight (OR, 1.8; 95% CI, 1.2-2.7; P = 0.01) and obese (OR, 2.3; 95% CI, 1.3-3.9; P = 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1-5.6; P = 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6-7.7; P = 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1-1.5; P < 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P < 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P < 0.001) mortality.
We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 00552357).
ABSTRACT
We constrain the Hubble constant H0 using Fast Radio Burst (FRB) observations from the Australian Square Kilometre Array Pathfinder (ASKAP) and Murriyang (Parkes) radio telescopes. We use ...the redshift-dispersion measure (‘Macquart’) relationship, accounting for the intrinsic luminosity function, cosmological gas distribution, population evolution, host galaxy contributions to the dispersion measure (DMhost), and observational biases due to burst duration and telescope beamshape. Using an updated sample of 16 ASKAP FRBs detected by the Commensal Real-time ASKAP Fast Transients (CRAFT) Survey and localized to their host galaxies, and 60 unlocalized FRBs from Parkes and ASKAP, our best-fitting value of H0 is calculated to be $73_{-8}^{+12}$ km s−1 Mpc−1. Uncertainties in FRB energetics and DMhost produce larger uncertainties in the inferred value of H0 compared to previous FRB-based estimates. Using a prior on H0 covering the 67–74 km s−1 Mpc−1 range, we estimate a median ${\rm DM}_{\rm host}= 186_{-48}^{+59}\,{\rm pc \, cm^{-3}}$, exceeding previous estimates. We confirm that the FRB population evolves with redshift similarly to the star-formation rate. We use a Schechter luminosity function to constrain the maximum FRB energy to be log10Emax$=41.26_{-0.22}^{+0.27}$ erg assuming a characteristic FRB emission bandwidth of 1 GHz at 1.3 GHz, and the cumulative luminosity index to be $\gamma =-0.95_{-0.15}^{+0.18}$. We demonstrate with a sample of 100 mock FRBs that H0 can be measured with an uncertainty of ±2.5 km s−1 Mpc−1, demonstrating the potential for clarifying the Hubble tension with an upgraded ASKAP FRB search system. Last, we explore a range of sample and selection biases that affect FRB analyses.
The concordance of RNA-sequencing (RNA-seq) with microarrays for genome-wide analysis of differential gene expression has not been rigorously assessed using a range of chemical treatment conditions. ...Here we use a comprehensive study design to generate Illumina RNA-seq and Affymetrix microarray data from the same liver samples of rats exposed in triplicate to varying degrees of perturbation by 27 chemicals representing multiple modes of action (MOAs). The cross-platform concordance in terms of differentially expressed genes (DEGs) or enriched pathways is linearly correlated with treatment effect size (R(2)0.8). Furthermore, the concordance is also affected by transcript abundance and biological complexity of the MOA. RNA-seq outperforms microarray (93% versus 75%) in DEG verification as assessed by quantitative PCR, with the gain mainly due to its improved accuracy for low-abundance transcripts. Nonetheless, classifiers to predict MOAs perform similarly when developed using data from either platform. Therefore, the endpoint studied and its biological complexity, transcript abundance and the genomic application are important factors in transcriptomic research and for clinical and regulatory decision making.
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