Gravitational waves from binary supermassive black holes missing in pulsar observations.

This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aab1910Gravitational waves are expected to be radiated by supermassive black hole binaries formed during galaxy mergers. A stochastic superposition of gravitational waves from all such binary systems would modulate the arrival times of pulses from radio pulsars. Using observations of millisecond pulsars obtained with the Parkes radio telescope, we constrained the characteristic amplitude of this background, A(c,yr), to be <1.0 × 10(-15) with 95% confidence. This limit excludes predicted ranges for A(c,yr) from current models with 91 to 99.7% probability. We conclude that binary evolution is either stalled or dramatically accelerated by galactic-center environments and that higher-cadence and shorter-wavelength observations would be more sensitive to gravitational waves.The PPTA project was initiated with support from R.N.M.’s Australian Research Council (ARC) Federation Fellowship (grant FF0348478) and from CSIRO under that fellowship program. The PPTA project has also received support from ARC through Discovery Project grants DP0985272 and DP140102578. N.D.R.B. acknowledges support from a Curtin University research fellowship. G.H. and Y.L. are recipients of ARC Future Fellowships (respectively, grants FT120100595 and FT110100384). S.O. is supported by the Alexander von Humboldt Foundation. R.M.S. acknowledges travel support from CSIRO through a John Philip Award for excellence in early-career research. The authors declare no conflicts of interest. Data used in this analysis can be accessed via the Australian National Data Service (www.ands.org.au)

A tumor cord model for Doxorubicin delivery and dose optimization in solid tumors

<p>Abstract</p> <p>Background</p> <p>Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments.</p> <p>Methods</p> <p>A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration.</p> <p>Results</p> <p>The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy.</p> <p>Conclusion</p> <p>Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors.</p

PuLSE:Quality control and quantification of peptide sequences explored by phage display libraries

The design of highly diverse phage display libraries is based on assumption that DNA bases are incorporated at similar rates within the randomized sequence. As library complexity increases and expected copy numbers of unique sequences decrease, the exploration of library space becomes sparser and the presence of truly random sequences becomes critical. We present the program PuLSE (Phage Library Sequence Evaluation) as a tool for assessing randomness and therefore diversity of phage display libraries. PuLSE runs on a collection of sequence reads in the fastq file format and generates tables profiling the library in terms of unique DNA sequence counts and positions, translated peptide sequences, and normalized 'expected' occurrences from base to residue codon frequencies. The output allows at-a-glance quantitative quality control of a phage library in terms of sequence coverage both at the DNA base and translated protein residue level, which has been missing from toolsets and literature. The open source program PuLSE is available in two formats, a C++ source code package for compilation and integration into existing bioinformatics pipelines and precompiled binaries for ease of use

The mediating role of self/everyday creativity and depression on the relationship between creative personality traits and problematic social media use among emerging adults

Personality is one of the important contributory factors in the development of problematic technology use. The purpose of the present study was to investigate the direct and indirect associations of creative personality traits with problematic social media use via self/everyday creativity, depression, and loneliness. A total of 460 Turkish emerging adults aged between 18 and 26 years (61% female) were surveyed. Findings indicated that (i) task-orientedness was indirectly associated with problematic social media use via self/everyday creativity, (ii) self-confidence was directly and indirectly associated with problematic social media use via self/everyday creativity and depression, (iii) risk-taking was indirectly associated with problematic social media use via depression, and (iv) self/everyday creativity and depression were directly associated with problematic social media use. The present study is the first to suggest that creative personality traits (i.e., task-orientedness, self-confidence, and risk-taking) and self/everyday creativity are associated with problematic social media use and that these factors should be taken into account when considering the etiology of problematic social media use

SLEPR: A Sample-Level Enrichment-Based Pathway Ranking Method — Seeking Biological Themes through Pathway-Level Consistency

Analysis of microarray and other high throughput data often involves identification of genes consistently up or down-regulated across samples as the first step in extraction of biological meaning. This gene-level paradigm can be limited as a result of valid sample fluctuations and biological complexities. In this report, we describe a novel method, SLEPR, which eliminates this limitation by relying on pathway-level consistencies. Our method first selects the sample-level differentiated genes from each individual sample, capturing genes missed by other analysis methods, ascertains the enrichment levels of associated pathways from each of those lists, and then ranks annotated pathways based on the consistency of enrichment levels of individual samples from both sample classes. As a proof of concept, we have used this method to analyze three public microarray datasets with a direct comparison with the GSEA method, one of the most popular pathway-level analysis methods in the field. We found that our method was able to reproduce the earlier observations with significant improvements in depth of coverage for validated or expected biological themes, but also produced additional insights that make biological sense. This new method extends existing analyses approaches and facilitates integration of different types of HTP data

Self-reported drunkenness among adolescents in four sub-Saharan African countries: associations with adverse childhood experiences

<p>Abstract</p> <p>Background</p> <p>Consumption of alcohol is associated with acute and chronic adverse health outcomes. There is a paucity of studies that explore the determinants of alcohol use among adolescents in sub-Saharan Africa and, in particular, that examine the effects of adverse childhood experiences on alcohol use.</p> <p>Methods</p> <p>The paper draws on nationally-representative data from 9,819 adolescents aged 12-19 years from Burkina Faso, Ghana, Malawi, and Uganda. Logistic regression models were employed to identify correlates of self-reported past-year drunkenness. Exposure to four adverse childhood experiences comprised the primary independent variables: living in a food-insecure household, living with a problem drinker, having been physically abused, and having been coerced into having sex. We controlled for age, religiosity, current schooling status, the household head's sex, living arrangements, place of residence, marital status, and country of survey. All analyses were conducted separately for males and females.</p> <p>Results</p> <p>At the bivariate level, all independent variables (except for coerced sex among males) were associated with the outcome variable. Overall, 9% of adolescents reported that they had been drunk in the 12 months preceding the survey. In general, respondents who had experienced an adverse event during childhood were more likely to report drunkenness. In the multivariate analysis, only two adverse childhood events emerged as significant predictors of self-reported past-year drunkenness among males: living in a household with a problem drinker before age 10, and being physically abused before age 10. For females, exposure to family-alcoholism, experience of physical abuse, and coerced sex increased the likelihood of reporting drunkenness in the last 12 months. The association between adverse events and reported drunkenness was more pronounced for females. For both males and females there was a graded relationship between the number of adverse events experienced and the proportion reporting drunkenness.</p> <p>Conclusions</p> <p>We find an association between experience of adverse childhood events and drunkenness among adolescents in four sub-Saharan African countries. The complex impacts of adverse childhood experiences on young people's development and behavior may have an important bearing on the effectiveness of interventions geared at reducing alcohol dependence among the youth.</p

A Scalable System for Production of Functional Pancreatic Progenitors from Human Embryonic Stem Cells

Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process. We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo. In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors. This system has been optimized for the CyT49 cell line. Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing. Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50–100 fold expansion per week. Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol. Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population. Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice. By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia. In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry

Testing Developmental Pathways to Antisocial Personality Problems

This study examined the development of antisocial personality problems (APP) in young adulthood from disruptive behaviors and internalizing problems in childhood and adolescence. Parent ratings of 507 children’s (aged 6–8 years) symptoms of attention deficit hyperactivity disorder, oppositional defiant disorder, and anxiety, were linked to self-ratings of adolescents’ (aged 14–16 years) symptoms of depression, substance use, conduct problems, and somatic problems, to predict self-ratings of APP in young adulthood (age 20–22 years). The findings suggested a hierarchical development of antisocial behavior problems. Despite being positively associated with conduct problems in adolescence, neither internalizing problems nor substance use added to the prediction of APP in young adulthood from conduct problems in adolescence. The developmental pathways to APP in young adulthood did not differ by gender