Predicting gene expression in the human malaria parasite Plasmodium falciparum using histone modification, nucleosome positioning, and 3D localization features.

Empirical evidence suggests that the malaria parasite Plasmodium falciparum employs a broad range of mechanisms to regulate gene transcription throughout the organism's complex life cycle. To better understand this regulatory machinery, we assembled a rich collection of genomic and epigenomic data sets, including information about transcription factor (TF) binding motifs, patterns of covalent histone modifications, nucleosome occupancy, GC content, and global 3D genome architecture. We used these data to train machine learning models to discriminate between high-expression and low-expression genes, focusing on three distinct stages of the red blood cell phase of the Plasmodium life cycle. Our results highlight the importance of histone modifications and 3D chromatin architecture in Plasmodium transcriptional regulation and suggest that AP2 transcription factors may play a limited regulatory role, perhaps operating in conjunction with epigenetic factors

NASA's Space Launch System: A Transformative Capability for Exploration

Currently making rapid progress toward first launch in 2018, NASA's exploration-class Space Launch System (SLS) represents a game-changing new spaceflight capability, enabling mission profiles that are currently impossible. Designed to launch human deep-space missions farther into space than ever before, the initial configuration of SLS will be able to deliver more than 70 metric tons of payload to low Earth orbit (LEO), and will send NASA's new Orion crew vehicle into lunar orbit. Plans call for the rocket to evolve on its second flight, via a new upper stage, to a more powerful configuration capable of lofting 105 tons to LEO or co-manifesting additional systems with Orion on launches to the lunar vicinity. Ultimately, SLS will evolve to a configuration capable of delivering more than 130 tons to LEO. SLS is a foundational asset for NASA's Journey to Mars, and has been recognized by the International Space Exploration Coordination Group as a key element for cooperative missions beyond LEO. In order to enable human deep-space exploration, SLS provides unrivaled mass, volume, and departure energy for payloads, offering numerous benefits for a variety of other missions. For robotic science probes to the outer solar system, for example, SLS can cut transit times to less than half that of currently available vehicles, producing earlier data return, enhancing iterative exploration, and reducing mission cost and risk. In the field of astrophysics, SLS' high payload volume, in the form of payload fairings with a diameter of up to 10 meters, creates the opportunity for launch of large-aperture telescopes providing an unprecedented look at our universe, and offers the ability to conduct crewed servicing missions to observatories stationed at locations beyond low Earth orbit. At the other end of the spectrum, SLS opens access to deep space for low-cost missions in the form of smallsats. The first launch of SLS will deliver beyond LEO 13 6-unit smallsat payloads, representing multiple disciplines, including three spacecraft competitively chosen through NASA's Centennial Challenges competition. Private organizations have also identified benefits of SLS for unique public-private partnerships. This paper will give an overview of SLS' capabilities and its current status, and discuss the vehicle's potential for human exploration of deep space and other game-changing utilization opportunities

Time Course of Changes in Peripheral Blood Gene Expression During Medication Treatment for Major Depressive Disorder.

Changes in gene expression (GE) during antidepressant treatment may increase understanding of the action of antidepressant medications and serve as biomarkers of efficacy. GE changes in peripheral blood are desirable because they can be assessed easily on multiple occasions during treatment. We report here on GE changes in 68 individuals who were treated for 8 weeks with either escitalopram alone, or escitalopram followed by bupropion. GE changes were assessed after 1, 2, and 8 weeks of treatment, with significant changes observed in 156, 121, and 585 peripheral blood gene transcripts, respectively. Thirty-one transcript changes were shared between the 1- and 8-week time points (seven upregulated, 24 downregulated). Differences were detected between the escitalopram- and bupropion-treated subjects, although there was no significant association between GE changes and clinical outcome. A subset of 18 genes overlapped with those previously identified as differentially expressed in subjects with MDD compared with healthy control subjects. There was statistically significant overlap between genes differentially expressed in the current and previous studies, with 10 genes overlapping in at least two previous studies. There was no enrichment for genes overexpressed in nervous system cell types, but there was a trend toward enrichment for genes in the WNT/β-catenin pathway in the anterior thalamus; three genes in this pathway showed differential expression in the present and in three previous studies. Our dataset and other similar studies will provide an important source of information about potential biomarkers of recovery and for potential dysregulation of GE in MDD

An Implementation of the Generalized Basis Reduction Algorithm for Integer Programming

In recent years many advances have been made in solution techniques for specially structured 0–1 integer programming problems. In contrast, very little progress has been made on solving general (mixed integer) problems. This, of course, is not true when viewed from the theoretical side: Lenstra (1981) made a major breakthrough, obtaining a polynomial-time algorithm when the number of integer variables is fixed. We discuss a practical implementation of a Lenstra-like algorithm, based on the generalized basis reduction method of Lovasz and Scarf (1988). This method allows us to avoid the ellipsoidal approximations required in Lenstra’s algorithm. We report on the solution of a number of small (but difficult) examples, up to 100 integer variables. Our computer code uses the linear programming optimizer CPlex as a subroutine to solve the linear programming problems that arise

Concomitant medication use and clinical outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder.

BackgroundRepetitive Transcranial Magnetic Stimulation (rTMS) is commonly administered to Major Depressive Disorder (MDD) patients taking psychotropic medications, yet the effects on treatment outcomes remain unknown. We explored how concomitant medication use relates to clinical response to a standard course of rTMS.MethodsMedications were tabulated for 181 MDD patients who underwent a six-week rTMS treatment course. All patients received 10 Hz rTMS administered to left dorsolateral prefrontal cortex (DLPFC), with 1 Hz administered to right DLPFC in patients with inadequate response to and/or intolerance of left-sided stimulation. Primary outcomes were change in Inventory of Depressive Symptomatology Self Report (IDS-SR30) total score after 2, 4, and 6 weeks.ResultsUse of benzodiazepines was associated with less improvement at week 2, whereas use of psychostimulants was associated with greater improvement at week 2 and across 6 weeks. These effects were significant controlling for baseline variables including age, overall symptom severity, and severity of anxiety symptoms. Response rates at week 6 were lower in benzodiazepine users versus non-users (16.4% vs. 35.5%, p = 0.008), and higher in psychostimulant users versus non-users (39.2% vs. 22.0%, p = 0.02).ConclusionsConcomitant medication use may impact rTMS treatment outcome. While the differences reported here could be considered clinically significant, results were not corrected for multiple comparisons and findings should be replicated before clinicians incorporate the evidence into clinical practice. Prospective, hypothesis-based treatment studies will aid in determining causal relationships between medication treatments and outcome

An exploration of 1st and 2nd generation CPTED for end of year school leavers at Rottnest Island

The end-of-year post exam celebrations for Year 12 secondary school students presents a unique crime prevention proposition in Australia each year. Students of approximately 17 years of age congregate in a variety of locations in large groups known as ‘Leavers’. Traditionally a number of \u27rite of passage\u27 activities, fuelled by additional factors such as alcohol, drugs and peer pressure, have resulted in an increased risk of crime and anti-social behaviour. This paper examines mitigation strategies aligned with Crime Prevention Through Environmental Design (CPTED) when placed at an event. Using the annual Leavers cohort at Rottnest Island, W.A., a number of 1st and 2nd generation CPTED instruments are discussed and evaluated. The additional isolation factor of the island highlights the value of 2nd generation social cohesion and its likely impact in reducing a number of crime-related social issues. The paper concludes that increased 2nd generation CPTED treatments significantly improve crime reduction and fear of crime in temporary locations when used for mass gatherings at events

Nonsense-Mediated RNA Decay Influences Human Embryonic Stem Cell Fate.

Nonsense-mediated RNA decay (NMD) is a highly conserved pathway that selectively degrades specific subsets of RNA transcripts. Here, we provide evidence that NMD regulates early human developmental cell fate. We found that NMD factors tend to be expressed at higher levels in human pluripotent cells than in differentiated cells, raising the possibility that NMD must be downregulated to permit differentiation. Loss- and gain-of-function experiments in human embryonic stem cells (hESCs) demonstrated that, indeed, NMD downregulation is essential for efficient generation of definitive endoderm. RNA-seq analysis identified NMD target transcripts induced when NMD is suppressed in hESCs, including many encoding signaling components. This led us to test the role of TGF-β and BMP signaling, which we found NMD acts through to influence definitive endoderm versus mesoderm fate. Our results suggest that selective RNA decay is critical for specifying the developmental fate of specific human embryonic cell lineages

Controlled ecological evaluation of an implemented exercise training programme to prevent lower limb injuries in sport: Differences in implementation activity

OBJECTIVE: The public health benefits of injury prevention programmes are maximised when programmes are widely adopted and adhered to. Therefore, these programmes require appropriate implementation support. This study evaluated implementation activity outcomes associated with the implementation of FootyFirst, an exercise training injury prevention programme for community Australian football, both with (FootyFirst+S) and without (FootyFirst+NS) implementation support. METHOD: An evaluation plan based on the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) Sports Setting Matrix was applied in a controlled ecological evaluation of the implementation of FootyFirst. RE-AIM dimension-specific (range: 0-2) and total RE-AIM scores (range: 0-10) were derived by triangulating data from a number of sources (including surveys, interviews, direct observations and notes) describing FootyFirst implementation activities. The mean dimension-specific and total scores were compared for clubs in regions receiving FootyFirst+S and FootyFirst+NS, through analysis of variance. RESULTS: The mean total RE-AIM score forclubs in the FootyFirst+S regions was 2.4 times higher than for clubs in the FootyFirst+NS region (4.73 vs 1.94; 95% CI for the difference: 1.64 to 3.74). Similarly, all dimension-specific scores were significantly higher for clubs in the FootyFirst+S regions compared with clubs in the FootyFirst+NS region. In all regions, the dimension-specific scores were highest for reach and adoption, and lowest for implementation. CONCLUSION: Implementing exercise training injury prevention programmes in community sport is challenging. Delivering programme content supported by a context-specific and evidence-informed implementation plan leads to greater implementation activity, which is an important precursor to injury reductions