It's Time for Summer: An Analysis of Recent Policy and Funding Opportunities

Recommends ways to improve and expand summer learning programs by better coordinating federal, state and local programs, including ensuring that federal program regulations explicitly allow spending for summer programs and creating funding collaboratives

Effects of NGF, NT-3 and GDNF family members on neurite outgrowth and migration from pelvic ganglia from embryonic and newborn mice

<p>Abstract</p> <p>Background</p> <p>Pelvic ganglia are derived from the sacral neural crest and contain both sympathetic and parasympathetic neurons. Various members of the neurotrophin and GDNF families of neurotrophic factors have been shown to play important roles in the development of a variety of peripheral sympathetic and parasympathetic neurons; however, to date, the role of these factors in the development of pelvic ganglia has been limited to postnatal and older ages. We examined the effects of NGF, NT-3, GDNF, neurturin and artemin on cell migration and neurite outgrowth from explants of the pelvic ganglia from embryonic and newborn mice grown on collagen gels, and correlated the responses with the immunohistochemical localization of the relevant receptors in fixed tissue.</p> <p>Results</p> <p>Cell migration assays showed that GDNF strongly stimulated migration of tyrosine hydroxylase (TH) cells of pelvic ganglia from E11.5, E14.5 and P0 mice. Other factors also promoted TH cell migration, although to a lesser extent and only at discrete developmental stages. The cells and neurites of the pelvic ganglia were responsive to each of the GDNF family ligands – GDNF, neurturin and artemin – from E11.5 onwards. In contrast, NGF and NT-3 did not elicit a significant neurite outgrowth effect until E14.5 onwards. Artemin and NGF promoted significant outgrowth of sympathetic (TH+) neurites only, whereas neurturin affected primarily parasympathetic (TH-negative) neurite outgrowth, and GDNF and NT-3 enhanced both sympathetic and parasympathetic neurite outgrowth. In comparison, collagen gel assays using gut explants from E11.5 and E14.5 mice showed neurite outgrowth only in response to GDNF at E11.5 and to neurturin only in E14.5 mice.</p> <p>Conclusion</p> <p>Our data show that there are both age-dependent and neuron type-dependent differences in the responsiveness of embryonic and neo-natal pelvic ganglion neurons to growth factors.</p

Volume and Intensity of Locomotor Activity in International Men's Field Hockey Matches Over a 2-Year Period

The locomotor demands of international men's field hockey matches were investigated across positions (DEF, MID, FWD) and playing quarters. Volume (i.e., total values) and intensity (i.e., relative to playing time) data were collected using 10-Hz GPS/100-Hz accelerometer units from the #11 world-ranked (WR) team, during 71 matches, against 24 opponents [WR 12 ± 11 (range, 1–60)]. Mean ± SD team total distance (TD) was 4,861 ± 871 m, with 25% (1,193 ± 329 m) “high-speed running” (>14.5 km h−1) and 8% (402 ± 144 m) “sprinting” (>19.0 km h−1). Reduced TD (range, −3 to 4%) and average speed (range, −3.4 to 4.7%) occurred through subsequent quarters, vs. Q1 (p 2 m s−2; DEF, 48 ± 12; MID, 51 ± 11; FWD, 50 ± 14). Intensity variables similarly revealed positional differences (p < 0.05) but with a different pattern between positions; average speed (DEF, 115 ± 10 m min−1; MID, 132 ± 10 m min−1; FWD, 134 ± 15 m min−1), sprinting (DEF, 7 ± 3 m min−1; MID, 12 ± 4 m min−1; FWD, 14 ± 4 m min−1), and accelerations (DEF, 1.1 ± 0.3 n min−1; MID, 1.4 ± 0.2 n min−1; FWD, 1.5 ± 0.3 n min−1). Physical outputs reduced across playing quarters, despite unlimited substitutions, demonstrating the importance of optimizing physical preparation prior to international competition. Volume and intensity data highlight specific positional requirements, with forwards displaying shorter playing durations but greater high-intensity activities than defenders

Sequence analysis and characterization of active human alu subfamilies based on the 1000 genomes pilot project

© The Author(s) 2015. The goal of the 1000 Genomes Consortium is to characterize human genome structural variation (SV), including forms of copy number variations such as deletions, duplications, and insertions. Mobile element insertions, particularly Alu elements, are major contributors to genomic SV among humans. During the pilot phase of the project we experimentally validated 645 (611 intergenic and 34 exon targeted) polymorphic young Alu insertion events, absent fromthe human reference genome. Here, we report high resolution sequencing of 343 (322 unique) recent Alu insertion events, along with their respective target site duplications, precise genomic breakpoint coordinates, subfamily assignment, percent divergence, and estimated A-rich tail lengths.All the sequenced Alu lociwerederived from the Alu Y lineagewith no evidence of retrotransposition activity involving older Alu families (e.g., AluJandAluS). AluYa5 is currently themost active Alu subfamily in the human lineage, followed by AluYb8, andmany others including three newly identified subfamilieswe have termed AluYb7a3, AluYb8b1, and AluYa4a1. This report provides the structural details of 322 unique Alu variants from individual human genomes collectively adding about 100 kb of genomic variation. Many Alu subfamilies are currently active in human populations, including a surprising level of AluY retrotransposition. Human Alu subfamilies exhibit continuous evolution with potential drivers sprouting new Alu lineages

The relationship between sensory sensitivity and autistic traits in the general population.

Individuals with Autism Spectrum Disorders (ASDs) tend to have sensory processing difficulties (Baranek et al. in J Child Psychol Psychiatry 47:591–601, 2006). These difficulties include over- and under-responsiveness to sensory stimuli, and problems modulating sensory input (Ben-Sasson et al. in J Autism Dev Disorders 39:1–11, 2009). As those with ASD exist at the extreme end of a continuum of autistic traits that is also evident in the general population, we investigated the link between ASD and sensory sensitivity in the general population by administering two questionnaires online to 212 adult participants. Results showed a highly significant positive correlation (r = .775, p &#60; .001) between number of autistic traits and the frequency of sensory processing problems. These data suggest a strong link between sensory processing and autistic traits in the general population, which in turn potentially implicates sensory processing problems in social interaction difficulties

Establishing a Pragmatic Framework to Optimise Health Outcomes in Heart Failure and Multimorbidity (ARISE-HF): A Multidisciplinary Position Statement

Background Multimorbidity in heart failure (HF), defined as HF of any aetiology and multiple concurrent conditions that require active management, represents an emerging problem within the ageing HF patient population worldwide. Methods To inform this position paper, we performed: 1) an initial review of the literature identifying the ten most common conditions, other than hypertension and ischaemic heart disease, complicating the management of HF (anaemia, arrhythmias, cognitive dysfunction, depression, diabetes, musculoskeletal disorders, renal dysfunction, respiratory disease, sleep disorders and thyroid disease) and then 2) a review of the published literature describing the association between HF with each of the ten conditions. From these data we describe a clinical framework, comprising five key steps, to potentially improve historically poor health outcomes in this patient population. Results We identified five key steps (ARISE-HF) that could potentially improve clinical outcomes if applied in a systematic manner: 1) Acknowledge multimorbidity as a clinical syndrome that is associated with poor health outcomes, 2) Routinely profile (using a standardised protocol — adapted to the local health care system) all patients hospitalised with HF to determine the extent of concurrent multimorbidity, 3) Identify individualised priorities and person-centred goals based on the extent and nature of multimorbidity, 4) Support individualised, home-based, multidisciplinary, case management to supplement standard HF management, and 5) Evaluate health outcomes well beyond acute hospitalisation and encompass all-cause events and a person-centred perspective in affected individuals. Conclusions We propose ARISE-HF as a framework for improving typically poor health outcomes in those affected by multimorbidity in HF

Optimising medication data collection in a large-scale clinical trial

© 2019 Lockery et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective: Pharmaceuticals play an important role in clinical care. However, in community-based research, medication data are commonly collected as unstructured free-text, which is prohibitively expensive to code for large-scale studies. The ASPirin in Reducing Events in the Elderly (ASPREE) study developed a two-pronged framework to collect structured medication data for 19,114 individuals. ASPREE provides an opportunity to determine whether medication data can be cost-effectively collected and coded, en masse from the community using this framework. Methods: The ASPREE framework of type-to-search box with automated coding and linked free text entry was compared to traditional method of free-text only collection and post hoc coding. Reported medications were classified according to their method of collection and analysed by Anatomical Therapeutic Chemical (ATC) group. Relative cost of collecting medications was determined by calculating the time required for database set up and medication coding. Results Overall, 122,910 participant structured medication reports were entered using the type-tosearch box and 5,983 were entered as free-text. Free-text data contributed 211 unique medications not present in the type-to-search box. Spelling errors and unnecessary provision of additional information were among the top reasons why medications were reported as freetext. The cost per medication using the ASPREE method was approximately USD $0.03 compared with USD$0.20 per medication for the traditional method. Conclusion Implementation of this two-pronged framework is a cost-effective alternative to free-text only data collection in community-based research. Higher initial set-up costs of this combined method are justified by long term cost effectiveness and the scientific potential for analysis and discovery gained through collection of detailed, structured medication data

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine