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Deep reinforcement learning (deep RL) has achieved superior performance in complex sequential tasks by using deep neural networks as function approximators to learn directly from raw input images. However, learning directly from raw images is data inefficient. The agent must learn feature representation of complex states in addition to learning a policy. As a result, deep RL typically suffers from slow learning speeds and often requires a prohibitively large amount of training time and data to reach reasonable performance, making it inapplicable to real-world settings where data are expensive. In this work, we improve data efficiency in deep RL by addressing one of the two learning goals, feature learning. We leverage supervised learning to pre-train on a small set of non-expert human demonstrations and empirically evaluate our approach using the asynchronous advantage actor-critic algorithms in the Atari domain. Our results show significant improvements in learning speed, even when the provided demonstration is noisy and of low quality.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent a disease continuum with common genetic causes and molecular pathology. We recently identified mutations in the T-cell restricted intracellular antigen-1 (TIA1) protein as a cause of ALS +/− FTD. TIA1 is an RNA-binding protein containing a low complexity domain (LCD) that promotes the assembly of membrane-less organelles, such as stress granules (SG). Whole exome sequencing of two family members with fALS/FTD revealed a novel missense mutation in the TIA1 LCD (P362L). Subsequent screening identified five more TIA1 mutations in six additional ALS patients, but none in controls. All mutation carriers presented with weakness, behavioral abnormalities or language impairments and had a final diagnosis of ALS +/− FTD. Autopsy on five TIA1 mutation carriers showed widespread neurodegeneration with TDP-43 pathology. Round eosinophilic inclusions in lower motor neurons were a consistent feature. Cellular assays revealed abnormal SG dynamics in the presence of TIA1 mutations. In summary, missense mutations in the LCD of TIA1 are a newly recognized cause of ALS/FTD with TDP-43 pathology and strengthen the role of RNA metabolism in the pathogenesis in this disease.
The high yielding dairy cow is expected to produce a substantial milk output every year and at the same time to conceive and maintain a pregnancy to term. To fulfil lifetime production potential a balance between yield, fertility and other influential factors has to be achieved. Any inability on the part of the management system to identify and rectify problems or on the part of the cow to cope with metabolic demands invariably results in economic or welfare issues. Our studies of high yielding dairy cows have revealed that some animals are capable of normal reproductive function whilst others are classic repeat breeders (requiring 3+ services per conception) or simply fail to rebreed. It is well established that the somatotrophic axis (growth hormone and insulin-like growth factors) drives lactation in ruminants but it is also intimately involved in reproductive processes. An awareness of metabolic adaptations to lactation that impact on reproduction in dairy cows is needed for appropriate management.
The objective of our studies was to explore the metabolic profiles of high yielding dairy cows to identify factors influencing their ovarian function and fertility, hence to characterise the physiological adaptations involved. Our studies revealed different relationships between progesterone profile categories and metabolic status post partum. Delayed ovulation (DOV) or persistent corpora lutea (PCL) may be an appropriate response to a nutritional state or physiological situation and it may therefore be inaccurate to refer to these as ‘abnormal’. Whilst associated with high milk yields, not all profile categories detrimentally affected fertility parameters. Delayed ovulation postcalving (DOV1) was identified as the most prevalent abnormal profile encountered in first lactation high yielding cows. This may have occurred because the cows were not yet physically mature and unable to sustain both milk production and growth. The condition lasted long enough (71 ± 8.3 days from calving) to have a detrimental impact on their overall fertility parameters and was associated with significant physiological changes, representative of tissue mobilisation. Although the incidence of persistent luteal phases (PCL1 and PCL2) in dairy cows is increasing, this condition was not found to have any substantial detrimental effects on fertility or production parameters of the primiparous or multiparous cows in these studies. The main reproductive problems in our high yielding primiparous and multiparous cows appeared to be a failure to ovulate and conceive at the expected time or to maintain a pregnancy. These situations were associated predominantly with high milk yields and low concentrations of plasma IGF-I. A failure to ovulate appears to occur when body reserves are mobilised to maintain milk yield at the expense of reproduction and seems most likely to occur in primiparous high yielding cows or those experiencing GH-resistance (low IGF-I) due to excessive body condition loss, reduced feed intakes and factors such as stress and disease. More detailed investigations of dietary means of increasing IGF-I and optimising insulin concentrations, targeted at important reproductive times, are required in high yielding dairy cows, to aid in their management.
Ice cores provide a robust reconstruction of past climate. However, development of timescales by annual-layer counting, essential to detailed climate reconstruction and interpretation, on ice cores collected at low-accumulation sites or in regions of compressed ice, is problematic due to closely spaced layers. Ice-core analysis by laser ablation–inductively coupled plasma–mass spectrometry (LA-ICP-MS) provides sub-millimeter-scale sampling resolution (on the order of 100 μm in this study) and the low detection limits (ng L−1) necessary to measure the chemical constituents preserved in ice cores. We present a newly developed cryocell that can hold a 1 m long section of ice core, and an alternative strategy for calibration. Using ice-core samples from central Greenland, we demonstrate the repeatability of multiple ablation passes, highlight the improved sampling resolution, verify the calibration technique and identify annual layers in the chemical profile in a deep section of an ice core where annual layers have not previously been identified using chemistry. In addition, using sections of cores from the Swiss/Italian Alps we illustrate the relationship between Ca, Na and Fe and particle concentration and conductivity, and validate the LA-ICP-MS Ca profile through a direct comparison with continuous flow analysis results.
Driving anxiety can range from driving reluctance to driving phobia, and 20% of young older adults experience mild driving anxiety, whereas 6% report moderate to severe driving anxiety. However, we do not know what impact driving anxiety has on health and well-being, especially among older drivers. This is problematic because there is a growing proportion of older adult drivers and a potential for driving anxiety to result in premature driving cessation that can impact on health and mortality. The purpose of the current study was to examine the impact of driving anxiety on young older adults’ health and well-being.
Data were taken from a longitudinal study of health and aging that included 2,473 young older adults aged 55–70 years. The outcome measures were mental and physical health (SF-12) and quality of life (WHOQOL-8).
Hierarchical multiple regression analyses demonstrated that driving anxiety was associated with poorer mental health, physical health, and quality of life, over and above the effect of socio-demographic variables. Sex moderated the effect of driving anxiety on mental health and quality of life in that, as driving anxiety increased, men and women were more likely to have lower mental health and quality of life, but women were more likely to have higher scores compared to men.
Further research is needed to investigate whether driving anxiety contributes to premature driving cessation. If so, self-regulation of driving and treating driving anxiety could be important in preventing or reducing the declines in health and quality of life associated with driving cessation for older adults affected by driving anxiety.
Osteocalcin, a non-collagen bone-matrix protein, has been examined as a possible source of autochthonous 14C data in fossil bones where collagen has been seriously degraded. Extraction procedures for osteocalcin yield a well-characterized product that can be clearly distinguished from collagen. The Gla content indicates that osteocalcin is present in the fossil bones at levels similar to the range present in modern bone. However, it appears to be extracted primarily as proteolytic polypeptide fragments rather than as an intact protein. Concordant 14C determinations are obtained on osteocalcin and gelatin extracts from the same bone when the collagen is relatively well preserved. However, increasing discordances in the 14C values of the osteocalcin and gelatin fractions are associated with reduced concentrations of the gelatin extract in the bone.
Background: Aggressive surgical resections of posterior fossa tumours result in tremendous neurological sequelae as a result of damage to the brainstem. As such we sought to re-evaluate the role of aggressive surgical resections in the molecular era. Methods: 820 posterior fossa ependymoma and 787 medulloblastoma were genomically profiled and correlated with pertinent clinical variables. Results: Across 787 medulloblastoma cases, the value of extent of resection was greatly dampened when accounting for molecular subgroup. Near-total resections are equivalent to gross total resections across all four subgroups even when correcting for treatment. The prognostic value of a gross total resection as compared to a subtotal resection (>1.5cm2 residual) was restricted to Group 4 tumours (HR 1.26). Across 820 posterior fossa ependymoma PFA ependymoma was a very high risk group compared to PFB ependymoma, and a subtotal PFA ependymoma conferred an extremely poor prognosis. Gross totally resected PFB ependymoma could be cured with surgery alone. Prognostic nomograms in both medulloblastoma and ependymoma revealed molecular subgroup to be the most important predictor of outcome. Conclusions: The prognostic benefit of EOR for patients with medulloblastoma is marginal after accounting for molecular subgroup affiliation. In both molecular subgroups of posterior fossa ependymoma, gross total resection remains an important predictor of outcome.
Interest in minor planets and comets continued to grow during the triennium, sparked in part by the highly successful 1983 mission of the Infrared Astronomy Satellite (IRAS) as well as by activities associated with the return of P/Halley and the first spacecraft missions to comets. A trial of the Astrometry Network of the International Halley Watch (IHW) on P/Crommelin was quite successful. Yet with an increasing need for precise ephemerides, there continued to be concern for acquisition and timely reporting of astrometric observations of even the best known comets.
This study used a prospective longitudinal design to examine the early developmental pathways that underlie language growth in infants at high risk (n = 50) and low risk (n = 34) for autism spectrum disorder in the first 18 months of life. While motor imitation and responding to joint attention (RJA) have both been found to predict expressive language in children with autism spectrum disorder and those with typical development, the longitudinal relation between these capacities has not yet been identified. As hypothesized, results revealed that 15-month RJA mediated the association between 12-month motor imitation and 18-month expressive vocabulary, even after controlling for earlier levels of RJA and vocabulary. These results provide new information about the developmental sequencing of skills relevant to language growth that may inform future intervention efforts for children at risk for language delay or other developmental challenges.
Four accelerator mass spectrometry (AMS) facilities undertook an interlaboratory exercise designed to examine the reliability and reproducibility of radiocarbon determinations on bone by dating a sample of elk (Alces alces) from Miesenheim IV. This specimen is derived from a secure geological context directly beneath the Laacher See tephra, which provides a precise terminus ante quern of ∼11,060 yr BP (∼13,050 cal yr BP). Regrettably, the results of the intercomparison exercise were complicated by evident contamination of the bone sample by exogenous organic material. This contaminant, probably humic acid, resulted in a wide span of ages (10,010 ± 30 to 11,100 ± 45 BP). The only method that yielded an accurate determination, consistent with the age of the tephra, was Oxford's single amino acid technique, which targets hydroxyproline. An acid hydrolysis step seems to have been crucial in breaking the bonds between the bone collagen and the contaminant.
Background: There are no disease modifying agents for the treatment of Alzheimer’s disease (AD). Pathologically, AD is associated with the misfolding of two peptides: beta-amyloid (plaques) and tau (tangles). Methods: Using large-scale computer simulations, we modelled the misfolding of both beta-amyloid and tau, identifying a common conformational motif (CCM; i.e. an abnormal peptide shape), present in both beta-amyloid and tau, that promotes their misfolding. We screened a library of 11.8 million compounds against this in silico model of protein misfolding, identifying three novel molecular classes of putative therapeutics as anti-protein misfolding agents. We synthesized approximately 400 new chemical entity drug-like molecules in each of these three classes (i.e. 1200 potential drug candidates). These were comprehensively screened in a battery of five in vitro protein oligomerization assays. Selected compounds were next evaluated in the APP/PS1 doubly transgenic mouse model of AD. Results: Two new classes of molecules were identified with the ability to block the oligomerization of both beta-amyloid and tau. These compounds are drug-like with good pharmacokinetic properties and are brain-penetrant. They exhibit excellent efficacy in transgenic mouse models. Conclusion: Computer aided drug design has enabled the discovery of novel drug-like molecules able to inhibit both tau and beta-amyloid misfolding.
Euclid is the next ESA mission devoted to cosmology. It aims at observing most of the extragalactic sky, studying both gravitational lensing and clustering over ~15,000 square degrees. The mission is expected to be launched in year 2020 and to last six years. The sheer amount of data of different kinds, the variety of (un)known systematic effects and the complexity of measures require efforts both in sophisticated simulations and techniques of data analysis. We review the mission main characteristics, some aspects of the the survey and highlight some of the areas of interest to this meeting.
The future of centimetre and metre-wave astronomy lies with the Square Kilometre Array (SKA), a telescope under development by a consortium of 17 countries that will be 50 times more sensitive than any existing radio facility. Most of the key science for the SKA will be addressed through large-area imaging of the Universe at frequencies from a few hundred MHz to a few GHz. The Australian SKA Pathfinder (ASKAP) is a technology demonstrator aimed in the mid-frequency range, and achieves instantaneous wide-area imaging through the development and deployment of phased-array feed systems on parabolic reflectors. The large field-of-view makes ASKAP an unprecedented synoptic telescope that will make substantial advances in SKA key science. ASKAP will be located at the Murchison Radio Observatory in inland Western Australia, one of the most radio-quiet locations on the Earth and one of two sites selected by the international community as a potential location for the SKA. In this paper, we outline an ambitious science program for ASKAP, examining key science such as understanding the evolution, formation and population of galaxies including our own, understanding the magnetic Universe, revealing the transient radio sky and searching for gravitational waves.
Campylobacter is a common but decreasing cause of foodborne infections in the USA. Outbreaks are uncommon and have historically differed from sporadic cases in seasonality and contamination source. We reviewed reported outbreaks of campylobacteriosis. From 1997 to 2008, 262 outbreaks were reported, with 9135 illnesses, 159 hospitalizations, and three deaths. The annual mean was 16 outbreaks for 1997–2002, and 28 outbreaks for 2003–2008. Almost half occurred in warmer months. Foodborne transmission was reported in 225 (86%) outbreaks, water in 24 (9%), and animal contact in seven (3%). Dairy products were implicated in 65 (29%) foodborne outbreaks, poultry in 25 (11%), and produce in 12 (5%). Reported outbreaks increased during a period of declining overall incidence, and seasonality of outbreaks resembled that of sporadic infections. Unlike sporadic illnesses, which are primarily attributed to poultry, dairy products are the most common vehicle identified for outbreaks.
The aim of this study was to estimate the amount of childhood hepatitis B virus transmission in children born in the UK, a very low-prevalence country, that is preventable only by universal hepatitis B immunization of infants. Oral fluid specimens were collected from schoolchildren aged 7–11 years in four inner city multi-ethnic areas and tested for the presence of antibody to hepatitis B core antigen (anti-HBc). Those found positive or indeterminate were followed up with testing on serum to confirm their hepatitis B status. The overall prevalence of anti-HBc in children was low [0·26%, 95% confidence interval (CI) 0·14–0·44]. The estimated average annual incidence of hepatitis B was estimated to be 29·26/100 000 children (95% CI 16·00–49·08). The total incidence that is preventable only by a universal infant immunization programme in the UK was estimated to be between 5·00 and 12·49/100 000. The study demonstrates that the extent of horizontal childhood hepatitis B virus transmission is low in children born in the UK and suggests that schools in the UK are an uncommon setting for the transmission of the virus. Targeted hepatitis B testing and immunization of migrants from intermediate- and high-prevalence countries is likely to be a more effective measure to reduce childhood transmission than a universal infant immunization programme.
A study has been carried out on the evolution of light induced defects in protocrystalline (diluted) a-Si:H films under 1 sun illumination. A room temperature reversal is observed in the photocurrents at 25°C, which is consistent with the relaxation in the recombination currents on corresponding p-i-n solar cells. It is also consistent with the pressure of “fast” states such as have been observed after high intensity illumination. Even with the limitations imposed by the relaxation in the light induced changes on the subgap absorption measurements, the evolution of distinctly different gap states centered around 0.9 and 1.15eV from the conduction band was identified. The kinetics of the electron occupied states, kN(E), at these two energies is compared with that of the neutral dangling bond (D0) densities as measured with electron spin resonance. Because of the similarity between the preliminary results of these kinetics it has not been possible to identify which states correspond to the D0 nor to draw any reliable conclusions about the nature of the different states.