Abstract: p62/SQSTM1 is a stress-inducible cellular protein that is conserved among metazoans but not in plants and fungi. p62/SQSTM1 has multiple domains that mediate its interactions with various binding partners and it serves as a signaling hub for diverse cellular events such as amino acid sensing and the oxidative stress response. In addition, p62/SQSTM1 functions as a selective autophagy receptor for degradation of ubiqutinated substrates. In the present review, we describe the current knowledge about p62 with regard to mammalian target of rapamycin complex 1 activation, the Keap1-Nrf2 pathway and selective autophagy.

Abstract: Diabetes retinopathy (DR) is a leading cause of vision loss in middle-aged and elderly people globally. Early detection and prompt treatment allow prevention of diabetes-related visual impairment. Patients with diabetes require regular follow-up with primary care physicians to optimize their glycaemic, blood pressure and lipid control to prevent development and progression of DR and other diabetes-related complications. Other risk factors of DR include higher body mass index, puberty and pregnancy, and cataract surgery. There are weaker associations with some genetic and inflammatory markers. With the rising incidence and prevalence of diabetes and DR, public health systems in both developing and developed countries will be faced with increasing costs of implementation and maintenance of a DR screening program for people with diabetes. To reduce the impact of DR-related visual loss, it is important that all stakeholders continue to look for innovative ways of managing and preventing diabetes, and optimize cost-effective screening programs within the community.

Abstract: The impact of cancer immunotherapy on clinical cancer care is growing rapidly. However, different immunotherapies remedy distinct problems in cancer–immune system interactions. What would be the most effective therapy for an individual patient? Here, a framework is proposed for describing the different interactions between cancer and the immune system in individual cases, with the aim to focus biomarker research and to help guide treatment choice.

Abstract: Triboelectric nanogenerators have been invented as a highly efficient, cost-effective and easy scalable energy-harvesting technology for converting ambient mechanical energy into electricity. Four basic working modes have been demonstrated, each of which has different designs to accommodate the corresponding mechanical triggering conditions. A common standard is thus required to quantify the performance of the triboelectric nanogenerators so that their outputs can be compared and evaluated. Here we report figure-of-merits for defining the performance of a triboelectric nanogenerator, which is composed of a structural figure-of-merit related to the structure and a material figure of merit that is the square of the surface charge density. The structural figure-of-merit is derived and simulated to compare the triboelectric nanogenerators with different configurations. A standard method is introduced to quantify the material figure-of-merit for a general surface. This study is likely to establish the standards for developing TENGs towards practical applications and industrialization.

Abstract: Convolutional neural networks (CNNs) have achieved great successes in many computer vision problems. Unlike existing works that designed CNN architectures to improve performance on a single task of a single domain and not generalizable, we present IBN-Net, a novel convolutional architecture, which remarkably enhances a CNN’s modeling ability on one domain (e.g. Cityscapes) as well as its generalization capacity on another domain (e.g. GTA5) without finetuning. IBN-Net carefully integrates Instance Normalization (IN) and Batch Normalization (BN) as building blocks, and can be wrapped into many advanced deep networks to improve their performances. This work has three key contributions. (1) By delving into IN and BN, we disclose that IN learns features that are invariant to appearance changes, such as colors, styles, and virtuality/reality, while BN is essential for preserving content related information. (2) IBN-Net can be applied to many advanced deep architectures, such as DenseNet, ResNet, ResNeXt, and SENet, and consistently improve their performance without increasing computational cost. (3) When applying the trained networks to new domains, e.g. from GTA5 to Cityscapes, IBN-Net achieves comparable improvements as domain adaptation methods, even without using data from the target domain. With IBN-Net, we won the 1st place on the WAD 2018 Challenge Drivable Area track, with an mIoU of 86.18%.

Abstract: Sodium–glucose cotransporter (SGLT)2 inhibitors have been demonstrated to reduce cardiovascular events, particularly heart failure, in cardiovascular outcome trials. Here, we review the proposed mechanistic underpinnings of this benefit. Specifically, we focus on the role of SGLT2 inhibitors in optimising ventricular loading conditions through their effect on diuresis and natriuresis, in addition to reducing afterload and improving vascular structure and function. Further insights into the role of SGLT2 inhibition in myocardial metabolism and substrate utilisation are outlined. Finally, we discuss two emerging themes: how SGLT2 inhibitors may regulate Na+/H+ exchange at the level of the heart and kidney and how they may modulate adipokine production. The mechanistic discussion is placed in the context of completed and ongoing trials of SGLT2 inhibitors in the prevention and treatment of heart failure in individuals with and without diabetes.

Abstract: OBJECTIVE Despite the importance of diabetes for global health, the future economic consequences of the disease remain opaque. We forecast the full global costs of diabetes in adults through the year 2030 and predict the economic consequences of diabetes if global targets under the Sustainable Development Goals (SDG) and World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020 are met. RESEARCH DESIGN AND METHODS We modeled the absolute and gross domestic product (GDP)-relative economic burden of diabetes in individuals aged 20–79 years using epidemiological and demographic data, as well as recent GDP forecasts for 180 countries. We assumed three scenarios: prevalence and mortality 1 ) increased only with urbanization and population aging (baseline scenario), 2 ) increased in line with previous trends (past trends scenario), and 3 ) achieved global targets (target scenario). RESULTS The absolute global economic burden will increase from U.S. $1.3 trillion (95% CI 1.3–1.4) in 2015 to $2.2 trillion (2.2–2.3) in the baseline, $2.5 trillion (2.4–2.6) in the past trends, and $2.1 trillion (2.1–2.2) in the target scenarios by 2030. This translates to an increase in costs as a share of global GDP from 1.8% (1.7–1.9) in 2015 to a maximum of 2.2% (2.1–2.2). CONCLUSIONS The global costs of diabetes and its consequences are large and will substantially increase by 2030. Even if countries meet international targets, the global economic burden will not decrease. Policy makers need to take urgent action to prepare health and social security systems to mitigate the effects of diabetes.

Abstract: Objective The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result of clinical and genetic heterogeneity. The phenotypic spectrum of mitochondrial disease has expanded significantly since the original reports that associated classic clinical syndromes with mitochondrial DNA (mtDNA) rearrangements and point mutations. The revolution in genetic technologies has allowed interrogation of the nuclear genome in a manner that has dramatically improved the diagnosis of mitochondrial disorders. We comprehensively assessed the prevalence of all forms of adult mitochondrial disease to include pathogenic mutations in both nuclear and mtDNA. Methods Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center from 1990 to 2014. For the midyear period of 2011, we evaluated the minimum prevalence of symptomatic nuclear DNA mutations and symptomatic and asymptomatic mtDNA mutations causing mitochondrial diseases. Results The minimum prevalence rate for mtDNA mutations was 1 in 5,000 (20 per 100,000), comparable with our previously published prevalence rates. In this population, nuclear mutations were responsible for clinically overt adult mitochondrial disease in 2.9 per 100,000 adults. Interpretation Combined, our data confirm that the total prevalence of adult mitochondrial disease, including pathogenic mutations of both the mitochondrial and nuclear genomes (≈1 in 4,300), is among the commonest adult forms of inherited neurological disorders. These figures hold important implications for the evaluation of interventions, provision of evidence-based health policies, and planning of future services. Ann Neurol 2015 Ann Neurol 2015;77:753–759

Abstract: The Spin-plane double probe instrument (SDP) is part of the FIELDS instrument suite of the Magnetospheric Multiscale mission (MMS). Together with the Axial double probe instrument (ADP) and the Electron Drift Instrument (EDI), SDP will measure the 3-D electric field with an accuracy of 0.5 mV/m over the frequency range from DC to 100 kHz. SDP consists of 4 biased spherical probes extended on 60 m long wire booms 90∘ apart in the spin plane, giving a 120 m baseline for each of the two spin-plane electric field components. The mechanical and electrical design of SDP is described, together with results from ground tests and calibration of the instrument.

Abstract: Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

Abstract: HuR influences gene expression programs and hence cellular phenotypes by binding to hundreds of coding and noncoding linear RNAs. However, whether HuR binds to circular RNAs (circRNAs) and impacts on their function is unknown. Here, we have identified en masse circRNAs binding HuR in human cervical carcinoma HeLa cells. One of the most prominent HuR target circRNAs was hsa_circ_0031288, renamed CircPABPN1 as it arises from the PABPN1 pre-mRNA. Further analysis revealed that HuR did not influence CircPABPN1 abundance; interestingly, however, high levels of CircPABPN1 suppressed HuR binding to PABPN1 mRNA. Evaluation of PABPN1 mRNA polysomes indicated that PABPN1 translation was modulated positively by HuR and hence negatively by CircPABPN1. We propose that the extensive binding of CircPABPN1 to HuR prevents HuR binding to PABPN1 mRNA and lowers PABPN1 translation, providing the first example of competition between a circRNA and its cognate mRNA for an RBP that affects translation.

Abstract: The reliability and reproducibility of science are under scrutiny. However, a major cause of this lack of repeatability is not being considered: the wide sample-to-sample variability in the P value. We explain why P is fickle to discourage the ill-informed practice of interpreting analyses based predominantly on this statistic.

Abstract: OBJECTIVE To conduct a systematic review of cross-sectional and prospective human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on prediabetes and type 2 diabetes. RESEARCH DESIGN AND METHODS We searched MEDLINE and EMBASE databases through August 2015. We conducted a qualitative review of cross-sectional and prospective studies. Additionally, meta-analyses of metabolite markers, with data estimates from at least three prospective studies, and type 2 diabetes risk were conducted, and multivariable-adjusted relative risks of type 2 diabetes were calculated per study-specific SD difference in a given metabolite. RESULTS We identified 27 cross-sectional and 19 prospective publications reporting associations of metabolites and prediabetes and/or type 2 diabetes. Carbohydrate (glucose and fructose), lipid (phospholipids, sphingomyelins, and triglycerides), and amino acid (branched-chain amino acids, aromatic amino acids, glycine, and glutamine) metabolites were higher in individuals with type 2 diabetes compared with control subjects. Prospective studies provided evidence that blood concentrations of several metabolites, including hexoses, branched-chain amino acids, aromatic amino acids, phospholipids, and triglycerides, were associated with the incidence of prediabetes and type 2 diabetes. We meta-analyzed results from eight prospective studies that reported risk estimates for metabolites and type 2 diabetes, including 8,000 individuals of whom 1,940 had type 2 diabetes. We found 36% higher risk of type 2 diabetes per study-specific SD difference for isoleucine (pooled relative risk 1.36 [1.24–1.48]; I2 = 9.5%), 36% for leucine (1.36 [1.17–1.58]; I2 = 37.4%), 35% for valine (1.35 [1.19–1.53]; I2 = 45.8%), 36% for tyrosine (1.36 [1.19–1.55]; I2 = 51.6%), and 26% for phenylalanine (1.26 [1.10–1.44]; I2 = 56%). Glycine and glutamine were inversely associated with type 2 diabetes risk (0.89 [0.81–0.96] and 0.85 [0.82–0.89], respectively; both I2 = 0.0%). CONCLUSIONS In studies using high-throughput metabolomics, several blood amino acids appear to be consistently associated with the risk of developing type 2 diabetes.

Abstract: Semantic parsing aims at mapping natural language to machine interpretable meaning representations. Traditional approaches rely on high-quality lexicons, manually-built templates, and linguistic features which are either domainor representation-specific. In this paper we present a general method based on an attention-enhanced encoder-decoder model. We encode input utterances into vector representations, and generate their logical forms by conditioning the output sequences or trees on the encoding vectors. Experimental results on four datasets show that our approach performs competitively without using hand-engineered features and is easy to adapt across domains and meaning representations.

Abstract: Lithium-ion batteries are becoming increasingly important for electrifying the modern transportation system and, thus, hold the promise to enable sustainable mobility in the future. However, their large-scale application is hindered by severe safety concerns when the cells are exposed to mechanical, thermal, or electrical abuse conditions. These safety issues are intrinsically related to their superior energy density, combined with the (present) utilization of highly volatile and flammable organic-solvent-based electrolytes. Herein, state-of-the-art electrolyte systems and potential alternatives are briefly surveyed, with a particular focus on their (inherent) safety characteristics. The challenges, which so far prevent the widespread replacement of organic carbonate-based electrolytes with LiPF6 as the conducting salt, are also reviewed herein. Starting from rather "facile" electrolyte modifications by (partially) replacing the organic solvent or lithium salt and/or the addition of functional electrolyte additives, conceptually new electrolyte systems, including ionic liquids, solvent-free, and/or gelled polymer-based electrolytes, as well as solid-state electrolytes, are also considered. Indeed, the opportunities for designing new electrolytes appear to be almost infinite, which certainly complicates strict classification of such systems and a fundamental understanding of their properties. Nevertheless, these innumerable opportunities also provide a great chance of developing highly functionalized, new electrolyte systems, which may overcome the afore-mentioned safety concerns, while also offering enhanced mechanical, thermal, physicochemical, and electrochemical performance.

Abstract: Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy.

Abstract: Higher-order topological insulators1–5 are a family of recently predicted topological phases of matter that obey an extended topological bulk–boundary correspondence principle. For example, a two-dimensional (2D) second-order topological insulator does not exhibit gapless one-dimensional (1D) topological edge states, like a standard 2D topological insulator, but instead has topologically protected zero-dimensional (0D) corner states. The first prediction of a second-order topological insulator1, based on quantized quadrupole polarization, was demonstrated in classical mechanical6 and electromagnetic7,8 metamaterials. Here we experimentally realize a second-order topological insulator in an acoustic metamaterial, based on a ‘breathing’ kagome lattice9 that has zero quadrupole polarization but a non-trivial bulk topology characterized by quantized Wannier centres2,9,10. Unlike previous higher-order topological insulator realizations, the corner states depend not only on the bulk topology but also on the corner shape; we show experimentally that they exist at acute-angled corners of the kagome lattice, but not at obtuse-angled corners. This shape dependence allows corner states to act as topologically protected but reconfigurable local resonances. A second-order topological insulator in an acoustical metamaterial with a breathing kagome lattice, supporting one-dimensional edge states and zero-dimensional corner states is demonstrated.

Abstract: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain.We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28.A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).

Abstract: There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

Abstract: During the past two decades we have seen a phenomenal evolution of bispecific antibodies for therapeutic applications. The ‘zoo’ of bispecific antibodies is populated by many different species, comprising around 100 different formats, including small molecules composed solely of the antigen-binding sites of two antibodies, molecules with an IgG structure, and large complex molecules composed of different antigen-binding moieties often combined with dimerization modules. The application of sophisticated molecular design and genetic engineering has solved many of the technical problems associated with the formation of bispecific antibodies such as stability, solubility and other parameters that confer drug properties. These parameters may be summarized under the term ‘developability’. In addition, different ‘target product profiles’, i.e., desired features of the bispecific antibody to be generated, mandates the need for access to a diverse panel of formats. These may vary in size, arrangement, vale...

Abstract: Objective A systematic review of factors that might be associated with, or influence, clinical recovery from sport-related concussion. Clinical recovery was defined functionally as a return to normal activities, including school and sports, following injury. Design Systematic review. Data sources PubMed, PsycINFO, MEDLINE, CINAHL, Cochrane Library, EMBASE, SPORTDiscus, Scopus and Web of Science. Eligibility criteria for selecting studies Studies published by June of 2016 that addressed clinical recovery from concussion. Results A total of 7617 articles were identified using the search strategy, and 101 articles were included. There are major methodological differences across the studies. Many different clinical outcomes were measured, such as symptoms, cognition, balance, return to school and return to sports, although symptom outcomes were the most frequently measured. The most consistent predictor of slower recovery from concussion is the severity of a person’s acute and subacute symptoms. The development of subacute problems with headaches or depression is likely a risk factor for persistent symptoms lasting greater than a month. Those with a preinjury history of mental health problems appear to be at greater risk for having persistent symptoms. Those with attention deficit hyperactivity disorder (ADHD) or learning disabilities do not appear to be at substantially greater risk. There is some evidence that the teenage years, particularly high school, might be the most vulnerable time period for having persistent symptoms—with greater risk for girls than boys. Conclusion The literature on clinical recovery from sport-related concussion has grown dramatically, is mostly mixed, but some factors have emerged as being related to outcome.

Abstract: The author’s presentation of multilevel Monte Carlo path simulation at the MCQMC 2006 conference stimulated a lot of research into multilevel Monte Carlo methods. This paper reviews the progress since then, emphasising the simplicity, flexibility and generality of the multilevel Monte Carlo approach. It also offers a few original ideas and suggests areas for future research.

Abstract: A widely used term, “photocatalysis”, generally addresses photocatalytic (energetically downhill) and photosynthetic (energetically uphill) reactions and refers to the use of photonic energy as a driving force for chemical transformations, i.e., electron reorganization to form/break chemical bonds. Although there are many such important reactions, this contribution focuses on the fundamental aspects of photocatalytic water splitting into hydrogen and oxygen by using light from the solar spectrum, which is one of the most investigated photosynthetic reactions. Photocatalytic water splitting using solar energy is considered to be artificial photosynthesis that produces a solar fuel because the reaction mimics nature’s photosynthesis not only in its redox reaction type but also in its thermodynamics (water splitting: 1.23 eV vs glucose formation: 1.24 eV). To achieve efficient photocatalytic water splitting, all of the parameters, though involved at different time scales and spatial resolutions, should be op...

Abstract: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ∼50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRH-synthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ∼10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

Abstract: In recent years deep reinforcement learning (RL) systems have attained superhuman performance in a number of challenging task domains. However, a major limitation of such applications is their demand for massive amounts of training data. A critical present objective is thus to develop deep RL methods that can adapt rapidly to new tasks. In the present work we introduce a novel approach to this challenge, which we refer to as deep meta-reinforcement learning. Previous work has shown that recurrent networks can support meta-learning in a fully supervised context. We extend this approach to the RL setting. What emerges is a system that is trained using one RL algorithm, but whose recurrent dynamics implement a second, quite separate RL procedure. This second, learned RL algorithm can differ from the original one in arbitrary ways. Importantly, because it is learned, it is configured to exploit structure in the training domain. We unpack these points in a series of seven proof-of-concept experiments, each of which examines a key aspect of deep meta-RL. We consider prospects for extending and scaling up the approach, and also point out some potentially important implications for neuroscience.

Abstract: Globally, ovarian cancer is the seventh most common cancer in women and the eighth most common cause of cancer death, with five-year survival rates below 45%. Although age-standardised rates are stable or falling in most high-income countries, they are rising in many low and middle income countries. Furthermore, with increasing life-expectancy, the number of cases diagnosed each year is increasing. To control ovarian cancer we need to understand the causes. This will allow better prediction of those at greatest risk for whom screening might be appropriate, while identification of potentially modifable causes provides an opportunity for intervention to reduce rates. In this paper we will summarise the current state of knowledge regarding the known and possible causes of epithelial ovarian cancer and discuss some of the main theories of ovarian carcinogenesis. We will also briefly review the relationship between lifestyle and survival after a diagnosis of ovarian cancer.