Reliable Eigenspectra for New Generation Surveys

We present a novel technique to overcome the limitations of the applicability of Principal Component Analysis to typical real-life data sets, especially astronomical spectra. Our new approach addresses the issues of outliers, missing information, large number of dimensions and the vast amount of data by combining elements of robust statistics and recursive algorithms that provide improved eigensystem estimates step-by-step. We develop a generic mechanism for deriving reliable eigenspectra without manual data censoring, while utilising all the information contained in the observations. We demonstrate the power of the methodology on the attractive collection of the VIMOS VLT Deep Survey spectra that manifest most of the challenges today, and highlight the improvements over previous workarounds, as well as the scalability of our approach to collections with sizes of the Sloan Digital Sky Survey and beyond.Comment: 7 pages, 3 figures, accepted to MNRA

Interpretable Fully Convolutional Classification of Intrapapillary Capillary Loops for Real-Time Detection of Early Squamous Neoplasia

In this work, we have concentrated our efforts on the interpretability of classification results coming from a fully convolutional neural network. Motivated by the classification of oesophageal tissue for real-time detection of early squamous neoplasia, the most frequent kind of oesophageal cancer in Asia, we present a new dataset and a novel deep learning method that by means of deep supervision and a newly introduced concept, the embedded Class Activation Map (eCAM), focuses on the interpretability of results as a design constraint of a convolutional network. We present a new approach to visualise attention that aims to give some insights on those areas of the oesophageal tissue that lead a network to conclude that the images belong to a particular class and compare them with those visual features employed by clinicians to produce a clinical diagnosis. In comparison to a baseline method which does not feature deep supervision but provides attention by grafting Class Activation Maps, we improve the F1-score from 87.3% to 92.7% and provide more detailed attention maps

Covariance Matrix Adaptation Pareto Archived Evolution Strategy with Hypervolume-sorted Adaptive Grid Algorithm.

Real-world problems often involve the optimisation of multiple conflicting objectives. These problems, referred to as multi-objective optimisation problems, are especially challenging when more than three objectives are considered simultaneously. This paper proposes an algorithm to address this class of problems. The proposed algorithm is an evolutionary algorithm based on an evolution strategy framework, and more specifically, on the Covariance Matrix Adaptation Pareto Archived Evolution Strategy (CMA-PAES). A novel selection mechanism is introduced and integrated within the framework. This selection mechanism makes use of an adaptive grid to perform a local approximation of the hypervolume indicator which is then used as a selection criterion. The proposed implementation, named Covariance Matrix Adaptation Pareto Archived Evolution Strategy with Hypervolume-sorted Adaptive Grid Algorithm (CMA-PAES-HAGA), overcomes the limitation of CMA-PAES in handling more than two objectives and displays a remarkably good performance on a scalable test suite in five, seven, and ten-objective problems. The performance of CMA-PAES-HAGA has been compared with that of a competition winning meta-heuristic, representing the state-of-the-art in this sub-field of multi-objective optimisation. The proposed algorithm has been tested in a seven-objective real-world application, i.e. the design of an aircraft lateral control system. In this optimisation problem, CMA-PAES-HAGA greatly outperformed its competitors

Reduction of blood pressure, plasma cholesterol, and atherosclerosis by elevated endothelial nitric oxide.

In the vascular system, nitric oxide is generated by endothelial NO synthase (eNOS). NO has pleiotropic effects, most of which are believed to be atheroprotective. Therefore, it has been argued that patients suffering from cardiovascular disease could benefit from an increase in eNOS activity. However, increased NO production can cause oxidative damage, cell toxicity, and apoptosis and hence could be atherogenic rather than beneficial. To study the in vivo effects of increased eNOS activity, we created transgenic mice overexpressing human eNOS. Aortic blood pressure was approximately 20 mm Hg lower in the transgenic mice compared with control mice because of lower systemic vascular resistance. The effects of eNOS overexpression on diet-induced atherosclerosis were studied in apolipoprotein E-deficient mice. Elevation of eNOS activity decreased blood pressure ( approximately 20 mm Hg) and plasma levels of cholesterol (approximately 17%), resulting in a reduction in atherosclerotic lesions by 40%. We conclude that an increase in eNOS activity is beneficial and provides protection against atherosclerosis

Metastatic secondary gliosarcoma: patient series.

BACKGROUND: Gliosarcoma is a rare and highly malignant cancer of the central nervous system with the ability to metastasize. Secondary gliosarcoma, or the evolution of a spindle cell-predominant tumor after the diagnosis of a World Health Organization grade IV glioblastoma, has also been shown to metastasize. There is little information on metastatic secondary gliosarcoma. OBSERVATIONS: The authors present a series of 7 patients with previously diagnosed glioblastoma presenting with recurrent tumor and associated metastases with repeat tissue diagnosis consistent with gliosarcoma. The authors describe the clinical, imaging, and pathological characteristics in addition to carrying out a systematic review on metastases in secondary gliosarcoma. LESSONS: The present institutional series and the systematic review of the literature show that metastatic secondary gliosarcoma is a highly aggressive disease with a poor prognosis

Measurement properties of tools used to assess depression in adults with and without Autism Spectrum Conditions: a systematic review

Depression is the most commonly experienced mental health condition in adults with Autism Spectrum Conditions (ASC). However, it is unclear what tools are currently being used to assess depression in ASC, or whether tools need to be adapted for this group. This systematic review therefore aimed to identify tools used to assess depression in adults with and without ASC, and then evaluate these tools for their appropriateness and measurement properties. Medline, PsychINFO and Web of Knowledge were searched for studies of depression in: a) adults with ASC, without co-morbid intellectual disability; and b) adults from the general population without co-morbid conditions. Articles examining the measurement properties of these tools were then searched for using a methodological filter in PubMed, and the quality of the evidence was evaluated using the COSMIN checklist. Twelve articles were identified which utilised three tools to assess depression in adults with ASC, but only one article which assessed the measurement properties of one of these tools was identified and thus evaluated. Sixty-five articles were identified which utilised five tools to assess depression in general population adults, and 14 articles had assessed the measurement properties of these tools. Overall, two tools were found to be robust in their measurement properties in the general population – the Beck Depression Inventory (BDI-II), and the Patient Health Questionnaire (PHQ-9). Crucially only one study was identified from the COSMIN search, which showed weak evidence in support of the measurement properties of the BDI-II in an ASC sample. Implications for effective measurement of depression in ASC are discussed

Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma

Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of cancer-testis antigens (CTA) in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using New York esophageal squamous cell carcinoma 1 (NY-ESO-1) as a representative inducible CTA, we demonstrate in patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres that basal CTA expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing to render NY-ESO-1 and other CTA into inducible tumor antigens at single-cell resolution. Functionally, NY-ESO-1 T-cell receptor-engineered effector cell targeting of DAC-induced antigen in primary glioma cells promotes specific and polyfunctional T-cell cytokine profiles. In addition to induction of CTA, DAC concomitantly reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I. Overall, we demonstrate that DAC induces targetable tumor antigen and enhances T-cell functionality against GBM, ultimately contributing to the improvement of targeted immune therapies in glioma.SignificanceThis study dissects the tumor-intrinsic epigenetic and transcriptional mechanisms underlying enhanced T-cell functionality targeting decitabine-induced cancer-testis antigens in glioma. Our findings demonstrate concomitant induction of tumor antigens, reactivation of human endogenous retroviruses, and stimulation of interferon signaling as a mechanistic rationale to epigenetically prime human gliomas to immunotherapeutic targeting

Clinical Research in Hepatology in the COVID‐19 Pandemic and Post‐Pandemic Era: Challenges and the Need for Innovation

The severe acute respiratory syndrome coronavirus 2 pandemic has drastically altered all facets of clinical care and research. Clinical research in hepatology has had a rich tradition in several domains, including the discovery and therapeutic development for diseases such as hepatitis B and C and studying the natural history of many forms of chronic liver disease. National Institutes of Health, foundation, and industry funding have provided important opportunities to advance the academic careers of young investigators while they strived to make contributions to the field. Instantaneously, however, all nonessential research activities were halted when the pandemic started, forcing those involved in clinical research to rethink their research strategy, including a shift to coronavirus disease 2019 research while endeavoring to maintain their preexisting agenda. Strategies to maintain the integrity of ongoing studies, including patient follow-up, safety assessments, and continuation of investigational products, have included a shift to telemedicine, remote safety laboratory monitoring, and shipping of investigational products to study subjects. As a revamp of research is being planned, unique issues that face the research community include maintenance of infrastructure, funding, completion of studies in the predetermined time frame, and the need to reprogram career path timelines. Real-world databases, biomarker and long-term follow up studies, and research involving special groups (children, the homeless, and other marginalized populations) are likely to face unique challenges. The implementation of telemedicine has been dramatically accelerated and will serve as a backbone for the future of clinical research. As we move forward, innovation in clinical trial design will be essential for conducting optimized clinical research

Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG repeats in the huntingtin gene (HTT). Although HD has been shown to have a developmental component, how early during human embryogenesis the HTT-CAG expansion can cause embryonic defects remains unknown. Here, we demonstrate a specific and highly reproducible CAG length-dependent phenotypic signature in a synthetic model for human gastrulation derived from human embryonic stem cells (hESCs). Specifically, we observed a reduction in the extension of the ectodermal compartment that is associated with enhanced activin signaling. Surprisingly, rather than a cell-autonomous effect, tracking the dynamics of TGFβ signaling demonstrated that HTT-CAG expansion perturbs the spatial restriction of activin response. This is due to defects in the apicobasal polarization in the context of the polarized epithelium of the 2D gastruloid, leading to ectopic subcellular localization of TGFβ receptors. This work refines the earliest developmental window for the prodromal phase of HD to the first 2 weeks of human development, as modeled by our 2D gastruloids

Cross-translational studies in human and Drosophila identify markers of sleep loss

Inadequate sleep has become endemic, which imposes a substantial burden for public health and safety. At present, there are no objective tests to determine if an individual has gone without sleep for an extended period of time. Here we describe a novel approach that takes advantage of the evolutionary conservation of sleep to identify markers of sleep loss. To begin, we demonstrate that IL-6 is increased in rats following chronic total sleep deprivation and in humans following 30 h of waking. Discovery experiments were then conducted on saliva taken from sleep-deprived human subjects to identify candidate markers. Given the relationship between sleep and immunity, we used Human Inflammation Low Density Arrays to screen saliva for novel markers of sleep deprivation. Integrin αM (ITGAM) and Anaxin A3 (AnxA3) were significantly elevated following 30 h of sleep loss. To confirm these results, we used QPCR to evaluate ITGAM and AnxA3 in independent samples collected after 24 h of waking; both transcripts were increased. The behavior of these markers was then evaluated further using the power of Drosophila genetics as a cost-effective means to determine whether the marker is associated with vulnerability to sleep loss or other confounding factors (e.g., stress). Transcript profiling in flies indicated that the Drosophila homologues of ITGAM were not predictive of sleep loss. Thus, we examined transcript levels of additional members of the integrin family in flies. Only transcript levels of scab, the Drosophila homologue of Integrin α5 (ITGA5), were associated with vulnerability to extended waking. Since ITGA5 was not included on the Low Density Array, we returned to human samples and found that ITGA5 transcript levels were increased following sleep deprivation. These cross-translational data indicate that fly and human discovery experiments are mutually reinforcing and can be used interchangeably to identify candidate biomarkers of sleep loss