Semi-Supervised Learning with Graphs: Covariance Based Superpixels for Hyperspectral Image Classification

In this paper, we present a graph-based semi-supervised framework for hyperspectral image classification. We first introduce a novel superpixel algorithm based on the spectral covariance matrix representation of pixels to provide a better representation of our data. We then construct a superpixel graph, based on carefully considered feature vectors, before performing classification. We demonstrate, through a set of experimental results using two benchmarking datasets, that our approach outperforms three state-of-the-art classification frameworks, especially when an extremely small amount of labelled data is used.Case Studentship with the NP

A General Framework for Interrogation of mRNA Stability Programs Identifies RNA-Binding Proteins that Govern Cancer Transcriptomes

Widespread remodeling of the transcriptome is a signature of cancer; however, little is known about the post-transcriptional regulatory factors, including RNA-binding proteins (RBPs) that regulate mRNA stability, and the extent to which RBPs contribute to cancer-associated pathways. Here, by modeling the global change in gene expression based on the effect of sequence-specific RBPs on mRNA stability, we show that RBP-mediated stability programs are recurrently deregulated in cancerous tissues. Particularly, we uncovered several RBPs that contribute to the abnormal transcriptome of renal cell carcinoma (RCC), including PCBP2, ESRP2, and MBNL2. Modulation of these proteins in cancer cell lines alters the expression of pathways that are central to the disease and highlights RBPs as driving master regulators of RCC transcriptome. This study presents a framework for the screening of RBP activities based on computational modeling of mRNA stability programs in cancer and highlights the role of post-transcriptional gene dysregulation in RCC. Perron et al. develop a computational approach that models the functional activity of RBPs in individual cancer samples by monitoring their associated RNA stability programs. Applying this method to renal cell carcinoma transcriptomes, the authors identify RBPs that enhance cancer-associated pathways including hypoxia and cell cycle

Amino Terminal Domains of the NMDA Receptor Are Organized as Local Heterodimers

The N-methyl-D-aspartate (NMDA) receptor, an obligate heterotetrameric assembly organized as a dimer of dimers, is typically composed of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits. Despite the crucial role that the NMDA receptor plays in the nervous system, the specific arrangement of subunits within the dimer-of-dimer assemblage is not conclusively known. Here we studied the organization of the amino terminal domain (ATD) of the rat GluN1/GluN2A and GluN1/GluN2B NMDA receptors by cysteine-directed, disulfide bond-mediated cross-linking. We found that GluN1 ATDs and GluN2 ATDs spontaneously formed disulfide bond-mediated dimers after introducing cysteines into the L1 interface of GluN2A or GluN2B ATD. The formation of dimer could be prevented by knocking out endogenous cysteines located near the L1 interface of GluN1. These results indicate that GluN1 and GluN2 ATDs form local heterodimers through the interactions in the L1-L1 interface and further demonstrate a dimer-of-heterodimer arrangement in GluN1/GluN2A and GluN1/GluN2B NMDA receptors

Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice

Background & Aims Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. Methods We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. Results In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. Conclusions In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer

Suppression of Ribosomal Function Triggers Innate Immune Signaling through Activation of the NLRP3 Inflammasome

Some inflammatory stimuli trigger activation of the NLRP3 inflammasome by inducing efflux of cellular potassium. Loss of cellular potassium is known to potently suppress protein synthesis, leading us to test whether the inhibition of protein synthesis itself serves as an activating signal for the NLRP3 inflammasome. Murine bone marrow-derived macrophages, either primed by LPS or unprimed, were exposed to a panel of inhibitors of ribosomal function: ricin, cycloheximide, puromycin, pactamycin, and anisomycin. Macrophages were also exposed to nigericin, ATP, monosodium urate (MSU), and poly I:C. Synthesis of pro-IL-ß and release of IL-1ß from cells in response to these agents was detected by immunoblotting and ELISA. Release of intracellular potassium was measured by mass spectrometry. Inhibition of translation by each of the tested translation inhibitors led to processing of IL-1ß, which was released from cells. Processing and release of IL-1ß was reduced or absent from cells deficient in NLRP3, ASC, or caspase-1, demonstrating the role of the NLRP3 inflammasome. Despite the inability of these inhibitors to trigger efflux of intracellular potassium, the addition of high extracellular potassium suppressed activation of the NLRP3 inflammasome. MSU and double-stranded RNA, which are known to activate the NLRP3 inflammasome, also substantially inhibited protein translation, supporting a close association between inhibition of translation and inflammasome activation. These data demonstrate that translational inhibition itself constitutes a heretofore-unrecognized mechanism underlying IL-1ß dependent inflammatory signaling and that other physical, chemical, or pathogen-associated agents that impair translation may lead to IL-1ß-dependent inflammation through activation of the NLRP3 inflammasome. For agents that inhibit translation through decreased cellular potassium, the application of high extracellular potassium restores protein translation and suppresses activation of the NLRP inflammasome. For agents that inhibit translation through mechanisms that do not involve loss of potassium, high extracellular potassium suppresses IL-1ß processing through a mechanism that remains undefined

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Patterns of tobacco use, quit attempts, readiness to quit and self-efficacy among smokers with anxiety or depression: Findings among six countries of the EUREST-PLUS ITC Europe Surveys

Introduction: We compared smoking behaviors, past quit attempts, readiness to quit and beliefs about quitting among current cigarette smokers with probable anxiety or depression (PAD) to those without PAD, from six European Union (EU) Member States (MS). Methods: A nationally representative cross-sectional sample of 6011 adult cigarette smokers from six EU MS (Germany, Greece, Hungary, Poland, Romania, Spain) was randomly selected through a multistage cluster sampling design in 2016. Respondents were classified as having PAD based on self-reported current diagnosis or treatment for anxiety or depression, or a positive screen for major depression, according to a validated two-item instrument. Sociodemographic characteristics, patterns of tobacco use, past quitting, readiness to quit, self-efficacy and beliefs about quitting were assessed for patients with and without PAD. Logistic regression was used to examine predictors of PAD. All analyses were conducted using the complex samples package of SPSS. Results: Among smokers sampled, 21.0% (95% CI: 19.3–22.9) were identified as having PAD. Logistic regression analyses controlling for socioeconomic variables and cigarettes smoked per day found smokers with PAD were more likely to have made an attempt to quit smoking in the past (AOR=1.48; 95% CI: 1.25–1.74), made a quit attempt in the last 12 months (AOR=1.75; 95% CI: 1.45–2.11), and report lower self-efficacy with quitting (AOR=1.83; 95% CI: 1.44–2.32) compared to smokers without PAD. Additionally, it was found that individuals with PAD were more likely to report having received advice to quit from a doctor or health professional and having used quitline support as part of their last quit attempt. Conclusions: Smokers with PAD report a greater interest in quitting in the future and more frequent failed quit attempts than smokers without PAD; however, the high rates of untreated anxiety or depression, nicotine dependence, low confidence in the ability to quit, infrequent use of cessation methods, as well as socioeconomic factors may make quitting difficult

Social norms towards smoking and electronic cigarettes among adult smokers in seven European Countries: Findings from the EUREST-PLUS ITC Europe Surveys

Introduction: This study explores whether current smokers’ social norms towards smoking and electronic cigarettes (e-cigarettes) vary across seven European countries alongside smoking and e-cigarette prevalence rates. At the time of surveying, England had the lowest current smoking prevalence and Greece the highest. Hungary, Romania and Spain had the lowest prevalence of any e-cigarette use and England the highest. // Methods: Respondents were adult (≥18 years) current smokers from the 2016 EUREST-PLUS ITC (Romania, Spain, Hungary, Poland, Greece, Germany) and ITC 4CV England Surveys (N=7779). Using logistic regression, associations between country and (a) smoking norms and (b) e-cigarette norms were assessed, adjusting for age, sex, income, education, smoking status, heaviness of smoking, and e-cigarette status. // Results: Compared with England, smoking norms were higher in all countries: reporting that at least three of five closest friends smoke (19% vs 65–84% [AOR=6.9–24.0; Hungary–Greece]), perceiving that people important to them approve of smoking (8% vs 14–57% [1.9–51.1; Spain–Hungary]), perceiving that the public approves of smoking (5% vs 6–37% [1.7–15.8; Spain–Hungary]), disagreeing that smokers are marginalised (9% vs 16–50% [2.3–12.3; Poland–Greece]) except in Hungary. Compared with England: reporting that at least one of five closest friends uses e-cigarettes was higher in Poland (28% vs 36% [2.7]) but lower in Spain and Romania (28% vs 6–14% [0.3–0.6]), perceiving that the public approves of e-cigarettes was higher in Poland, Hungary and Greece (32% vs 36–40% [1.5–1.6]) but lower in Spain and Romania in unadjusted analyses only (32% vs 24–26%), reporting seeing e-cigarette use in public at least some days was lower in all countries (81% vs 12–55% [0.1–0.4]; Spain–Greece). // Conclusions: Smokers from England had the least pro-smoking norms. Smokers from Spain had the least pro-e-cigarette norms. Friend smoking and disagreeing that smokers are marginalised broadly aligned with country-level current smoking rates. Seeing e-cigarette use in public broadly aligned with countrylevel any e-cigarette use. Generally, no other norms aligned with product prevalence