Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer

Transfer RNA (tRNA) activity is tightly regulated to provide a physiological protein translation, and tRNA chemical modifications control its function in a complex with ribosomes and messenger RNA5 (mRNA5). In this regard, the correct hypermodification of position G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events. Here we report that the tRNA-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional silencing in human cancer, particularly in colorectal tumors. The epigenetic loss of TYW2 induces guanosine hypomodification in phenylalanine-tRNA, an increase in -1 ribosome frameshift events, and down-regulation of transcripts by mRNA decay, such as of the key cancer gene ROBO1. Importantly, TYW2 epigenetic inactivation is linked to poor overall survival in patients with early-stage colorectal cancer, a finding that could be related to the observed acquisition of enhanced migration properties and epithelial-to-mesenchymal features in the colon cancer cells that harbor TYW2 DNA methylation-associated loss. These findings provide an illustrative example of how epigenetic changes can modify the epitranscriptome and further support a role for tRNA modifications in cancer biology

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicenter, retrospective analysis

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10 −4–0·0282; p=0·0067) and overall survival (0·080, 0·017–0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149–0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209–0·802; p=0·0063) and overall survival (0·409, 0·220–0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies

Identification of Stage-Specific Breast Markers using Quantitative Proteomics

YesMatched healthy and diseased tissues from breast cancer patients were analyzed by quantitative proteomics. By comparing proteomic profiles of fibroadenoma (benign tumors, three patients), DCIS (noninvasive cancer, three patients), and invasive ductal carcinoma (four patients), we identified protein alterations that correlated with breast cancer progression. Three 8-plex iTRAQ experiments generated an average of 826 protein identifications, of which 402 were common. After excluding those originating from blood, 59 proteins were significantly changed in tumor compared with normal tissues, with the majority associated with invasive carcinomas. Bioinformatics analysis identified relationships between proteins in this subset including roles in redox regulation, lipid transport, protein folding, and proteasomal degradation, with a substantial number increased in expression due to Myc oncogene activation. Three target proteins, cofilin-1 and p23 (increased in invasive carcinoma) and membrane copper amine oxidase 3 (decreased in invasive carcinoma), were subjected to further validation. All three were observed in phenotype-specific breast cancer cell lines, normal (nontransformed) breast cell lines, and primary breast epithelial cells by Western blotting, but only cofilin-1 and p23 were detected by multiple reaction monitoring mass spectrometry analysis. All three proteins were detected by both analytical approaches in matched tissue biopsies emulating the response observed with proteomics analysis. Tissue microarray analysis (361 patients) indicated cofilin-1 staining positively correlating with tumor grade and p23 staining with ER positive status; both therefore merit further investigation as potential biomarkers.Cyprus Research Promotion Foundation, Yorkshire Cancer Researc

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders

This recession is wearing me out! Health-related quality of life and economic downturns

Health-related quality of life refers to an individual's perceived physical and mental health and goes beyond the presence or absence of illnesses to encompass a multidimensional concept of well being. Previous research on the relationships between macroeconomic conditions and health status reveal improvements in physical health during economic downturns. However, few studies have examined whether mental health status improves or declines during tough economic times. The main objective of this paper is to provide new evidence on the impact of macroeconomic conditions on Health-related quality of life (HRQL), or functional health, by analyzing the physical and mental health summary scores of the 12-Item Short Form Health Survey (SF-12). The analysis uses panel data from Waves 1 and 2 of the National Epidemiological Survey of Alcohol and Related Conditions (NESARC) for individuals 18-59 years (in Wave 1), for a final sample of 26,313 individuals. The NESARC collected and reported data on the SF-12 health scores, including a physical health score (PCS) for overall physical functioning, and a mental health score (MCS) for mental/psychological functioning. To analyze the impact of economic downturns on HRQL, the study matches the NESARC variables with data on state-level macroeconomic conditions. To estimate the effects of macroeconomic conditions on HRQL, this paper takes advantage of the longitudinal nature of the dataset and uses individual fixed-effect models to account for both individual and state-level heterogeneity. Although it is unlikely for individual omitted variables (e.g., individuals' preferences and attitudes) to be significantly correlated with the state unemployment rate, using longitudinal data allows for the estimation of a more fully specified model. Findings consistently indicate that an increase in the average state unemployment rate worsens an individual's HRQL, suggesting that the loss of jobs and income and/or the economic distress associated with economic downturns have a detrimental effect on people's daily lives. Although the magnitudes of the changes are generally small, results show that mental health decreases more than physical health during tough economic times. With the recent worldwide economic recession causing steep drops in the U.S. Gross Domestic Product along with double-digit unemployment rates, the implications of this study are disheartening. Besides macroeconomic policies to help stimulate the economy, government officials and policymakers should also consider social policies to help people cope with the recession and buffer the potential negative health impact, both mental and physical. Moreover, policymakers should keep in mind that the mental health effects might be greater and longer lasting

Toward a New Social Contract : Taking on Distributional Tensions in Europe and Central Asia

The growing economic fissures in the societies of Europe and Central Asia between generations, between insiders and outsiders in the labor market, between rural and urban communities, and between the super-rich and everyone else, are threatening the sustainability of the social contract. The institutions that helped achieving a remarkable degree of equity and prosperity over the course of several decades now face considerable difficulties in coping with the challenges presented by these emerging forms of inequality. Public surveys reveal rising concerns over inequality of opportunity, while electoral results show a marked shift to populist parties that offer radical solutions to voters dissatisfied with the status quo. There is no single solution to relieve these tensions, and attempts to address them will vary considerably across the region. However, this publication proposes three broad policy principles: (1) promote labor market flexibility while maintaining protection for all types of labor contracts; (2) seek universality in the provision of social assistance, social insurance, and basic quality services; and (3) expand the tax base by complementing progressive labor-income taxation with taxation of capital. These principles could guide the rethinking of the social contract and fulfil European citizens’ aspirations for growth and equity

Design and Implementation of a Real Time Control System for a 2DOF Robot Based on Recurrent High Order Neural Network Using a Hardware in the Loop Architecture

In this paper, a real-time implementation of a sliding-mode control (SMC) in a hardware-in-loop architecture is presented for a robot with two degrees of freedom (2DOF). It is based on a discrete-time recurrent neural identification method, as well as the high performance obtained from the advantages of this architecture. The identification process uses a discrete-time recurrent high-order neural network (RHONN) trained with a modified extended Kalman filter (EKF) algorithm. This is a method for calculating the covariance matrices in the EKF algorithm, using a dynamic model with the associated and measurement noises, and it increases the performance of the proposed methodology. On the other hand, the decentralized discrete-time SMC technique is used to minimize the motion error. A Virtex 7 field programmable gate array (FPGA) is configured based on a hardware-in-loop real-time implementation to validate the proposed controller. A series of several experiments demonstrates the robustness of the algorithm, as well as its immunity to noise and the inherent robustness to external perturbation, as are typically found in the input reference signals of a 2DOF manipulator robot