Diagnostic accuracy of TB-LAMP for pulmonary tuberculosis: a systematic review and meta-analysis.

BACKGROUND:The need for a rapid, molecular test to diagnose tuberculosis (TB) has prompted exploration of TB-LAMP (Eiken; Tokyo, Japan) for use in resource-limited settings. We conducted a systematic review to assess the accuracy of TB-LAMP as a diagnostic test for pulmonary TB. METHODS:We analyzed individual-level data for eligible patients from all studies of TB-LAMP conducted between Jan 2012 and October 2015 to compare the diagnostic accuracy of TB-LAMP with that of smear microscopy and Xpert MTB/RIF® using 3 reference standards of varying stringency. Pooled sensitivity and specificity and pooled differences in sensitivity and specificity were estimated using random effects meta-analysis. Study quality was evaluated using QUADAS-2. RESULTS:Four thousand seven hundred sixty individuals across 13 studies met eligibility criteria. Methodological quality was judged to be low for all studies. TB-LAMP had higher sensitivity than sputum smear microscopy (pooled sensitivity difference + 13·2, 95% CI 4·5-21·9%) and similar sensitivity to Xpert MTB/RIF (pooled sensitivity difference - 2·5, 95% CI -8·0 to + 2·9) using the most stringent reference standard available. Specificity of TB-LAMP was similar to that of sputum smear microscopy (pooled specificity difference - 1·8, 95% CI -3·8 to + 0·2) and Xpert MTB/RIF (pooled specificity difference 0·5, 95% CI -0·9 to + 1·8). CONCLUSIONS:From the perspective of diagnostic accuracy, TB-LAMP may be considered as an alternative test for sputum smear microscopy. Additional factors such as cost, feasibility, and acceptability in settings that continue to rely on sputum smear microscopy should be considered when deciding to adopt this technology. Xpert MTB/RIF should continue to be preferred in settings where resource and infrastructure requirements are adequate and where HIV co-infection or drug-resistance is of concern

Trisubstituted pyrazolopyrimidines as novel angiogenesis inhibitors.

Current inhibitors of angiogenesis comprise either therapeutic antibodies (e.g. bevacicumab binding to VEGF-A) or small molecular inhibitors of receptor tyrosin kinases like e.g. sunitinib, which inhibits PDGFR and VEGFR. We have recently identified cyclin-dependent kinase 5 (Cdk5) as novel alternative and pharmacologically accessible target in the context of angiogenesis. In the present work we demonstrate that trisubstituted pyrazolo[4,3-d]pyrimidines constitute a novel class of compounds which potently inhibit angiogenesis. All seven tested compounds inhibited endothelial cell proliferation with IC(50) values between 1 and 18 µM. Interestingly, this seems not to be due to cytotoxicity, since none of them showed acute cytotoxic effects on endothelial cells at a concentration of 10 µM,. The three most potent compounds (LGR1404, LGR1406 and LGR1407) also inhibited cell migration (by 27, 51 and 31%, resp.), chemotaxis (by 50, 70 and 60% in accumulative distance, resp.), and tube formation (by 25, 60 and 30% of total tube length, resp.) at the non-toxic concentration of 10 µM. Furthermore, angiogenesis was reduced in vivo in the CAM assay by these three compounds. A kinase selectivity profiling revealed that the compounds prevalently inhibit Cdk2, Cdk5 and Cdk9. The phenotype of the migrating cells (reduced formation of lamellipodia, loss of Rac-1 translocation to the membrane) resembles the previously described effects of silencing of Cdk5 in endothelial cells. We conclude that especially LGR1406 and LGR1407 are highly attractive anti-angiogenic compounds, whose effects seem to largely depend on their Cdk5 inhibiting properties

Changes in the gut microbiota of mice orally exposed to methylimidazolium ionic liquids

Ionic liquids are salts used in a variety of industrial processes, and being relatively non-volatile, are proposed as environmentally-friendly replacements for existing volatile liquids. Methylimidazolium ionic liquids resist complete degradation in the environment, likely because the imidazolium moiety does not exist naturally in biological systems. However, there is limited data available regarding their mammalian effects in vivo. This study aimed to examine the effects of exposing mice separately to 2 different methylimidazolium ionic liquids (BMI and M8OI) through their addition to drinking water. Potential effects on key target organs-the liver and kidney-were examined, as well as the gut microbiome. Adult male mice were exposed to drinking water containing ionic liquids at a concentration of 440 mg/L for 18 weeks prior to examination of tissues, serum, urine and the gut microbiome. Histopathology was performed on tissues and clinical chemistry on serum for biomarkers of hepatic and renal injury. Bacterial DNA was isolated from the gut contents and subjected to targeted 16S rRNA sequencing. Mild hepatic and renal effects were limited to glycogen depletion and mild degenerative changes respectively. No hepatic or renal adverse effects were observed. In contrast, ionic liquid exposure altered gut microbial composition but not overall alpha diversity. Proportional abundance of Lachnospiraceae, Clostridia and Coriobacteriaceae spp. were significantly greater in ionic liquid-exposed mice, as were predicted KEGG functional pathways associated with xenobiotic and amino acid metabolism. Exposure to ionic liquids via drinking water therefore resulted in marked changes in the gut microbiome in mice prior to any overt pathological effects in target organs. Ionic liquids may be an emerging risk to health through their potential effects on the gut microbiome, which is implicated in the causes and/or severity of an array of chronic disease in humans

The DAG1 transcription factor negatively regulates the seed-to-seedling transition in Arabidopsis acting on ABA and GA levels

BACKGROUND: In seeds, the transition from dormancy to germination is regulated by abscisic acid (ABA) and gibberellins (GAs), and involves chromatin remodelling. Particularly, the repressive mark H3K27 trimethylation (H3K27me3) has been shown to target many master regulators of this transition. DAG1 (DOF AFFECTING GERMINATION1), is a negative regulator of seed germination in Arabidopsis, and directly represses the GA biosynthetic gene GA3ox1 (gibberellin 3-β-dioxygenase 1). We set to investigate the role of DAG1 in seed dormancy and maturation with respect to epigenetic and hormonal control. RESULTS: We show that DAG1 expression is controlled at the epigenetic level through the H3K27me3 mark during the seed-to-seedling transition, and that DAG1 directly represses also the ABA catabolic gene CYP707A2; consistently, the ABA level is lower while the GA level is higher in dag1 mutant seeds. Furthermore, both DAG1 expression and protein stability are controlled by GAs. CONCLUSIONS: Our results point to DAG1 as a key player in the control of the developmental switch between seed dormancy and germination

Deep reinforcement learning in World-Earth system models to discover sustainable management strategies

Increasingly complex, non-linear World-Earth system models are used for describing the dynamics of the biophysical Earth system and the socio-economic and socio-cultural World of human societies and their interactions. Identifying pathways towards a sustainable future in these models for informing policy makers and the wider public, e.g. pathways leading to a robust mitigation of dangerous anthropogenic climate change, is a challenging and widely investigated task in the field of climate research and broader Earth system science. This problem is particularly difficult when constraints on avoiding transgressions of planetary boundaries and social foundations need to be taken into account. In this work, we propose to combine recently developed machine learning techniques, namely deep reinforcement learning (DRL), with classical analysis of trajectories in the World-Earth system. Based on the concept of the agent-environment interface, we develop an agent that is generally able to act and learn in variable manageable environment models of the Earth system. We demonstrate the potential of our framework by applying DRL algorithms to two stylized World-Earth system models. Conceptually, we explore thereby the feasibility of finding novel global governance policies leading into a safe and just operating space constrained by certain planetary and socio-economic boundaries. The artificially intelligent agent learns that the timing of a specific mix of taxing carbon emissions and subsidies on renewables is of crucial relevance for finding World-Earth system trajectories that are sustainable on the long term.Comment: 16 pages, 8 figure

Physically Constrained Generative Adversarial Networks for Improving Precipitation Fields from Earth System Models

Precipitation results from complex processes across many scales, making its accurate simulation in Earth system models (ESMs) challenging. Existing post-processing methods can improve ESM simulations locally, but cannot correct errors in modelled spatial patterns. Here we propose a framework based on physically constrained generative adversarial networks (GANs) to improve local distributions and spatial structure simultaneously. We apply our approach to the computationally efficient ESM CM2Mc-LPJmL. Our method outperforms existing ones in correcting local distributions, and leads to strongly improved spatial patterns especially regarding the intermittency of daily precipitation. Notably, a double-peaked Intertropical Convergence Zone, a common problem in ESMs, is removed. Enforcing a physical constraint to preserve global precipitation sums, the GAN can generalize to future climate scenarios unseen during training. Feature attribution shows that the GAN identifies regions where the ESM exhibits strong biases. Our method constitutes a general framework for correcting ESM variables and enables realistic simulations at a fraction of the computational costs

The role of cytokinins in clubroot disease

Clubroot (Plasmodiophora brassicae) is a pathogen of Brassicaceae that causes significant reductions in yield as a consequence of gall formation in the root and hypocotyl of infected plants. The pathogen hijacks host vascular cambium development, and cytokinins are implicated in this process. This paper uses transcriptomics and metabolomics to investigate changes in cytokinin metabolism during gall formation of clubroot-infected Arabidopsis thaliana. RNASeq analysis of infected tissue showed that host cytokinin metabolism was strongly down-regulated both at the onset and late stages of gall formation. Expression of host genes associated with cytokinin biosynthesis, signalling, degradation and conjugation was strongly repressed. Analysis of cytokinin precursors, active components and conjugates by microanalytical techniques was consistent with these transcriptional responses. Two isopentenyltransferase genes associated with cytokinin biosynthesis are present in the P. brassicae genome and are expressed throughout gall formation. The impact of pathogen-derived cytokinins on the total cytokinin content of infected tissue and host gene expression was minimal in wild type plants. However, infection of ipt1;3;5;7 mutants that are severely restricted in their ability to synthesise active cytokinins led to an increase in expression of host cytokinin-responsive genes. We interpret these results as indicating that P. brassicae can synthesise small amounts of cytokinin, but this has little impact on the host plant as the ipt1;3;5;7 phenotype is not rescued. Intriguingly, plasmodial development was slowed and spore viability reduced in these mutants indicating a potential role for cytokinins in plasmodial development