An investigation of the color reproduction accuracy of two halftoning algorithms for dot matrix systems

The recent popularity of dot matrix printing technologies has renewed interest in developing color halftoning techniques for these systems. A color reproduction scheme based on colorimetric principles would provide accurate color rendition, and can be configured to different hardware implementations. Additionally, where there are demands for multiple copies, color reproduction accuracy is assured to the nth generation. A binary dot matrix halftoning algorithm previously used for black-and-white reproduction (error diffusion) and a new algorithm to be described (EZ method) were investigated in terms of their color reproduction capabilities, with the objective to achieve colorimetric color reproduction. The error diffusion technique made poor system color selections when used in XYZ tristimulus space. As a result, large hue, saturation, and ΔE*ab errors were experienced. The EZ Color Algorithm provided better color accuracy, with an average color difference of less than three for a 4x4 cell size. A uniform color space, such as CIELAB, is considered a minimum requirement in order for the error diffusion algorithm to provide colorimetric color reproduction. Hue, saturation, and ΔE*ab errors were minimized when this color space was used. The EZ Color Algorithm provides several important features including the incorporation of the black colorant explicity in the color formulation, selection of system colors prior to quantizing, and quantization of system color areas instead of reflectance values

Leveraging genomic annotations and pleiotropic enrichment for improved replication rates in schizophrenia GWAS

Most of the genetic architecture of schizophrenia (SCZ) has not yet been identified. Here, we apply a novel statistical algorithm called Covariate-Modulated Mixture Modeling (CM3), which incorporates auxiliary information (heterozygosity, total linkage disequilibrium, genomic annotations, pleiotropy) for each single nucleotide polymorphism (SNP) to enable more accurate estimation of replication probabilities, conditional on the observed test statistic (“z-score”) of the SNP. We use a multiple logistic regression on z-scores to combine information from auxiliary information to derive a “relative enrichment score” for each SNP. For each stratum of these relative enrichment scores, we obtain nonparametric estimates of posterior expected test statistics and replication probabilities as a function of discovery z-scores, using a resampling-based approach that repeatedly and randomly partitions meta-analysis sub-studies into training and replication samples. We fit a scale mixture of two Gaussians model to each stratum, obtaining parameter estimates that minimize the sum of squared differences of the scale-mixture model with the stratified nonparametric estimates. We apply this approach to the recent genome-wide association study (GWAS) of SCZ (n = 82,315), obtaining a good fit between the model-based and observed effect sizes and replication probabilities. We observed that SNPs with low enrichment scores replicate with a lower probability than SNPs with high enrichment scores even when both they are genome-wide significant (p < 5x10-8). There were 693 and 219 independent loci with model-based replication rates ≥80% and ≥90%, respectively. Compared to analyses not incorporating relative enrichment scores, CM3 increased out-of-sample yield for SNPs that replicate at a given rate. This demonstrates that replication probabilities can be more accurately estimated using prior enrichment information with CM3

MESSENGER at Mercury: Early Orbital Operations

The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft, launched in August 2004 under NASA's Discovery Program, was inserted into orbit about the planet Mercury in March 2011. MESSENGER's three flybys of Mercury in 2008-2009 marked the first spacecraft visits to the innermost planet since the Mariner 10 flybys in 1974-1975. The unprecedented orbital operations are yielding new insights into the nature and evolution of Mercury. The scientific questions that frame the MESSENGER mission led to the mission measurement objectives to be achieved by the seven payload instruments and the radio science experiment. Interweaving the full set of required orbital observations in a manner that maximizes the opportunity to satisfy all mission objectives and yet meet stringent spacecraft pointing and thermal constraints was a complex optimization problem that was solved with a software tool that simulates science observations and tracks progress toward meeting each objective. The final orbital observation plan, the outcome of that optimization process, meets all mission objectives. MESSENGER's Mercury Dual Imaging System is acquiring a global monochromatic image mosaic at better than 90% coverage and at least 250 m average resolution, a global color image mosaic at better than 90% coverage and at least 1 km average resolution, and global stereo imaging at better than 80% coverage and at least 250 m average resolution. Higher-resolution images are also being acquired of targeted areas. The elemental remote sensing instruments, including the Gamma-Ray and Neutron Spectrometer and the X-Ray Spectrometer, are being operated nearly continuously and will establish the average surface abundances of most major elements. The Visible and Infrared Spectrograph channel of MESSENGER's Mercury Atmospheric and Surface Composition Spectrometer is acquiring a global map of spectral reflectance from 300 to 1450 nm wavelength at a range of incidence and emission angles. Targeted areas have been selected for spectral coverage into the ultraviolet with the Ultraviolet and Visible Spectrometer (UVVS). MESSENGER's Mercury Laser Altimeter is acquiring topographic profiles when the slant range to Mercury's surface is less than 1800 km, encompassing latitudes from 20 deg. S to the north pole. Topography over the remainder of the southern hemisphere will be derived from stereo imaging, radio occultations, and limb profiles. MESSENGER's radio science experiment is determining Mercury's gravity field from Doppler signals acquired during frequent downlinks. MESSENGER's Magnetometer is measuring the vector magnetic field both within Mercury's magnetosphere and in Mercury's solar wind environment at an instrument sampling rate of up to 20 samples/s. The UVVS is determining the three-dimensional, time-dependent distribution of Mercury's exospheric neutral and ionic species via their emission lines. During each spacecraft orbit, the Energetic Particle Spectrometer measures energetic electrons and ions, and the Fast Imaging Plasma Spectrometer measures the energies and mass per charge of thermal plasma components, both within Mercury's magnetosphere and in Mercury's solar-wind environment. The primary mission observation sequence will continue for one Earth year, until March 2012. An extended mission, currently under discussion with NASA, would add a second year of orbital observations targeting a set of focused follow-on questions that build on observations to date and take advantage of the more active Sun expected during 2012-2013. MESSENGER's total primary mission cost, projected at $446 M in real-year dollars, is comparable to that of Mariner 10 after adjustment for inflation

Red Waters of Myrionecta rubra are Biogeochemical Hotspots for the Columbia River Estuary with Impacts on Primary/Secondary Productions and Nutrient Cycles

The localized impact of blooms of the mixotrophic ciliate Myrionecta rubra in the Columbia River estuary during 2007-2010 was evaluated with biogeochemical, light microscopy, physiological, and molecular data. M. rubra affected surrounding estuarine nutrient cycles, as indicated by high and low concentrations of organic nutrients and inorganic nitrogen, respectively, associated with red waters. M. rubra blooms also altered the energy transfer pattern in patches of the estuarine water that contain the ciliate by creating areas characterized by high primary production and elevated levels of fresh autochthonous particulate organic matter, therefore shifting the trophic status in emergent red water areas of the estuary from net heterotrophy towards autotrophy. The pelagic estuarine bacterial community structure was unaffected by M. rubra abundance, but red waters of the ciliate do offer a possible link between autotrophic and heterotrophic processes since they were associated with elevated dissolved organic matter and showed a tendency for enhanced microbial secondary production. Taken together, these findings suggest that M. rubra red waters are biogeochemical hotspots of the Columbia River estuary.Keywords: Myrionecta rubra, Biogeochemical cycles, Red waters, Mesodinium rubrum, Columbia River estuar

Toward understanding and exploiting tumor heterogeneity

The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here

Novel vaccine safety issues and areas that would benefit from further research.

Vaccine licensure requires a very high safety standard and vaccines routinely used are very safe. Vaccine safety monitoring prelicensure and postlicensure enables continual assessment to ensure the benefits outweigh the risks and, when safety problems arise, they are quickly identified, characterised and further problems prevented when possible. We review five vaccine safety case studies: (1) dengue vaccine and enhanced dengue disease, (2) pandemic influenza vaccine and narcolepsy, (3) rotavirus vaccine and intussusception, (4) human papillomavirus vaccine and postural orthostatic tachycardia syndrome and complex regional pain syndrome, and (5) RTS,S/adjuvant system 01 malaria vaccine and meningitis, cerebral malaria, female mortality and rebound severe malaria. These case studies were selected because they are recent and varied in the vaccine safety challenges they elucidate. Bringing these case studies together, we develop lessons learned that can be useful for addressing some of the potential safety issues that will inevitably arise with new vaccines

Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML

Phenotype Enhancement Screen of a Regulatory spx Mutant Unveils a Role for the ytpQ Gene in the Control of Iron Homeostasis

Spx is a global regulator of genes that are induced by disulfide stress in Bacillus subtilis. The regulon that it governs is comprised of over 120 genes based on microarray analysis, although it is not known how many of these are under direct Spx control. Most of the Spx-regulated genes (SRGs) are of unknown function, but many encode products that are conserved in low %GC Gram-positive bacteria. Using a gene-disruption library of B. subtilis genomic mutations, the SRGs were screened for phenotypes related to Spx-controlled activities, such as poor growth in minimal medium and sensitivity to methyglyoxal, but nearly all of the SRG mutations showed little if any phenotype. To uncover SRG function, the mutations were rescreened in an spx mutant background to determine which mutant SRG allele would enhance the spx mutant phenotype. One of the SRGs, ytpQ was the site of a mutation that, when combined with an spx null mutation, elevated the severity of the Spx mutant phenotype, as shown by reduced growth in a minimal medium and by hypersensitivity to methyglyoxal. The ytpQ mutant showed elevated oxidative protein damage when exposed to methylglyoxal, and reduced growth rate in liquid culture. Proteomic and transcriptomic data indicated that the ytpQ mutation caused the derepression of the Fur and PerR regulons of B. subtilis. Our study suggests that the ytpQ gene, encoding a conserved DUF1444 protein, functions directly or indirectly in iron homeostasis. The ytpQ mutant phenotype mimics that of a fur mutation, suggesting a condition of low cellular iron. In vitro transcription analysis indicated that Spx stimulates transcription from the ytpPQR operon within which the ytpQ gene resides. The work uncovers a link between Spx and control of iron homeostasis

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Direct Visualization by Cryo-EM of the Mycobacterial Capsular Layer: A Labile Structure Containing ESX-1-Secreted Proteins

The cell envelope of mycobacteria, a group of Gram positive bacteria, is composed of a plasma membrane and a Gram-negative-like outer membrane containing mycolic acids. In addition, the surface of the mycobacteria is coated with an ill-characterized layer of extractable, non-covalently linked glycans, lipids and proteins, collectively known as the capsule, whose occurrence is a matter of debate. By using plunge freezing cryo-electron microscopy technique, we were able to show that pathogenic mycobacteria produce a thick capsule, only present when the cells were grown under unperturbed conditions and easily removed by mild detergents. This detergent-labile capsule layer contains arabinomannan, α-glucan and oligomannosyl-capped glycolipids. Further immunogenic and proteomic analyses revealed that Mycobacterium marinum capsule contains high amounts of proteins that are secreted via the ESX-1 pathway. Finally, cell infection experiments demonstrated the importance of the capsule for binding to cells and dampening of pro-inflammatory cytokine response. Together, these results show a direct visualization of the mycobacterial capsular layer as a labile structure that contains ESX-1-secreted proteins