[No abstract]

The Multi Conjugate Adaptive Optics Relay (MAORY) for the European Extremely Large Telescope shall re-image the telescope focal plane for the client instruments installed on two exit ports. By means of natural and artificial (laser) reference sources for wavefront sensing, and of deformable mirrors for wavefront correction, MAORY shall be able to compensate the wavefront disturbances affecting the scientific observations, achieving high Strehl ratio and high sky coverage. The optical interfaces to the client instruments must replicate the telescope one while the volume allocation on the Nasmyth platform is under definition at the moment of this writing. We show the latest version of the optical design that matches the current requests and its optical performance. The laser guide stars channel, separated from the science path by means of a dichroic beam-splitter, is also presented.

Intracellular metabolism is central to cell activity and function. CD4(+)CD25(+) regulatory T cells (Tregs) that express the transcription factor FOXP3 play a pivotal role in the maintenance of immune tolerance to self. Recent studies showed that the metabolism and function of Tregs are influenced significantly by local environmental conditions and the availability of certain metabolites. It also was reported that defined metabolic programs associate with Treg differentiation, expression of FOXP3, and phenotype stabilization. This article reviews how metabolism modulates FOXP3 expression and Treg function, what environmental factors are involved, and how metabolic manipulation could alter Treg frequency and function in physiopathologic conditions.

The human DNA base excision repair enzyme MUTYH (MutY homolog DNA glycosylase) excises undamaged adenine that has been misincorporated opposite the oxidatively damaged 8-oxoG, preventing transversion mutations and serving as an important defense against the deleterious effects of this damage. Mutations in the MUTYH gene predispose patients to MUTYH-associated polyposis and colorectal cancer, and MUTYH expression has been documented as a biomarker for pancreatic cancer. Measuring MUTYH activity is therefore critical for evaluating and diagnosing disease states as well as for testing this enzyme as a potential therapeutic target. However, current methods for measuring MUTYH activity rely on indirect electrophoresis and radioactivity assays, which are difficult to implement in biological and clinical settings. Herein, we synthesize and identify novel fluorescent adenine derivatives that can act as direct substrates for excision by MUTYH as well as bacterial MutY. When incorporated into synthetic DNAs, the resulting fluorescently modified adenine-release turn-on (FMART) probes report on enzymatic base excision activity in real time, both in vitro and in mammalian cells and human blood. We also employ the probes to identify several promising small-molecule modulators of MUTYH by employing FMART probes for in vitro screening.

Dust generation is a world-wide issue due to its serious deleterious effects on the environment, human health and safety, and the economy. Although various dust suppression methods have been used for decades, some critical drawbacks in state-of-the-art technology still remain unsolved, such as short-lasting, ground water impact, and prone to water. This work reports a soil stabilizer based on non-toxic material and forms a ductile and durable double-network in soil, namely “D3 soil stabilizer”, which not only improves soil mechanical toughness of surface soil but also suppresses dust generation. A copolymer comprising hydrophilic and hydrophobic components combined with enzyme-induced carbonate precipitation is utilized as an in-situ gelation binder to soil particle. The tunable hydrophobic-to-hydrophilic component ratio minimizes undesirable soil matrix expansion and mechanical strength loss upon experiencing wet-dry processes, while still retains good water affinity. We further demonstrated controllable treatment depth by fine-tuning precursor composition, which is essential to minimize environmental impact. The double-network morphology with carbonate precipitate embedded uniformly in polymer matrix is observed via microscopic imaging. The nature of outstanding ductility, high durability against water, and good long-term stability were supported by systematic unconfined compressive strength (UCS) measurements on treated soil, which show strong inter-particles binding, good retention of peak strength, increased strain at peak strength, and increased toughness after soil samples have experienced wet-dry processes.

Background

The effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples.

Methods and results

Stroke-free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71±9 years, 60% women, 15% non-Hispanic white, 17% non-Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6-9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI, 1.1-1.9), ischemic stroke (HR: 1.3; 95% CI, 1.0-1.8), and cryptogenic stroke (HR: 2.2; 95% CI, 1.1-4.4). White and black but not Hispanic participants had increased stroke risk (P<0.05 for heterogeneity for all and ischemic stroke). Those with subclinical brain infarct had greater risk for all stroke types (HR: 1.9; 95% CI, 1.1-3.3), ischemic stroke (HR: 2.2; 95% CI, 1.3-3.8), lacunar (HR: 4.0; 95% CI, 1.3-12.3), and cryptogenic stroke (HR: 3.6; 95% CI, 1.0-12.7), without significant heterogeneity across race/ethnic groups. Greater white matter hyperintensity volume increased both vascular (HR: 1.3; 95% CI, 1.1-1.7) and nonvascular (HR: 1.2; 95% CI, 1.0-1.5) mortality among Hispanic and white but not black participants (P=0.040 for heterogeneity). Subclinical brain infarct was associated with increased vascular mortality among Hispanic participants only (HR: 2.9; 95% CI, 1.4-5.8).

Conclusions

In this urban US sample, subclinical cerebrovascular lesions increased the risk of clinical stroke and vascular mortality and varied by race/ethnicity and lesion type.

The interferon gamma, enzyme-linked immunospot (IFN-γ ELISpot) assay is widely used to identify viral antigen-specific T cells is frequently employed to quantify T cell responses in HIV vaccine studies. It can be used to define T cell epitope specificities using panels of peptide antigens, but with sample and cost constraints there is a critical need to improve the efficiency of epitope mapping for large and variable pathogens. We evaluated two epitope mapping strategies, based on group testing, for their ability to identify vaccine-induced T-cells from participants in the Step HIV-1 vaccine efficacy trial, and compared the findings to an approach of assaying each peptide individually. The group testing strategies reduced the number of assays required by >7-fold without significantly altering the accuracy of T-cell breadth estimates. Assays of small pools containing 7-30 peptides were highly sensitive and effective at detecting single positive peptides as well as summating responses to multiple peptides. Also, assays with a single 15-mer peptide, containing an identified epitope, did not always elicit a response providing validation that 15-mer peptides are not optimal antigens for detecting CD8+ T cells. Our findings further validate pooling-based epitope mapping strategies, which are critical for characterizing vaccine-induced T-cell responses and more broadly for informing iterative vaccine design. We also show ways to improve their application with computational peptide:MHC binding predictors that can accurately identify the optimal epitope within a 15-mer peptide and within a pool of 15-mer peptides.

Production of haploid gametes from diploid progenitor cells is mediated by a specialized cell division, meiosis, where two divisions, meiosis I and II, follow a single S phase. Errors in progression from meiosis I to meiosis II lead to aneuploid and polyploid gametes, but the regulatory mechanisms controlling this transition are poorly understood. Here, we demonstrate that the conserved kinase Ime2 regulates the timing and order of the meiotic divisions by controlling translation. Ime2 coordinates translational activation of a cluster of genes at the meiosis I-meiosis II transition, including the critical determinant of the meiotic chromosome segregation pattern CLB3. We further show that Ime2 mediates translational control through the meiosis-specific RNA-binding protein Rim4. Rim4 inhibits translation of CLB3 during meiosis I by interacting with the 5' untranslated region (UTR) of CLB3. At the onset of meiosis II, Ime2 kinase activity rises and triggers a decrease in Rim4 protein levels, thereby alleviating translational repression. Our results elucidate a novel developmentally regulated translational control pathway that establishes the meiotic chromosome segregation pattern.

Type 1 diabetes is characterized by autoimmune destruction of pancreatic β-cells in genetically susceptible individuals. Triggers of islet autoimmunity, time course, and the precise mechanisms responsible for the progressive β-cell failure are not completely understood. The recent escalation of obesity in affluent countries has been suggested to contribute to the increased incidence of type 1 diabetes. Understanding the link between metabolism and immune tolerance could lead to the identification of new markers for the monitoring of disease onset and progression. We studied several immune cell subsets and factors with high metabolic impact as markers associated with disease progression in high-risk subjects and type 1 diabetic patients at onset and at 12 and 24 months after diagnosis. A multiple correlation matrix among different parameters was evaluated statistically and assessed visually on two-dimensional graphs. Markers to predict residual β-cell function up to 1 year after diagnosis were identified in multivariate logistic regression models. The meta-immunological profile changed significantly over time in patients, and a specific signature that was associated with worsening disease was identified. A multivariate logistic regression model measuring age, BMI, fasting C-peptide, number of circulating CD3(+)CD16(+)CD56(+) cells, and the percentage of CD1c(+)CD19(-)CD14(-)CD303(-) type 1 myeloid dendritic cells at disease onset had a significant predictive value. The identification of a specific meta-immunological profile associated with disease status may contribute to our understanding of the basis of diabetes progression.

We explore the impact of outer stellar companions on the occurrence rate of giant planets detected with radial velocities. We searched for stellar and planetary companions to a volume-limited sample of solar-type stars within 25 pc. Using adaptive optics imaging observations from the Lick 3 m and Palomar 200″ Telescopes, we characterized the multiplicity of our sample stars, down to the bottom of the main sequence. With these data, we confirm field star multiplicity statistics from previous surveys. We additionally combined three decades of radial velocity (RV) data from the California Planet Search with newly collected RV data from Keck/HIRES and the Automated Planet Finder/Levy Spectrometer to search for planetary companions in these same systems. Using an updated catalog of both stellar and planetary companions, as well as detailed injection/recovery tests to determine our sensitivity and completeness, we measured the occurrence rate of planets among the single- and multiple-star systems. We found that planets with masses in the range of 0.1–10 MJ and with semimajor axes of 0.1–10 au have an occurrence rate of 0.18-+0.030.04 planets per star when they orbit single stars and an occurrence rate of 0.12 ± 0.04 planets per star when they orbit a star in a binary system. Breaking the sample down by the binary separation, we found that only one planet-hosting binary system had a binary separation <100 au, and none had a separation <50 au. These numbers yielded planet occurrence rates of 0.20-+0.060.07 planets per star for binaries with separation aB > 100 au and 0.04-+0.020.04 planets per star for binaries with separation aB < 100 au. The similarity in the planet occurrence rate around single stars and wide primaries implies that wide binary systems should actually host more planets than single-star systems, since they have more potential host stars. We estimated a system-wide planet occurrence rate of 0.3 planets per wide binary system for binaries with separations aB > 100 au. Finally, we found evidence that giant planets in binary systems have a different semimajor-axis distribution than their counterparts in single-star systems. The planets in the single-star sample had a significantly higher occurrence rate outside of 1 au than inside 1 au by nearly 4σ, in line with expectations that giant planets are most common near the snow line. However, the planets in the wide binary systems did not follow this distribution, but rather had equivalent occurrence rates interior and exterior to 1 au. This may point to binary-mediated planet migration acting on our sample, even in binaries wider than 100 au.