Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy.

The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates ≥98% of peripheral immune cells with ≥4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery

On the Ortho:Para Ratio of H3+ in Diffuse Molecular Clouds

The excitation temperature T_01 derived from the relative intensities of the J = 0 (para) and J = 1 (ortho) rotational levels of H2 has been assumed to be an accurate measure of the kinetic temperature in interstellar environments. In diffuse molecular clouds, the average value of T_01 is ~70 K. However, the excitation temperature T(H3+) derived from the (J,K) = (1,1) (para) and (1,0) (ortho) rotational levels of H3+ has been observed to be ~30 K in the same types of environments. In this work, we present observations of H3+ in three additional diffuse cloud sight lines for which H2 measurements are available, showing that in 4 of 5 cases T_01 and T(H3+) are discrepant. We then examine the thermalization mechanisms for the ortho:para ratios of H3+ and H2, concluding that indeed T_01 is an accurate measure of the cloud kinetic temperature, while the ortho:para ratio of H3+ need not be thermal. By constructing a steady-state chemical model taking into account the nuclear-spindependence of reactions involving H3+, we show that the ortho:para ratio of H3+ in diffuse molecular clouds is likely governed by a competition between dissociative recombination with electrons and thermalization via reactive collisions with H2.Comment: 13 pages, 8 figures, 5 tables, accepted for publication in Ap

Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy

The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates >= 98% of peripheral immune cells with >= 4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery

A New Automatic Method to Identify Galaxy Mergers I. Description and Application to the STAGES Survey

We present an automatic method to identify galaxy mergers using the morphological information contained in the residual images of galaxies after the subtraction of a Sersic model. The removal of the bulk signal from the host galaxy light is done with the aim of detecting the fainter minor mergers. The specific morphological parameters that are used in the merger diagnostic suggested here are the Residual Flux Fraction and the asymmetry of the residuals. The new diagnostic has been calibrated and optimized so that the resulting merger sample is very complete. However, the contamination by non-mergers is also high. If the same optimization method is adopted for combinations of other structural parameters such as the CAS system, the merger indicator we introduce yields merger samples of equal or higher statistical quality than the samples obtained through the use of other structural parameters. We explore the ability of the method presented here to select minor mergers by identifying a sample of visually classified mergers that would not have been picked up by the use of the CAS system, when using its usual limits. Given the low prevalence of mergers among the general population of galaxies and the optimization used here, we find that the merger diagnostic introduced in this work is best used as a negative merger test, i.e., it is very effective at selecting non-merging galaxies. As with all the currently available automatic methods, the sample of merger candidates selected is contaminated by non-mergers, and further steps are needed to produce a clean sample. This merger diagnostic has been developed using the HST/ACS F606W images of the A901/02 cluster (z=0.165) obtained by the STAGES team. In particular, we have focused on a mass and magnitude limited sample (log M/M_{O}>9.0, R_{Vega}<23.5mag)) which includes 905 cluster galaxies and 655 field galaxies of all morphological types.Comment: 25 pages, 14 figures, 4 tables. To appear in MNRA

PhMYB4 fine-tunes the floral volatile signature of Petunia×hybrida through PhC4H

In Petunia×hybrida cv ‘Mitchell Diploid’ (MD), floral volatile benzenoid/phenylpropanoid (FVBP) biosynthesis is controlled spatially, developmentally, and daily at molecular, metabolic, and biochemical levels. Multiple genes have been shown to encode proteins that either directly catalyse a biochemical reaction yielding FVBP compounds or are involved in metabolite flux prior to the formation of FVBP compounds. It was hypothesized that multiple transcription factors are involved in the precise regulation of all necessary genes, resulting in the specific volatile signature of MD flowers. After acquiring all available petunia transcript sequences with homology to Arabidopsis thaliana R2R3-MYB transcription factors, PhMYB4 (named for its close identity to AtMYB4) was identified, cloned, and characterized. PhMYB4 transcripts accumulate to relatively high levels in floral tissues at anthesis and throughout open flower stages, which coincides with the spatial and developmental distribution of FVBP production and emission. Upon RNAi suppression of PhMYB4 (ir-PhMYB4) both petunia CINNAMATE-4-HYDROXYLASE (PhC4H1 and PhC4H2) gene transcript levels were significantly increased. In addition, ir-PhMYB4 plants emit higher levels of FVBP compounds derived from p-coumaric acid (isoeugenol and eugenol) compared with MD. Together, these results indicate that PhMYB4 functions in the repression of C4H transcription, indirectly controlling the balance of FVBP production in petunia floral tissue (i.e. fine-tunes)

Kepler eclipsing binary stars. VII. the catalogue of eclipsing binaries found in the entire Kepler data set

The primary Kepler Mission provided nearly continuous monitoring of ~200,000 objects with unprecedented photometric precision. We present the final catalog of eclipsing binary systems within the 105 deg2 Kepler field of view. This release incorporates the full extent of the data from the primary mission (Q0-Q17 Data Release). As a result, new systems have been added, additional false positives have been removed, ephemerides and principal parameters have been recomputed, classifications have been revised to rely on analytical models, and eclipse timing variations have been computed for each system. We identify several classes of systems including those that exhibit tertiary eclipse events, systems that show clear evidence of additional bodies, heartbeat systems, systems with changing eclipse depths, and systems exhibiting only one eclipse event over the duration of the mission. We have updated the period and galactic latitude distribution diagrams and included a catalog completeness evaluation. The total number of identified eclipsing and ellipsoidal binary systems in the Kepler field of view has increased to 2878, 1.3% of all observed Kepler targets

Atorvastatin Improves Survival in Septic Rats: Effect on Tissue Inflammatory Pathway and on Insulin Signaling

The aim of the present study was to investigate whether the survival-improving effect of atorvastatin in sepsis is accompanied by a reduction in tissue activation of inflammatory pathways and, in parallel, an improvement in tissue insulin signaling in rats. Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Serum glucose and inflammatory cytokines levels were assessed 24 h after CLP. The effect of atorvastatin on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle and adipose tissue. Atorvastatin improves survival in septic rats and this improvement is accompanied by a marked improvement in insulin sensitivity, characterized by an increase in glucose disappearance rate during the insulin tolerance test. Sepsis induced an increase in the expression/activation of TLR4 and its downstream signaling JNK and IKK/NF-κB activation, and blunted insulin-induced insulin signaling in liver, muscle and adipose tissue; atorvastatin reversed all these alterations in parallel with a decrease in circulating levels of TNF-α and IL-6. In summary, this study demonstrates that atorvastatin treatment increased survival, with a significant effect upon insulin sensitivity, improving insulin signaling in peripheral tissues of rats during peritoneal-induced sepsis. The effect of atorvastatin on the suppression of the TLR-dependent inflammatory pathway may play a central role in regulation of insulin signaling and survival in sepsis insult

Female sweet-likers have enhanced cross-modal interoceptive abilities

There are well known phenotypic differences in sweet-liking across individuals, but it remains unknown whether these are related to broader underlying differences in interoceptive abilities (abilities to sense the internal state of the body). Here, healthy women (N = 64) classified as sweet likers (SLs) or sweet dislikers (SDs) completed a bimodal interoception protocol. A heartbeat tracking and a heartbeat discrimination task determined cardiac interoception; both were accompanied by confidence ratings. A water load task, where participants consumed water to satiation and then to maximum fullness was used to assess gastric interoceptive abilities. Motivational state, psychometric characteristics and eating behaviour were also assessed. SLs performed significantly better than SDs on both heartbeat tasks, independently of impulsivity, anxiety, depression, and alexithymia. No differences in metacognitive awareness and subjective interoceptive measures were found. With gastric interoception, SLs were more sensitive to stomach distention, and they ingested less water than SDs to reach satiety when accounting for stomach capacity. SLs also scored higher on mindful and intuitive eating scales and on emotional eating particularly in response to negative stimuli; emotional overeating was fully mediated via interoceptive performance. Overall, our data suggest the SL phenotype may reflect enhanced responsiveness to internal cues more broadly