Phenotypic and functional analysis of positive selection in the gamma/delta T cell lineage.

Recent evidence suggests that T cells expressing gamma/delta antigen receptors (T cell receptor [TCR]) are subject to positive selection during development. We have shown that T cells expressing a class I major histocompatibility complex (MHC)-specific gamma/delta TCR transgene (tg) are not positively selected in class I MHC-deficient, beta 2-microglobulin (beta 2m) gene knockout mice (tg+ beta 2m-). In this report, we examine phenotypic and functional parameters of gamma/delta positive selection in this transgenic model system. TCR-gamma/delta tg+ thymocytes of mature surface phenotype (heat stable antigen-, CD5hi) were found in beta 2m+ but not in beta 2m- mice. Moreover, subsets of tg+ thymocytes with the phenotype of activated T cells (interleukin [IL]2R+, CD44hi, or Mel-14lo) were also present only in the beta 2m+ mice. Cyclosporine A, which blocks positive selection of TCR-alpha/beta T cells, also inhibited gamma/delta tg+ T cell development. These results support the idea that positive selection of TCR-gamma/delta requires active TCR-mediated signal transduction. Whereas tg+ beta 2m+ thymocytes produced IL-2 and proliferated when stimulated by alloantigen, TCR engagement of tg+ beta 2m- thymocytes by antigen induced IL-2R expression but was uncoupled from the signal transduction pathway leading to IL-2 production and autocrine proliferation. Overall, these results demonstrate significant parallels between gamma/delta and alpha/beta lineage development, and suggest a general role for TCR signaling in thymic maturation

The fractal dimension of star-forming regions at different spatial scales in M33

We study the distribution of stars, HII regions, molecular gas, and individual giant molecular clouds in M33 over a wide range of spatial scales. The clustering strength of these components is systematically estimated through the fractal dimension. We find scale-free behavior at small spatial scales and a transition to a larger correlation dimension (consistent with a nearly uniform distribution) at larger scales. The transition region lies in the range 500-1000 pc. This transition defines a characteristic size that separates the regime of small-scale turbulent motion from that of large-scale galactic dynamics. At small spatial scales, bright young stars and molecular gas are distributed with nearly the same three-dimensional fractal dimension (Df <= 1.9), whereas fainter stars and HII regions exhibit higher values (Df = 2.2-2.5). Our results indicate that the interstellar medium in M33 is on average more fragmented and irregular than in the Milky Way.Comment: 18 pages including 4 figures. Accepted for publication in Ap

Dynamical Evolution of Young Embedded Clusters: A Parameter Space Survey

This paper investigates the dynamical evolution of embedded stellar clusters from the protocluster stage, through the embedded star-forming phase, and out to ages of 10 Myr -- after the gas has been removed from the cluster. The relevant dynamical properties of young stellar clusters are explored over a wide range of possible star formation environments using N-body simulations. Many realizations of equivalent initial conditions are used to produce robust statistical descriptions of cluster evolution including the cluster bound fraction, radial probability distributions, as well as the distributions of close encounter distances and velocities. These cluster properties are presented as a function of parameters describing the initial configuration of the cluster, including the initial cluster membership N, initial stellar velocities, cluster radii, star formation efficiency, embedding gas dispersal time, and the degree of primordial mass segregation. The results of this parameter space survey, which includes about 25,000 simulations, provide a statistical description of cluster evolution as a function of the initial conditions. We also present a compilation of the FUV radiation fields provided by these same cluster environments. The output distributions from this study can be combined with other calculations, such as disk photoevaporation models and planetary scattering cross sections, to ascertain the effects of the cluster environment on the processes involved in planet formation.Comment: 65 pages including 20 figures, accepted to ApJ Supplemen

Unreasonable Resentments

How ought we to evaluate and respond to expressions of anger and resentment? Can philosophical analysis of resentment as the emotional expression of a moral claim help us to distinguish which resentments ought to be taken seriously? Philosophers have tended to focus on what I call ‘reasonable’ resentments, presenting a technical, narrow account that limits resentment to the expression of recognizable moral claims. In the following paper, I defend three claims about the ethics and politics of resentment. First, if we care about socially just processes of reconciliation, we have good reason to pay attention to the logic of resentments. Second, the account philosophers offer of resentment – its distinctive features, aims, rationality, and gratification – will affect the conclusions we draw about which actual resentments to take seriously, which aspects of resentful claims need addressing, and what it means to address and repair them. In contesting definitions of resentment, I argue, we do more than simply perform housekeeping in philosophical taxonomies of emotion. Restricting our understanding to essentially ‘moral’ cases may cause us to lose sight of expressly political resentments. Instead, I argue, a plausible account of resentment must acknowledge that we resent violations and threats that are not necessarily self-pertaining, may not be expressible as individual, discrete injuries, and cannot always be construed as moral threats. Second, given the dependence of moral judgments on a broader horizon of moral possibility, philosophical standards of ‘reasonable’ or ‘appropriate’ resentment cannot avoid being politically charged. Thus, the widely accepted account of ‘reasonable’ resentment cannot make philosophical sense of the most interesting and perplexing cases. Ironically, a theoretical measure designed to revalue emotional expressions of moral protest may result in the exclusion and silencing of those with the most reasons to protest

The velocity distribution of nearby stars from Hipparcos data II. The nature of the low-velocity moving groups

The velocity distribution of nearby stars contains many "moving groups" that are inconsistent with the standard assumption of an axisymmetric, time-independent, and steady-state Galaxy. We study the age and metallicity properties of the low-velocity moving groups based on the reconstruction of the local velocity distribution in Paper I of this series. We perform stringent, conservative hypothesis testing to establish for each of these moving groups whether it could conceivably consist of a coeval population of stars. We conclude that they do not: the moving groups are not trivially associated with their eponymous open clusters nor with any other inhomogeneous star formation event. Concerning a possible dynamical origin of the moving groups, we test whether any of the moving groups has a higher or lower metallicity than the background population of thin disk stars, as would generically be the case if the moving groups are associated with resonances of the bar or spiral structure. We find clear evidence that the Hyades moving group has higher than average metallicity and weak evidence that the Sirius moving group has lower than average metallicity, which could indicate that these two groups are related to the inner Lindblad resonance of the spiral structure. Further we find weak evidence that the Hercules moving group has higher than average metallicity, as would be the case if it is associated with the bar's outer Lindblad resonance. The Pleiades moving group shows no clear metallicity anomaly, arguing against a common dynamical origin for the Hyades and Pleiades groups. Overall, however, the moving groups are barely distinguishable from the background population of stars, raising the likelihood that the moving groups are associated with transient perturbations. [abridged

Ecological succession of a Jurassic shallow-water ichthyosaur fall.

After the discovery of whale fall communities in modern oceans, it has been hypothesized that during the Mesozoic the carcasses of marine reptiles created similar habitats supporting long-lived and specialized animal communities. Here, we report a fully documented ichthyosaur fall community, from a Late Jurassic shelf setting, and reconstruct the ecological succession of its micro- and macrofauna. The early 'mobile-scavenger' and 'enrichment-opportunist' stages were not succeeded by a 'sulphophilic stage' characterized by chemosynthetic molluscs, but instead the bones were colonized by microbial mats that attracted echinoids and other mat-grazing invertebrates. Abundant cemented suspension feeders indicate a well-developed 'reef stage' with prolonged exposure and colonization of the bones prior to final burial, unlike in modern whale falls where organisms such as the ubiquitous bone-eating worm Osedax rapidly destroy the skeleton. Shallow-water ichthyosaur falls thus fulfilled similar ecological roles to shallow whale falls, and did not support specialized chemosynthetic communities

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Solution structure of a repeated unit of the ABA-1 nematode polyprotein allergen of ascaris reveals a novel fold and two discrete lipid-binding sites

Parasitic nematode worms cause serious health problems in humans and other animals. They can induce allergic-type immune responses, which can be harmful but may at the same time protect against the infections. Allergens are proteins that trigger allergic reactions and these parasites produce a type that is confined to nematodes, the nematode polyprotein allergens (NPAs). These are synthesized as large precursor proteins comprising repeating units of similar amino acid sequence that are subsequently cleaved into multiple copies of the allergen protein. NPAs bind small lipids such as fatty acids and retinol (Vitamin A) and probably transport these sensitive and insoluble compounds between the tissues of the worms. Nematodes cannot synthesize these lipids, so NPAs may also be crucial for extracting nutrients from their hosts. They may also be involved in altering immune responses by controlling the lipids by which the immune and inflammatory cells communicate. We describe the molecular structure of one unit of an NPA, the well-known ABA-1 allergen of Ascaris and find its structure to be of a type not previously found for lipid-binding proteins, and we describe the unusual sites where lipids bind within this structur

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Microevolution during the emergence of a monophasic Salmonella Typhimurium epidemic in the United Kingdom

Microevolutionary events associated with the emergence and clonal expansion of new 27 epidemic clones of bacterial pathogens hold the key to understanding the drivers of 28 epidemiological success. We describe a comparative whole genome sequence and 29 phylogenomic analysis of monophasic Salmonella Typhimurium isolates from the UK 30 and Italy from 2005-2012. Monophasic isolates from this time formed a single clade 31 distinct from recent monophasic epidemic clones described previously from North 32 America and Spain. The current UK monophasic epidemic clones encode a novel 33 genomic island encoding resistance to heavy metals (SGI-3), and composite transposon 34 encoding antibiotic resistance genes not present in other Typhimurium isolates, that 35 may have contributed to the epidemiological success. We also report a remarkable 36 degree of genotypic variation that accumulated during clonal expansion of a UK 37 epidemic including multiple independent acquisitions of a novel prophage carrying the 38 sopE gene and multiple deletion events affecting the phase II flagellin locus