Location, location, location: the evolutionary history of CD1 genes and the NKR-P1/ligand systems.

CD1 genes encode cell surface molecules that present lipid antigens to various kinds of T lymphocytes of the immune system. The structures of CD1 genes and molecules are like the major histocompatibility complex (MHC) class I system, the loading of antigen and the tissue distribution for CD1 molecules are like those in the class II system, and phylogenetic analyses place CD1 between class I and class II sequences, altogether leading to the notion that CD1 is a third ancient system of antigen presentation molecules. However, thus far, CD1 genes have only been described in mammals, birds and reptiles, leaving major questions as to their origin and evolution. In this review, we recount a little history of the field so far and then consider what has been learned about the structure and functional attributes of CD1 genes and molecules in marsupials, birds and reptiles. We describe the central conundrum of CD1 evolution, the genomic location of CD1 genes in the MHC and/or MHC paralogous regions in different animals, considering the three models of evolutionary history that have been proposed. We describe the natural killer (NK) receptors NKR-P1 and ligands, also found in different genomic locations for different animals. We discuss the consequence of these three models, one of which includes the repudiation of a guiding principle for the last 20 years, that two rounds of genome-wide duplication at the base of the vertebrates provided the extra MHC genes necessary for the emergence of adaptive immune system of jawed vertebrates.This is the final version of the article. It first appeared from Springer at http://dx.doi.org/10.1007/s00251-016-0938-6

Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms.

BackgroundAlthough differences in brain anatomy in autism have been difficult to replicate using manual tracing methods, automated whole brain analyses have begun to find consistent differences in regions of the brain associated with the social cognitive processes that are often impaired in autism. We attempted to replicate these whole brain studies and to correlate regional volume changes with several autism symptom measures.MethodsWe performed MRI scans on 24 individuals diagnosed with DSM-IV autistic disorder and compared those to scans from 23 healthy comparison subjects matched on age. All participants were male. Whole brain, voxel-wise analyses of regional gray matter volume were conducted using voxel-based morphometry (VBM).ResultsControlling for age and total gray matter volume, the volumes of the medial frontal gyri, left pre-central gyrus, right post-central gyrus, right fusiform gyrus, caudate nuclei and the left hippocampus were larger in the autism group relative to controls. Regions exhibiting smaller volumes in the autism group were observed exclusively in the cerebellum. Significant partial correlations were found between the volumes of the caudate nuclei, multiple frontal and temporal regions, the cerebellum and a measure of repetitive behaviors, controlling for total gray matter volume. Social and communication deficits in autism were also associated with caudate, cerebellar, and precuneus volumes, as well as with frontal and temporal lobe regional volumes.ConclusionGray matter enlargement was observed in areas that have been functionally identified as important in social-cognitive processes, such as the medial frontal gyri, sensorimotor cortex and middle temporal gyrus. Additionally, we have shown that VBM is sensitive to associations between social and repetitive behaviors and regional brain volumes in autism

A role for DNA hypomethylation and histone acetylation in maintaining allele-specific expression of mouse NKG2A in developing and mature NK cells.

The repertoire of receptors that is expressed by NK cells is critical for their ability to kill virally infected or transformed cells. However, the molecular mechanisms that determine whether and when NK receptor genes are transcribed during hemopoiesis remain unclear. In this study, we show that hypomethylation of a CpG-rich region in the mouse NKG2A gene is associated with transcription of NKG2A in ex vivo NK cells and NK cell lines. This observation was extended to various developmental stages of NK cells sorted from bone marrow, in which we demonstrate that the CpGs are methylated in the NKG2A-negative stages (hemopoietic stem cells, NK progenitors, and NKG2A-negative NK cells), and hypomethylated specifically in the NKG2A-positive NK cells. Furthermore, we provide evidence that DNA methylation is important in maintaining the allele-specific expression of NKG2A. Finally, we show that acetylated histones are associated with the CpG-rich region in NKG2A positive, but not negative, cell lines, and that treatment with the histone deacetylase inhibitor trichostatin A alone is sufficient to induce NKG2A expression. Treatment with the methyltransferase inhibitor 5-azacytidine only is insufficient to induce transcription, but cotreatment with both drugs resulted in a significantly greater induction, suggesting a cooperative role for DNA methylation and histone acetylation status in regulating gene expression. These results enhance our understanding of the formation and maintenance of NK receptor repertoires in developing and mature NK cells

Creation of the two isoforms of rodent NKG2D was driven by a B1 retrotransposon insertion

The mouse gene for the natural killer (NK) cell-activating receptor Nkg2d produces two protein isoforms, NKG2D-S and NKG2D-L, which differ by 13 amino acids at the N-terminus and have different signalling capabilities. These two isoforms are produced through differential splicing, but their regulation has not been investigated. In this study, we show that rat Nkg2d has the same splicing pattern as that of the mouse, and we mapped transcriptional start sites in both species. We found that the splice forms arise from alternative promoters and that the NKG2D-L promoter is derived from a rodent B1 retrotransposon that inserted before mouse–rat divergence. This B1 insertion is associated with loss of a nearby splice acceptor site that subsequently allowed creation of the short NKG2D isoform found in mouse but not human. Transient reporter assays indicate that the B1 element is a strong promoter with no inherent lymphoid tissue-specificity. We have also identified different binding sites for the ETS family member GABP within both the mouse and rat B1 elements that are necessary for high-promoter activity and for full Nkg2d-L expression. These findings demonstrate that a retroelement insertion has led to gene-regulatory change and functional diversification of rodent NKG2D

Expression of the leukemic prognostic marker CD7 is linked to epigenetic modifications in chronic myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Expression levels of the cell surface glycoprotein, CD7, and the serine protease, elastase 2 (ELA2), in the leukemic cells of patients with chronic myeloid leukemia (CML) have been associated with clinical outcome. However, little is known about the mechanisms that underlie the variable expression of these genes in the leukemic cells.</p> <p>Results</p> <p>To address this question, we compared the level of their expression with the DNA methylation and histone acetylation status of 5' sequences of both genes in leukemic cell lines and primitive (lin^-CD34⁺) leukemic cells from chronic phase CML patients. DNA methylation of the <it>ELA2 </it>gene promoter did not correlate with its expression pattern in lin^-CD34⁺cells from chronic phase CML patient samples even though there was clear differential DNA methylation of this locus in <it>ELA2</it>-expressing and non-expressing cell lines. In contrast, we found a strong relation between CD7 expression and transcription-permissive chromatin modifications, both at the level of DNA methylation and histone acetylation with evidence of hypomethylation of the <it>CD7 </it>promoter region in the lin^-CD34⁺cells from CML patients with high CD7 expression.</p> <p>Conclusion</p> <p>These findings indicate a link between epigenetic modifications and CD7 expression in primitive CML cells.</p

Overwintering habitat links to summer reproductive success: intercontinental carry-over effects in a declining migratory bird revealed using stable isotope analysis

Capsule: Breeding success in female Pied Flycatchers Ficedula hypoleuca is related to isotopic signature of feathers grown in Africa, suggesting wintering habitat links to breeding performance 5000km away. Aims: Better understanding of interseasonal carry-over effects is a research priority, especially for declining migrants. We use stable isotope analysis to relate Pied Flycatcher winter habitat to summer reproductive success. Methods: Flycatchers were captured in three UK woodlands in 2013-2015. An Africa-grown tertial was trimmed and analysed using Isotope Ratio Mass Spectrometry to quantify Nitrogen-15 (δ15N) and Carbon-13 (δ13C). In total, 135 samples were taken from 80 individuals. Results: Wintering δ15N and δ13C differed significantly between years. δ13C correlated with lay date, such that birds with lower carbon levels (indicative of more mesic habitat) bred earlier. There was a significant correlation between wintering δ13C and productivity after allowing for year, site, and lay date; birds with low δ13C were more successful. This suggests δ13C links productivity directly as well as indirectly through phenological effects. δ15N did not relate to phenology or productivity. Conclusion: This is the first evidence of carry-over effects between geographical regions for a European passerine. Conservation measures should focus on all aspects of seasonal cycles, not just breeding grounds

Defining Spoken Language Benchmarks and Selecting Measures of Expressive Language Development for Young Children With Autism Spectrum Disorders

Purpose The aims of this article are twofold: (a) to offer a set of recommended measures that can be used for evaluating the efficacy of interventions that target spoken language acquisition as part of treatment research studies or for use in applied settings and (b) to propose and define a common terminology for describing levels of spoken language ability in the expressive modality and to set benchmarks for determining a child’s language level in order to establish a framework for comparing outcomes across intervention studies. Method The National Institute on Deafness and Other Communication Disorders assembled a group of researchers with interests and experience in the study of language development and disorders in young children with autism spectrum disorders. The group worked for 18 months through a series of conference calls and correspondence, culminating in a meeting held in December 2007 to achieve consensus on these aims. Results The authors recommend moving away from using the term functional speech, replacing it with a developmental framework. Rather, they recommend multiple sources of information to define language phases, including natural language samples, parent report, and standardized measures. They also provide guidelines and objective criteria for defining children’s spoken language expression in three major phases that correspond to developmental levels between 12 and 48 months of age

A comparison of spectroscopic methods for detecting starlight scattered by transiting hot Jupiters, with application to Subaru data for HD 209458b and HD 189733b

The measurement of the light scattered from extrasolar planets informs atmospheric and formation models. With the discovery of many hot Jupiter planets orbiting nearby stars, this motivates the development of robust methods of characterisation from follow up observations. In this paper we discuss two methods for determining the planetary albedo in transiting systems. First, the most widely used method for measuring the light scattered by hot Jupiters (Collier Cameron et al.) is investigated for application for typical echelle spectra of a transiting planet system, showing that detection requires high signal-to-noise ratio data of bright planets. Secondly a new Fourier analysis method is also presented, which is model-independent and utilises the benefits of the reduced number of unknown parameters in transiting systems. This approach involves solving for the planet and stellar spectra in Fourier space by least-squares. The sensitivities of the methods are determined via Monte Carlo simulations for a range of planet-to-star fluxes. We find the Fourier analysis method to be better suited to the ideal case of typical observations of a well constrained transiting system than the Collier Cameron et al. method. We apply the Fourier analysis method for extracting the light scattered by transiting hot Jupiters from high resolution spectra to echelle spectra of HD 209458 and HD 189733. Unfortunately we are unable to improve on the previous upper limit of the planet-to-star flux for HD 209458b set by space-based observations. A 1{\sigma}upper limit on the planet-to-star flux of HD 189733b is measured in the wavelength range of 558.83-599.56 nm yielding {\epsilon} < 4.5 \times 10-4. Improvement in the measurement of the upper limit of the planet-to-star flux of this system, with ground-based capabilities, requires data with a higher signal-to-noise ratio, and increased stability of the telescope.Comment: 15 pages, 8 figures, 2 tables. Monthly Notices of the Royal Astronomical Society, in press. Accepted 2011 March 17. Received 2011 March 17; in original form 2010 June 2

Low Frequency Ventilation During Cardiopulmonary Bypass to Protect Postoperative Lung Function in Cardiac Valvular Surgery:The PROTECTION Phase II Randomized Trial

BackgroundCardiac surgery with cardiopulmonary bypass (CPB) triggers pulmonary injury. In this trial we assessed the feasibility, safety, and efficacy of low frequency ventilation (LFV) during CPB in patients undergoing valvular surgery.Methods and ResultsPatients with severe mitral or aortic valve disease were randomized to either LFV or usual care. Primary outcomes included release of generic inflammatory and vascular biomarkers and the lung‐specific biomarker sRAGE (soluble receptor for advance glycation end products) up to 24 hours postsurgery. Secondary outcomes included pulmonary function tests and 6‐minute walking test up to 8 weeks postdischarge. Sixty‐three patients were randomized (33 LFV versus 30 usual care). Mean age was 66.8 years and 30% were female. LFV was associated with changes of sRAGE (soluble receptor for advance glycation end products) levels (geometric mean ratio, 3.05; [95% CI, 1.13–8.24] 10 minutes post CPB, and 1.07 [95% CI, 0.64–1.79], 0.84 [95% CI, 0.55–1.27], 0.67 [95% CI, 0.42–1.07], and 0.62 [95% CI, 0.45–0.85] at 2, 6, 12, and 24 hours post CPB respectively). No changes were observed for any of the generic biomarkers. Respiratory index soon after surgery (mean difference, −0.61 [95% CI, −1.24 to 0.015] 10 minutes post end of CPB), forced expiratory volume after 1 second/forced vital capacity ratio (0.050 [95% CI, 0.007–0.093] at 6 to 8 weeks pos‐surgery), Forced vital capacity alone (95% CI, −0.191 L [−0.394 to 0.012]) and 6‐minute walking test score at discharge (63.2 m [95% CI, 12.9–113.6]) were better preserved in the LFV group. No other differences were noted.ConclusionsThe use of LFV during CPB in patients undergoing valvular surgery was feasible and safe and was associated with changes in sRAGE levels along with better preserved lung function and walking performance. These observations warrant further investigation in larger future studie

Impact of Scotland’s comprehensive, smoke-free legislation on stroke

&lt;p&gt;Background: Previous studies have reported a reduction in acute coronary events following smoke-free legislation. Evidence is lacking on whether stroke is also reduced. The aim was to determine whether the incidence of stroke, overalland by sub-type, fell following introduction of smoke-free legislation across Scotland on 26 March 2006.&lt;/p&gt; &lt;p&gt;Methods and Findings: A negative binomial regression model was used to determine whether the introduction of smokefree legislation resulted in a step and/or slope change in stroke incidence. The model was adjusted for age-group, sex, socioeconomic deprivation quintile, urban/rural residence and month. Interaction tests were also performed. Routine hospital administrative data and death certificates were used to identify all hospital admissions and pre-hospital deaths due to stroke (ICD10 codes I61, I63 and I64) in Scotland between 2000 and 2010 inclusive. Prior to the legislation, rates of all stroke, intracerebral haemorrhage and unspecified stroke were decreasing, whilst cerebral infarction was increasing at 0.97% per annum. Following the legislation, there was a dramatic fall in cerebral infarctions that persisted for around 20 months. No visible effect was observed for other types of stroke. The model confirmed an 8.90% (95% CI 4.85, 12.77, p,0.001) stepwise reduction in cerebral infarction at the time the legislation was implemented, after adjustment for potential cofounders.&lt;/p&gt; &lt;p&gt;Conclusions: Following introduction of national, comprehensive smoke-free legislation there was a selective reduction in cerebral infarction that was not apparent in other types of stroke.&lt;/p&gt