Interplay of Inflammatory, Antigen and Tissue-Derived Signals in the Development of Resident CD8 Memory T Cells

CD8 positive, tissue resident memory T cells (TRM) are a specialized subset of CD8 memory T cells that surveil tissues and provide critical first-line protection against tumors and pathogen re-infection. Recently, much effort has been dedicated to understanding the function, phenotype and development of TRM. A myriad of signals is involved in the development and maintenance of resident memory T cells in tissue. Much of the initial research focused on the roles tissue-derived signals play in the development of TRM, including TGFß and IL-33 which are critical for the upregulation of CD69 and CD103. However, more recent data suggest further roles for antigenic and pro-inflammatory cytokines. This review will focus on the interplay of pro-inflammatory, tissue and antigenic signals in the establishment of resident memory T cells

Reprograming of gut microbiome energy metabolism by the FUT2 Crohn's disease risk polymorphism.

Fucosyltransferase 2 (FUT2) is an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. The H antigen is an oligosaccharide moiety that acts as both an attachment site and carbon source for intestinal bacteria. Non-secretors, who are homozygous for the loss-of-function alleles of FUT2 gene (sese), have increased susceptibility to Crohn's disease (CD). To characterize the effect of FUT2 polymorphism on the mucosal ecosystem, we profiled the microbiome, meta-proteome and meta-metabolome of 75 endoscopic lavage samples from the cecum and sigmoid of 39 healthy subjects (12 SeSe, 18 Sese and 9 sese). Imputed metagenomic analysis revealed perturbations of energy metabolism in the microbiome of non-secretor and heterozygote individuals, notably the enrichment of carbohydrate and lipid metabolism, cofactor and vitamin metabolism and glycan biosynthesis and metabolism-related pathways, and the depletion of amino-acid biosynthesis and metabolism. Similar changes were observed in mice bearing the FUT2(-/-) genotype. Metabolomic analysis of human specimens revealed concordant as well as novel changes in the levels of several metabolites. Human metaproteomic analysis indicated that these functional changes were accompanied by sub-clinical levels of inflammation in the local intestinal mucosa. Therefore, the colonic microbiota of non-secretors is altered at both the compositional and functional levels, affecting the host mucosal state and potentially explaining the association of FUT2 genotype and CD susceptibility

New Constraints on Cosmic Reionization from the 2012 Hubble Ultra Deep Field Campaign

Understanding cosmic reionization requires the identification and characterization of early sources of hydrogen-ionizing photons. The 2012 Hubble Ultra Deep Field (UDF12) campaign has acquired the deepest infrared images with the Wide Field Camera 3 aboard Hubble Space Telescope and, for the first time, systematically explored the galaxy population deep into the era when cosmic microwave background (CMB) data indicates reionization was underway. The UDF12 campaign thus provides the best constraints to date on the abundance, luminosity distribution, and spectral properties of early star-forming galaxies. We synthesize the new UDF12 results with the most recent constraints from CMB observations to infer redshift-dependent ultraviolet (UV) luminosity densities, reionization histories, and electron scattering optical depth evolution consistent with the available data. Under reasonable assumptions about the escape fraction of hydrogen ionizing photons and the intergalactic medium clumping factor, we find that to fully reionize the universe by redshift z~6 the population of star-forming galaxies at redshifts z~7-9 likely must extend in luminosity below the UDF12 limits to absolute UV magnitudes of M_UV\sim -13 or fainter. Moreover, low levels of star formation extending to redshifts z~15-25, as suggested by the normal UV colors of z\simeq7-8 galaxies and the smooth decline in abundance with redshift observed by UDF12 to z\simeq10, are additionally likely required to reproduce the optical depth to electron scattering inferred from CMB observations.Comment: Version accepted by ApJ (originally submitted Jan 5, 2013). The UDF12 website can be found at http://udf12.arizona.ed

Measuring the impact of ambulatory red blood cell transfusion on home functional status: study protocol for a pilot randomized controlled trial

SPIRIT 2013: SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) Checklist for clinical trial protocols. (DOCX 65 kb

The Subaru-XMM-Newton Deep Survey (SXDS) VIII.: Multi-wavelength Identification, Optical/NIR Spectroscopic Properties, and Photometric Redshifts of X-ray Sources

We report the multi-wavelength identification of the X-ray sources found in the Subaru-XMM-Newton Deep Survey (SXDS) using deep imaging data covering the wavelength range between the far-UV to the mid-IR. We select a primary counterpart of each X-ray source by applying the likelihood ratio method to R-band, 3.6micron, near-UV, and 24micron source catalogs as well as matching catalogs of AGN candidates selected in 1.4GHz radio and i'-band variability surveys. Once candidates of Galactic stars, ultra-luminous X-ray sources in a nearby galaxy, and clusters of galaxies are removed there are 896 AGN candidates in the sample. We conduct spectroscopic observations of the primary counterparts with multi-object spectrographs in the optical and NIR; 65\% of the X-ray AGN candidates are spectroscopically-identified. For the remaining X-ray AGN candidates, we evaluate their photometric redshift with photometric data in 15 bands. Utilising the multi-wavelength photometric data of the large sample of X-ray selected AGNs, we evaluate the stellar masses, M*, of the host galaxies of the narrow-line AGNs. The distribution of the stellar mass is remarkably constant from z=0.1 to 4.0. The relation between M* and 2--10 keV luminosity can be explained with strong cosmological evolution of the relationship between the black hole mass and M*. We also evaluate the scatter of the UV-MIR spectral energy distribution (SED) of the X-ray AGNs as a function of X-ray luminosity and absorption to the nucleus. The scatter is compared with galaxies which have redshift and stellar mass distribution matched with the X-ray AGN. The UV-NIR SEDs of obscured X-ray AGNs are similar to those of the galaxies in the matched sample. In the NIR-MIR range, the median SEDs of X-ray AGNs are redder, but the scatter of the SEDs of the X-ray AGN broadly overlaps that of the galaxies in the matched sample.Comment: Accepted for publication in PASJ Subaru special issue. 42 pages, 22 figures. Entire contents of Tables 3, 8, 9, 10, and 11, and ASCII format tables are available from http://www.astr.tohoku.ac.jp/~akiyama/SXDS/index.htm

Exploring the Use of Cost-Benefit Analysis to Compare Pharmaceutical Treatments for Menorrhagia

Background: The extra-welfarist theoretical framework tends to focus on health-related quality of life, whilst the welfarist framework captures a wider notion of well-being. EQ-5D and SF-6D are commonly used to value outcomes in chronic conditions with episodic symptoms, such as heavy menstrual bleeding (clinically termed menorrhagia). Because of their narrow-health focus and the condition’s periodic nature these measures may be unsuitable. A viable alternative measure is willingness to pay (WTP) from the welfarist framework. Objective: We explore the use of WTP in a preliminary cost-benefit analysis comparing pharmaceutical treatments for menorrhagia. Methods: A cost-benefit analysis was carried out based on an outcome of WTP. The analysis is based in the UK primary care setting over a 24-month time period, with a partial societal perspective. Ninety-nine women completed a WTP exercise from the ex-ante (pre-treatment/condition) perspective. Maximum average WTP values were elicited for two pharmaceutical treatments, levonorgestrel-releasing intrauterine system (LNG-IUS) and oral treatment. Cost data were offset against WTP and the net present value derived for treatment. Qualitative information explaining the WTP values was also collected. Results: Oral treatment was indicated to be the most cost-beneficial intervention costing £107 less than LNG-IUS and generating £7 more benefits. The mean incremental net present value for oral treatment compared with LNG-IUS was £113. The use of the WTP approach was acceptable as very few protests and non-responses were observed. Conclusion: The preliminary cost-benefit analysis results recommend oral treatment as the first-line treatment for menorrhagia. The WTP approach is a feasible alternative to the conventional EQ-5D/SF-6D approaches and offers advantages by capturing benefits beyond health, which is particularly relevant in menorrhagia

Integrative analysis of the microbiome and metabolome of the human intestinal mucosal surface reveals exquisite inter-relationships

Background: Consistent compositional shifts in the gut microbiota are observed in IBD and other chronic intestinal disorders and may contribute to pathogenesis. The identities of microbial biomolecular mechanisms and metabolic products responsible for disease phenotypes remain to be determined, as do the means by which such microbial functions may be therapeutically modified. Results: The composition of the microbiota and metabolites in gut microbiome samples in 47 subjects were determined. Samples were obtained by endoscopic mucosal lavage from the cecum and sigmoid colon regions, and each sample was sequenced using the 16S rRNA gene V4 region (Illumina-HiSeq 2000 platform) and assessed by UPLC mass spectroscopy. Spearman correlations were used to identify widespread, statistically significant microbial-metabolite relationships. Metagenomes for identified microbial OTUs were imputed using PICRUSt, and KEGG metabolic pathway modules for imputed genes were assigned using HUMAnN. The resulting metabolic pathway abundances were mostly concordant with metabolite data. Analysis of the metabolome-driven distribution of OTU phylogeny and function revealed clusters of clades that were both metabolically and metagenomically similar. Conclusions: The results suggest that microbes are syntropic with mucosal metabolome composition and therefore may be the source of and/or dependent upon gut epithelial metabolites. The consistent relationship between inferred metagenomic function and assayed metabolites suggests that metagenomic composition is predictive to a reasonable degree of microbial community metabolite pools. The finding that certain metabolites strongly correlate with microbial community structure raises the possibility of targeting metabolites for monitoring and/or therapeutically manipulating microbial community function in IBD and other chronic diseases

The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve

First insights into the ISM at z > 8 with JWST: possible physical implications of a high [O III] λ4363/[O III] λ5007

© 2022 The Author(s). Published by Oxford University Press on behalf of Royal Astronomical Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.We present a detailed analysis of the rest-frame optical emission line ratios for three spectroscopically confirmed galaxies at z > 7.5. The galaxies were identified in the James Webb Space Telescope (JWST) Early Release Observations field SMACS J0723.3 − 7327. By quantitatively comparing Balmer and oxygen line ratios of these galaxies with various low-redshift ‘analogue’ populations (e.g. Green Peas, Blueberries, etc.), we show that no single analogue population captures the diversity of line ratios of all three galaxies observed at z > 7.5. We find that S06355 at z = 7.67 and S10612 at z = 7.66 are similar to local Green Peas and Blueberries. In contrast, S04590 at z = 8.50 appears to be significantly different from the other two galaxies, most resembling extremely low-metallicity systems in the local Universe. Perhaps the most striking spectral feature in S04590 is the curiously high [O III] λ4363/[O III] λ5007 ratio (RO3) of 0.048 (or 0.055 when dust-corrected), implying either extremely high electron temperatures, >3 × 104 K, or gas densities >104 cm−3. Observed line ratios indicate that this galaxy is unlikely to host an AGN. Using photoionization modelling, we show that the inclusion of high-mass X-ray binaries or a high cosmic ray background in addition to a young, low-metallicity stellar population can provide the additional heating necessary to explain the observed high RO3 while remaining consistent with other observed line ratios. Our models represent a first step at accurately characterizing the dominant sources of photoionization and heating at very high redshifts, demonstrating that non-thermal processes may become important as we probe deeper into the Epoch of Reionization.Peer reviewe