Resident Skin-specific γδ T Cells Provide Local, Nonredundant Regulation of Cutaneous Inflammation

The function of the intraepithelial lymphocyte (IEL) network of T cell receptor (TCR) γδ+ (Vγ5+) dendritic epidermal T cells (DETC) was evaluated by examining several mouse strains genetically deficient in γδ T cells (δ−/− mice), and in δ−/− mice reconstituted with DETC or with different γδ cell subpopulations. NOD.δ−/− and FVB.δ−/− mice spontaneously developed localized, chronic dermatitis, whereas interestingly, the commonly used C57BL/6.δ−/− strain did not. Genetic analyses indicated a single autosomal recessive gene controlled the dermatitis susceptibility of NOD.δ−/− mice. Furthermore, allergic and irritant contact dermatitis reactions were exaggerated in FVB.δ−/−, but not in C57BL/6.δ−/− mice. Neither spontaneous nor augmented irritant dermatitis was observed in FVB.β−/− δ−/− mice lacking all T cells, indicating that αβ T cell–mediated inflammation is the target for γδ-mediated down-regulation. Reconstitution studies demonstrated that both spontaneous and augmented irritant dermatitis in FVB.δ−/− mice were down-regulated by Vγ5+ DETC, but not by epidermal T cells expressing other γδ TCRs. This study demonstrates that functional impairment at an epithelial interface can be specifically attributed to absence of the local TCR-γδ+ IEL subset and suggests that systemic inflammatory reactions may more generally be subject to substantial regulation by local IELs

Guidelines and considerations for the use of system suitability and quality control samples in mass spectrometry assays applied in untargeted clinical metabolomic studies

Background Quality assurance (QA) and quality control (QC) are two quality management processes that are integral to the success of metabolomics including their application for the acquisition of high quality data in any high-throughput analytical chemistry laboratory. QA defines all the planned and systematic activities implemented before samples are collected, to provide confidence that a subsequent analytical process will fulfil predetermined requirements for quality. QC can be defined as the operational techniques and activities used to measure and report these quality requirements after data acquisition. Aim of review This tutorial review will guide the reader through the use of system suitability and QC samples, why these samples should be applied and how the quality of data can be reported. Key scientific concepts of review System suitability samples are applied to assess the operation and lack of contamination of the analytical platform prior to sample analysis. Isotopically-labelled internal standards are applied to assess system stability for each sample analysed. Pooled QC samples are applied to condition the analytical platform, perform intra-study reproducibility measurements (QC) and to correct mathematically for systematic errors. Standard reference materials and long-term reference QC samples are applied for inter-study and inter-laboratory assessment of data

The Distinct Contributions of Murine T Cell Receptor (TCR)γδ+ and TCRαβ+ T Cells to Different Stages of Chemically Induced Skin Cancer

Epithelial tissues in which carcinomas develop often contain systemically derived T cell receptor (TCR)αβ+ cells and resident intraepithelial lymphocytes that are commonly enriched in TCRγδ+ cells. Recent studies have demonstrated that γδ cells protect the host against chemically induced cutaneous malignancy, but the role of αβ T cells has been enigmatic, with both protective and tumor-enhancing contributions being reported in different systems. This study aims to clarify the contributions of each T cell type to the regulation of squamous cell carcinoma induced in FVB mice by a two-stage regimen of 7,12-dimethylbenz[a]anthracene initiation followed by repetitive application of the tumor promoter 12-O-tetradecanoylphorbol 13-acetate. This protocol permits one to monitor the induction of papillomas and the progression of those papillomas to carcinomas. The results show that whereas γδ cells are strongly protective, the nonredundant contributions of αβ T cells to the host's protection against papillomas are more modest. Furthermore, at both high and low doses of carcinogens, αβ T cells can contribute to rather than inhibit the progression of papillomas to carcinomas. As is likely to be the case in humans, this study also shows that the contribution of T cells to tumor immunosurveillance is regulated by modifier genes

Variability between human experts and artificial intelligence in identification of anatomical structures by ultrasound in regional anaesthesia: a framework for evaluation of assistive artificial intelligence

Background: ScanNavTM Anatomy Peripheral Nerve Block (ScanNav™) is an artificial intelligence (AI)-based device that produces a colour overlay on real-time B-mode ultrasound to highlight key anatomical structures for regional anaesthesia. This study compares consistency of identification of sono-anatomical structures between expert ultrasonographers and ScanNav™. Methods: Nineteen experts in ultrasound-guided regional anaesthesia (UGRA) annotated 100 structures in 30 ultrasound videos across six anatomical regions. These annotations were compared with each other to produce a quantitative assessment of the level of agreement amongst human experts. The AI colour overlay was then compared with all expert annotations. Differences in human–human and human–AI agreement are presented for each structure class (artery, muscle, nerve, fascia/serosal plane) and structure. Clinical context is provided through subjective assessment data from UGRA experts. Results: For human–human and human–AI annotations, agreement was highest for arteries (mean Dice score 0.88/0.86), then muscles (0.80/0.77), and lowest for nerves (0.48/0.41). Wide discrepancy exists in consistency for different structures, both with human–human and human–AI comparisons; highest for sartorius muscle (0.91/0.92) and lowest for the radial nerve (0.21/0.27). Conclusions: Human experts and the AI system both showed the same pattern of agreement in sono-anatomical structure identification. The clinical significance of the differences presented must be explored; however the perception that human expert opinion is uniform must be challenged. Elements of this assessment framework could be used for other devices to allow consistent evaluations that inform clinical training and practice. Anaesthetists should be actively engaged in the development and adoption of new AI technology

Impact of Achieved Blood Pressure on Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial

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Discovery and Timing of Millisecond Pulsars with the Arecibo 327 MHz Drift-Scan Survey

We present the discovery and timing solutions of four millisecond pulsars (MSPs) discovered in the Arecibo 327 MHz Drift-Scan Pulsar Survey. Three of these pulsars are in binary systems, consisting of a redback (PSR J2055+1545), a black widow (PSR J1630+3550), and a neutron star-white dwarf binary (PSR J2116+1345). The fourth MSP, PSR J2212+2450, is isolated. We present the multi-year timing solutions as well as polarization properties across a range of radio frequencies for each pulsar. We perform a multi-wavelength search for emission from these systems and find an optical counterpart for PSR J2055+1545 in Gaia DR3, as well as a gamma-ray counterpart for PSR J2116+1345 with the Fermi-LAT telescope. Despite the close co-location of PSR J2055+1545 with a Fermi source, we are unable to detect gamma-ray pulsations, likely due to the large orbital variability of the system. This work presents the first two binaries found by this survey with orbital periods shorter than a day; we expect to find more in the 40% of the survey data which have yet to be searched.Comment: 20 pages, 11 figures, 4 tables. Submitted to Ap

Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures