TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments.

T cell responses are inhibited by acidic environments. T cell receptor (TCR)-induced protein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination, but the mechanisms underlying sensitivity to acidic environments are not fully understood. Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitin ligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interaction depended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acid in an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumor models. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidity and regulates T cell responses, presenting a potential therapeutic target for improving anti-tumor immunity.

Evaluation of the effects of three different processing methods of aconite on rat metabolites based on high-coverage pseudotargeted metabolomics.

Aconite is the processed product of the seed root of Aconitum carmichaelii Debx. Aconite is a commonly used traditional Chinese medicine, which is generally used after processing. Black aconite, light aconite, and salted aconite are three different processed aconite products. They have the effects of restoring yang and saving energy enemy, dispersing cold, and relieving pain. However, clinical aconite poisoning cases have frequently been reported. In our study, we investigated the effects of three different processed aconite products on the changes of metabolites in vivo. A total of 42 rats were randomly divided into seven groups with six rats in each group. After three consecutive days of intragastric administration of 2.7 g/kg of the aconite-processed product, rat serums were obtained. The rat metabolites were detected using liquid chromatography-tandem mass spectrometry. The altered metabolites related to aconite-processed products were discovered by statistical analysis using metaboanalyst software. Our study is the first time to comprehensively evaluate the effects of three different processed aconite products on rat metabolites based on pseudotargeted metabolomics.

Revealing Variable Dependences in Hexagonal Boron Nitride Synthesis via Machine Learning.

Wafer-scale monolayer two-dimensional (2D) materials have been realized by epitaxial chemical vapor deposition (CVD) in recent years. To scale up the synthesis of 2D materials, a systematic analysis of how the growth dynamics depend on the growth parameters is essential to unravel its mechanisms. However, the studies of CVD-grown 2D materials mostly adopted the control variate method and considered each parameter as an independent variable, which is not comprehensive for 2D materials growth optimization. Herein, we synthesized a representative 2D material, monolayer hexagonal boron nitride (hBN), on single-crystalline Cu (111) by epitaxial chemical vapor deposition and varied the growth parameters to regulate the hBN domain sizes. Furthermore, we explored the correlation between two growth parameters and provided the growth windows for large flake sizes by the Gaussian process. This new analysis approach based on machine learning provides a more comprehensive understanding of the growth mechanism for 2D materials.

Correction: Highly reusable nanoporous silver sheet for sensitive SERS detection of pesticides.

Correction for 'Highly reusable nanoporous silver sheet for sensitive SERS detection of pesticides' by Huanyu Chi et al., Analyst, 2020, 145, 5158-5165, https://doi.org/10.1039/D0AN00999G.

Characterizing warm atmospheric boundary layer over land by combining Raman and Doppler lidar measurements.

PBL plays a critical role in the atmosphere by transferring heat, moisture, and momentum. The warm PBL has a distinct diurnal cycle including daytime convective mixing layer (ML) and nighttime residual layer developments. Thus, for PBL characterization and process study, simultaneous determinations of PBL height (PBLH) and ML height (MLH) are necessary. Here, new approaches are developed to provide reliable PBLH and MLH to characterize warm PBL evolution. The approaches use Raman lidar (RL) water vapor mixing ratio (WVMR) and Doppler lidar (DL) vertical velocity measurements at the Southern Great Plains (SGP) atmospheric observatory, which was established by the Atmospheric Radiation Measurement (ARM) user facility. Compared with widely used lidar aerosol measurements for PBLH, WVMR is a better trace for PBL vertical mixing. For PBLH, the approach classifies PBL water vapor structures into a few general patterns, then uses a slope method and dynamic threshold method to determine PBLH. For MLH, wavelet analysis is used to re-construct 2-D variance from DL vertical wind velocity measurements according to the turbulence eddy size to minimize the impacts of gravity wave and eddy size on variance calculations; then, a dynamic threshold method is used to determine MLH. Remotely-sensed PBLHs and MLHs are compared with radiosonde measurements based on the Richardson number method. Good agreements between them confirm that the proposed new algorithms are reliable for PBLH and MLH characterization. The algorithms are applied to warm seasons' RL and ML measurements at the SGP site for five years to study warm season PBL structure and processes. The weekly composited diurnal evolutions of PBLHs and MLHs in warm climate were provided to illustrate diurnal and seasonal PBL evolutions. This reliable PBLH and MLH dataset will be valuable for PBL process study, model evolution, and PBL parameterization improvement.

Highly reusable nanoporous silver sheet for sensitive SERS detection of pesticides.

Surface-enhanced Raman spectroscopy (SERS) enables pesticide detection at the point-of-need, but its practical application is limited by expensive and disposable SERS substrates. Here, we report a reusable nanoporous silver (NPAg) sheet for the SERS detection of organochlorine pesticides, aiming to maximize the cost-efficiency of substrate regeneration. The NPAg sheet is prepared by a reduction-induced decomposition method without chemical induced random aggregations. This SERS substrate is sensitive to various analytes regardless of their affinity to a metal surface such as rhodamine B, dichlorodiphenyl-trichloroethane (DDT), and lindane due to its large surface area and the coral rock-like morphology. The SERS signal of lindane, a typical organochlorine pesticide, is identified and quantified with a minimum detectable concentration of 3 × 10-7 M (87 ppb), which is below the maximum residue limits in various foods set by the regulators across the world. More importantly, after a few minutes of ultrasonic cleaning in water, the NPAg sheet can be reused at least 20 times with a reproducible SERS activity. Furthermore, the NPAg sheet remains stable in terms of its sensitivity and reusability after several months of bare strorage. Therefore, the NPAg sheet as a SERS substrate holds great promise for mass production and convenient applications in low-cost pesticide analysis.

Airborne compact rotational Raman lidar for temperature measurement.

We developed an airborne compact rotational Raman lidar (CRL) for use on the University of Wyoming King Air (UWKA) aircraft to obtain two-dimensional (2D) temperature disman tributions. It obtained fine-scale 2D temperature distributions within 3 km below the aircraft for the first time during the PECAN (Plains Elevated Convection At Night) campaign in 2015. The CRL provided nighttime temperature measurements with a random error of <0.5 K within 800 m below aircraft at 45 m vertical and 1000 m horizontal resolution. The temperatures obtained by the CRL and a radiosonde agreed. Along with water vapor and aerosol measurements, the CRL provides critical parameters on the state of the lower atmosphere for a wide range of atmospheric research.

Vertically resolved separation of dust and other aerosol types by a new lidar depolarization method.

This paper developed a new retrieval framework of external mixing of the dust and non-dust aerosol to predict the lidar ratio of the external mixing aerosols and to separate the contributions of non-spherical aerosols by using different depolarization ratios among dust, sea salt, smoke, and polluted aerosols. The detailed sensitivity tests and case study with the new method showed that reliable dust information could be retrieved even without prior information about the non-dust aerosol types. This new method is suitable for global dust retrievals with satellite observations, which is critical for better understanding global dust transportation and for model improvements.

Compact airborne Raman lidar for profiling aerosol, water vapor and clouds.

A compact airborne Raman lidar system, which can perform water vapor and aerosol measurements both during nighttime and daytime is described. The system design, setup and the data processing methods are described in the paper. The Raman lidar was tested on University of Wyoming King Air research aircraft (UWKA) during the Wyoming King Air PBL Exploratory Experiment (KAPEE) in 2010. An observation showing clouds, aerosols and a dry line is presented to illustrate the lidar detection capabilities. Comparisons of the water vapor and aerosol measurements using the Raman lidar and other in situ airborne instruments show good agreement.

Telocytes link epithelial nutrient sensing with amplification of the ILC2-tuft cell circuit.

Group 2 innate lymphocytes (ILC2s) are prevalent in small intestine but engagement of type 2 immunity during basal processes are incompletely described. Thymic stromal lymphopoietin (TSLP), a cytokine implicated in ILC2 activation, was constitutively expressed in villus telocytes and crypt-associated trophocytes, specialized fibroblasts that sustain epithelial identity. Feeding increased TSLP and induced ILC2 type 2 cytokines that were attenuated by deletion of TSLP in PDGFRα + stromal cells or TSLP receptor on ILC2s. Mouse and human telocytes expressed receptors for glucagon-like peptide-2 (GLP-2), which is released by enteroendocrine cells (EECs) after eating. GLP-2 induced intestinal TSLP, TSLP-dependent ILC2 cytokine production, and tuft cell hyperplasia. The telocyte-alarmin relay couples EEC nutrient detection with amplification of a tuft cell chemosensory circuit that diversifies surveillance of ingested cargo. One-Sentence Summary: Intestinal telocyte TSLP relays signals from enteroendocrine cells to ILC2s to amplify the tuft cell circuit in response to feeding.

Graphene-integrated mesh electronics with converged multifunctionality for tracking multimodal excitation-contraction dynamics in cardiac microtissues.

Cardiac microtissues provide a promising platform for disease modeling and developmental studies, which require the close monitoring of the multimodal excitation-contraction dynamics. However, no existing assessing tool can track these multimodal dynamics across the live tissue. We develop a tissue-like mesh bioelectronic system to track these multimodal dynamics. The mesh system has tissue-level softness and cell-level dimensions to enable stable embedment in the tissue. It is integrated with an array of graphene sensors, which uniquely converges both bioelectrical and biomechanical sensing functionalities in one device. The system achieves stable tracking of the excitation-contraction dynamics across the tissue and throughout the developmental process, offering comprehensive assessments for tissue maturation, drug effects, and disease modeling. It holds the promise to provide more accurate quantification of the functional, developmental, and pathophysiological states in cardiac tissues, creating an instrumental tool for improving tissue engineering and studies.

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This study presents a multi-center clinical data management platform that facilitates unified and structured management of real-world data and serves as an ideal tool to enhance the quality and progress of clinical research related to severe acute pancreatitis (SAP). The use of the platform enables clinical teams to obtain safe, accurate, structurally unified, traceable, scene-clear, and fully functional real-world medical data in the diagnosis, treatment, and research of acute pancreatitis (AP).

CD45-positive cells are not an essential component in cardiosphere formation.

The cardiosphere (CS) is composed of a heterogeneous population of cells, including CD45(+) cells that are bone marrow (BM)-derived. However, whether the CD45(+) cells are an essential cell component in CS formation is unknown. The current study was undertaken to address this question. Cardiospheres (CSs) were harvested from 1-week post-myocardial infarction (MI) or non-MI hearts of C57BL/6 J mice. The process of CS formation was observed by timelapse photography. To analyze the role of BM-derived CD45(+) cells in CS formation, CD45(+) cells were depleted from populations of CS-forming cells by immunomagnetic beads. We recorded the number of CSs formed in culture from the same amount (10(5)) of intact CS-forming cells, from CD45(+)-cell-depleted CS-forming cells and from CD45(+) cells alone (n=6-9/cell type). CS-forming cells selectively aggregated together to form CSs by 35 h after plating. The depletion of CD45(+) cells from CS-forming cells actually increased the formation of CSs (67±10 CSs/10(5) cells) compared with non-depleted CS-forming cells (51±6 CSs/10(5) cells, P<0.0001). Purified CD45(+) cells from CS-forming cells did not form CSs in culture. Thus, BM-derived CD45(+) cells including BM progenitors are neither necessary nor sufficient for CS formation.

Improved calibration method for depolarization lidar measurement.

An improved calibration method for lidar depolarization measurement is described. With this method the system constants including the electronic gain ratio of the parallel and perpendicular channels, the optical reflectance and transmission parameters of the polarizing beam splitter, and the linear polarization ratio of the emitting laser beam can be determined conveniently by using lidar measurements with a half-wave plate oriented at selected angles.

Retrieval of effective complex refractive index from intensive measurements of characteristics of ambient aerosols in the boundary layer.

Aerosol complex refractive index (ACRI) has attracted intensive attentions due to its significance in modeling aerosol radiative effects. Determinations of ACRI from surface measurements of aerosol scattering and absorption coefficients as well as number size distributions during June, 2008 based on an iterative Mie algorithm were performed. The aim of our study was to introduce an inversion approach with the merits of high time-resolutions to retrieve the optically effective ACRI, especially its imaginary part. Based on simultaneous measurements of aerosol characteristics, mean ACRI value of 1.50 ( ± 0.34)-i0.025 ( ± 0.015) at 550 nm in Hefei in summer was deducted. The lower imaginary parts with higher single scattering albedos and lower scattering Angstrom exponents were obtained for haze periods compared with nonhaze conditions with similar air-mass back-trajectories, indicating more large and scattering particles contributing to the formation of haze episodes. The derived imaginary parts of ACRI related to agricultural biomass burning were in the range from 0.013 to 0.029 at 550 nm. Significant negative correlations between retrieved imaginary parts of ACRI and measured single scattering albedos indicate that our retrieval approach is a reasonable method for determining the imaginary parts of complex refractive indices of aerosol particles.

Low-thermal-budget synthesis of monolayer molybdenum disulfide for silicon back-end-of-line integration on a 200 mm platform.

Two-dimensional (2D) materials are promising candidates for future electronics due to their excellent electrical and photonic properties. Although promising results on the wafer-scale synthesis (≤150 mm diameter) of monolayer molybdenum disulfide (MoS2) have already been reported, the high-quality synthesis of 2D materials on wafers of 200 mm or larger, which are typically used in commercial silicon foundries, remains difficult. The back-end-of-line (BEOL) integration of directly grown 2D materials on silicon complementary metal-oxide-semiconductor (CMOS) circuits is also unavailable due to the high thermal budget required, which far exceeds the limits of silicon BEOL integration (<400 °C). This high temperature forces the use of challenging transfer processes, which tend to introduce defects and contamination to both the 2D materials and the BEOL circuits. Here we report a low-thermal-budget synthesis method (growth temperature < 300 °C, growth time ≤ 60 min) for monolayer MoS2 films, which enables the 2D material to be synthesized at a temperature below the precursor decomposition temperature and grown directly on silicon CMOS circuits without requiring any transfer process. We designed a metal-organic chemical vapour deposition reactor to separate the low-temperature growth region from the high-temperature chalcogenide-precursor-decomposition region. We obtain monolayer MoS2 with electrical uniformity on 200 mm wafers, as well as a high material quality with an electron mobility of ~35.9 cm2 V-1 s-1. Finally, we demonstrate a silicon-CMOS-compatible BEOL fabrication process flow for MoS2 transistors; the performance of these silicon devices shows negligible degradation (current variation < 0.5%, threshold voltage shift < 20 mV). We believe that this is an important step towards monolithic 3D integration for future electronics.

Murine B cells regulate serum IgE levels in a CD23-dependent manner.

The manifestations of allergic disorders are closely tied to the biologic effects of IgE activation with Ag. In immediate hypersensitivity reactions, IgE effector function requires prior binding to innate immune cells, primarily mast cells and basophils, with the blood acting as a reservoir for unbound IgE. As the severity of allergic disease is proportional to the size of this unbound IgE pool, we hypothesized that cellular mechanisms exist to limit the size and/or enhance the clearance of free IgE molecules. We examined this in mice by engineering a reporter IgE molecule that allowed us to track the fate of IgE molecules in vivo. The absence of FcεRI-expressing cells did not affect serum IgE levels, but B cells regulated serum IgE by controlling the size of the free IgE pool. B cells captured IgE by direct binding to the low-affinity IgE receptor, CD23. These data indicate a mechanism regulating serum IgE and additionally clarify the role of CD23 in this process.

Lymphocyte development requires S-nitrosoglutathione reductase.

NO is critical to immunity, but its role in the development of the immune system is unknown. In this study, we show that S-nitrosoglutathione reductase (GSNOR), a protein key to the control of protein S-nitrosylation, is important for the development of lymphocytes. Genetic deletion of GSNOR in mice results in significant decrease in both T and B lymphocytes in the periphery. In thymus, GSNOR deficiency causes excessive protein S-nitrosylation, increases apoptosis, and reduces the number of CD4 single-positive thymocytes. Lymphopenia and increase in S-nitrosylation and apoptosis in GSNOR-deficient mice are largely abolished by genetic deletion of inducible NO synthase. Furthermore, the protection of lymphocyte development by GSNOR is apparently intrinsic to hematopoietic cells. Thus, GSNOR, likely through regulation of S-nitrosylation and apoptosis, physiologically plays a protective role in the development of the immune system.

The "Two-Step" approach for classifying the severity of acute pancreatitis: A retrospective study.

BACKGROUND: The Revised Atlanta Classification (RAC) and Determinant-Based Classification (DBC) are currently two widely adopted systems for evaluating the severity of acute pancreatitis (AP). This study aimed to overcome the inaccuracies and limitations that existed in them. METHODS: We retrospectively analyzed 298 patients with AP. The "Two-Step" approach was divided into an early organ failure (OF) assessment: (I) none, (II) transient, (III) single persistent, and (IV) multiple persistent; and a later local complications assessment: (A) none, (B) sterile, and (C) infectious. Patients with AP who died before the second step were classified into category X. The "Two-Step" approach was then compared to the RAC and DBC. RESULTS: As the patients' grades increased (I to IV), organ support treatment rates, intensive care unit lengths of stay, and mortalities increased. Invasive intervention rates displayed increasing trends with local complications aggravated (A to C). Patients in category X were older and had higher Marshall scores with the highest grades of severity. CONCLUSIONS: By combining the early OF grades and the late local complications, the "Two-Step" approach represents an accurate classification system required for stratified studies of AP, and introduces the category X as the severest forms of AP.

Cbl-b deficiency prevents functional but not phenotypic T cell anergy.

T cell anergy is an important peripheral tolerance mechanism. We studied how T cell anergy is established using an anergy model in which the Zap70 hypermorphic mutant W131A is coexpressed with the OTII TCR transgene (W131AOTII). Anergy was established in the periphery, not in the thymus. Contrary to enriched tolerance gene signatures and impaired TCR signaling in mature peripheral CD4 T cells, CD4SP thymocytes exhibited normal TCR signaling in W131AOTII mice. Importantly, the maintenance of T cell anergy in W131AOTII mice required antigen presentation via MHC-II. We investigated the functional importance of the inhibitory receptor PD-1 and the E3 ubiquitin ligases Cbl-b and Grail in this model. Deletion of each did not affect expression of phenotypic markers of anergic T cells or T reg numbers. However, deletion of Cbl-b, but not Grail or PD-1, in W131AOTII mice restored T cell responsiveness and signaling. Thus, Cbl-b plays an essential role in the establishment and/or maintenance of unresponsiveness in T cell anergy.