Absence of Appl2 sensitizes endotoxin shock through activation of PI3K/Akt pathway

BACKGROUND: The adapter proteins Appl1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif 1) and Appl2 are highly homologous and involved in several signaling pathways. While previous studies have shown that Appl1 plays a pivotal role in adiponectin signaling and insulin secretion, the physiological functions of Appl2 are largely unknown. RESULTS: In the present study, the role of Appl2 in sepsis shock was investigated by using Appl2 knockout (KO) mice. When challenged with lipopolysaccharides (LPS), Appl2 KO mice exhibited more severe symptoms of endotoxin shock, accompanied by increased production of proinflammatory cytokines. In comparison with the wild-type control, deletion of Appl2 led to higher levels of TNF-α and IL-1β in primary macrophages. In addition, phosphorylation of Akt and its downstream effector NF-κB was significantly enhanced. By co-immunoprecipitation, we found that Appl2 and Appl1 interacted with each other and formed a complex with PI3K regulatory subunit p85α, which is an upstream regulator of Akt. Consistent with these results, deletion of Appl1 in macrophages exhibited characteristics of reduced Akt activation and decreased the production of TNFα and IL-1β when challenged by LPS. CONCLUSIONS: Results of the present study demonstrated that Appl2 is a critical negative regulator of innate immune response via inhibition of PI3K/Akt/NF-κB signaling pathway by forming a complex with Appl1 and PI3K.published_or_final_versio

A State-of-the-Science Review on High-Resolution Metabolomics Application in Air Pollution Health Research: Current Progress, Analytical Challenges, and Recommendations for Future Direction

BACKGROUND: Understanding the mechanistic basis of air pollution toxicity is dependent on accurately characterizing both exposure and biological responses. Untargeted metabolomics, an analysis of small-molecule metabolic phenotypes, may offer improved estimation of exposures and corresponding health responses to complex environmental mixtures such as air pollution. The field remains nascent, however, with questions concerning the coherence and generalizability of findings across studies, study designs and analytical platforms. OBJECTIVES: We aimed to review the state of air pollution research from studies using untargeted high-resolution metabolomics (HRM), highlight the areas of concordance and dissimilarity in methodological approaches and reported findings, and discuss a path forward for future use of this analytical platform in air pollution research. METHODS: We conducted a state-of-the-science review to a) summarize recent research of air pollution studies using untargeted metabolomics and b) identify gaps in the peer-reviewed literature and opportunities for addressing these gaps in future designs. We screened articles published within Pubmed and Web of Science between 1 January 2005 and 31 March 2022. Two reviewers independently screened 2,065 abstracts, with discrepancies resolved by a third reviewer. RESULTS: We identified 47 articles that applied untargeted metabolomics on serum, plasma, whole blood, urine, saliva, or other biospecimens to investigate the impact of air pollution exposures on the human metabolome. Eight hundred sixteen unique features confirmed with level-1 or-2 evidence were reported to be associated with at least one or more air pollutants. Hypoxanthine, histidine, serine, aspartate, and glutamate were among the 35 metabolites consistently exhibiting associations with multiple air pollutants in at least 5 independent studies. Oxidative stress and inflammation-related pathways—including glycerophospholipid metabolism, pyrimidine metabolism, methionine and cysteine metabolism, tyrosine metabolism, and tryptophan metabolism—were the most commonly perturbed pathways reported in >70% of studies. More than 80% of the reported features were not chemically annotated, limiting the interpretability and generalizability of the findings. CONCLUSIONS: Numerous investigations have demonstrated the feasibility of using untargeted metabolomics as a platform linking exposure to internal dose and biological response. Our review of the 47 existing untargeted HRM–air pollution studies points to an underlying coherence and consistency across a range of sample analytical quantitation methods, extraction algorithms, and statistical modeling approaches. Future directions should focus on validation of these findings via hypothesis-driven protocols and technical advances in metabolic annotation and quantification. https://doi.org/10.1289/EHP11851

The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice

Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19+ cells. Increased myeloid subsets, including CD11c+ DCs and F4/80+ macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase

In situ tailored strategy to remove capping agents from copper sulfide for building better lithium–sulfur batteries

Capping agents are frequently used in the chemical synthesis of materials, to precisely tailor the size, shape, and composition, with the expectation of high-performance catalysis. However, the adsorbed capping agents also serve as a physical barrier to restrict the interaction between reactants and catalytically active sites on the material surface. In this article, an in situ tailored interface strategy is introduced for effectively removing capping agents (long-chain oleylamine) from the surface of copper sulfide, to maximize the catalytic activity. The interface long-chain molecules of oleylamine are replaced by the inorganic S2- ion via a facile stirring approach without harsh processing conditions or the need for additional non-commercial materials. The as-cleaned copper sulfide shows greatly enhanced activity toward lithium-sulfur batteries, with an impressive current rate, excellent cycling stability, and great rate capability. These "clean surface"strategies using interface engineering provide a significant insight into the structure-activity relationships to support advancements in electrocatalysis technology in lithium-sulfur batteries. This journal i

Harmine Induces Adipocyte Thermogenesis through RAC1-MEK-ERK-CHD4 Axis

© The Author(s) 2016.Harmine is a natural compound possessing insulin-sensitizing effect in db/db diabetic mice. However its effect on adipose tissue browning is unknown. Here we reveal that harmine antagonizes high fat diet-induced adiposity. Harmine-treated mice gained less weight on a high fat diet and displayed increased energy expenditure and adipose tissue thermogenesis. In vitro, harmine potently induced the expression of thermogenic genes in both brown and white adipocytes, which was largely abolished by inhibition of RAC1/MEK/ERK pathway. Post-transcriptional modification analysis revealed that chromodomain helicase DNA binding protein 4 (CHD4) is a potential downstream target of harmine-mediated ERK activation. CHD4 directly binds the proximal promoter region of Ucp1, which is displaced upon treatment of harmine, thereby serving as a negative modulator of Ucp1. Thus, here we reveal a new application of harmine in combating obesity via this off-target effect in adipocytes.published_or_final_versio

Study on Birkhoff orthogonality and symmetry of matrix operators

We focus on the problem of generalized orthogonality of matrix operators in operator spaces. Especially, on ℬ(l1n,lpn)(1≤p≤∞){\mathcal{ {\mathcal B} }}\left({l}_{1}^{n},{l}_{p}^{n})\left(1\le p\le \infty ), we characterize Birkhoff orthogonal elements of a certain class of matrix operators and point out the conditions for matrix operators which satisfy the Bhatia-Šemrl property. Furthermore, we give some conclusions which are related to the Bhatia-Šemrl property. In a certain class of matrix operator space, such as ℬ(l∞n){\mathcal{ {\mathcal B} }}\left({l}_{\infty }^{n}), the properties of the left and right symmetry are discussed. Moreover, the equivalence condition for the left symmetry of Birkhoff orthogonality of matrix operators on ℬ(lpn)(1<p<∞){\mathcal{ {\mathcal B} }}\left({l}_{p}^{n})\left(1\lt p\lt \infty ) is obtained

Digital Fluxgate Magnetometer for Detection of Microvibration

In engineering practice, instruments, such as accelerometer and laser interferometer, are widely used in vibration measurement of structural parts. A method for using a triaxial fluxgate magnetometer as a microvibration sensor to measure low-frequency pendulum microvibration (not translational vibration) is proposed in this paper, so as to detect vibration from low-frequency vibration sources, such as large rotating machine, large engineering structure, earthquake, and microtremor. This method provides vibration detection based on the environmental magnetic field signal to avoid increased measurement difficulty and error due to different relative positions of permanent magnet and magnetometer on the device under test (DUT) when using the original magnetic measurement method. After fixedly connecting the fluxgate probe with the DUT during the test, the angular displacement due to vibration can be deduced by measuring the geomagnetic field’s magnetic induction intensity change on the orthogonal three components during the vibration. The test shows that the microvibration sensor has angular resolution of over 0.05° and maximum measuring frequency of 64 Hz. As an exploring test aimed to detect the microvibration of earth-orbiting satellite in the in-orbit process, the simulation experiment successfully provides the real-time microvibration information for attitude and orbit control subsystem

Assessing the Impacts of Urbanization on Albedo in Jing-Jin-Ji Region of China

As an indicative parameter that represents the ability of the Earth&rsquo;s surface to reflect solar radiation, albedo determines the allocation of solar energy between the Earth&rsquo;s surface and the atmosphere, which plays an important role in both global and local climate change. Urbanization is a complicated progress that greatly affects urban albedo via land cover change, human heat, aerosol, and other human activities. Although many studies have been conducted to identify the effects of these various factors on albedo separately, there are few studies that have quantitatively determined the combined effects of urbanization on albedo. In this study, based on a partial derivative method, vegetation index data and nighttime light data were used to quantitatively calculate the natural climate change and human activities&rsquo; contributions to albedo variations in the Jing-Jin-Ji region, during its highest population growth period from 2001 to 2011. The results show that (1) 2005 is the year when urbanization starts accelerating in the Jing-Jin-Ji region; (2) albedo trends are equal to 0.0065 year&minus;1 before urbanization and 0.0012 year&minus;1 after urbanization, which is a reduction of 4/5; and (3) the contribution rate of urbanization increases from 15% to 48.4%, which leads to a decrease in albedo of approximately 0.05. Understanding the contribution of urbanization to variations in urban albedo is significant for future studies on urban climate change via energy balance and can provide scientific data for energy conservation policymaking

Characterization of transverse tensile, interlaminar shear and interlaminate fracture in CF/EP laminates with 10 wt% and 20 wt% silica nanoparticles in matrix resins

The transverse tensile properties, interlaminar shear strength (ILSS) and mode I and mode II interlaminar fracture toughness of carbon fibre/epoxy (CF/EP) laminates with 10 wt% and 20 wt% silica nanoparticles in matrix were investigated, and the influences of silica nanoparticle on those properties of CF/EP laminates were characterized. The transverse tensile properties and mode I interlaminar fracture toughness (G(IC)) increased with an increase in nanosilica concentration in the matrix resins. However, ILSS and the mode II interlaminar fracture toughness (G(IIC)) decreased with increasing nanosilica concentration, especially for the higher nanosilica concentration (20 wt%). The reduced G(IIC) value is attributed to two main competing mechanisms; one is the formation of zipper-like pattern associated with matrix microcracks aligned 45 degrees ahead of the crack tip, while the other is the shear failure of matrix. The ratio of G(IIC)/G(IC) decreased with the concentration of silica nanoparticles, comparable with similar CF/EP laminates with dispersed CNTs in matrix. Fractographic studies showed that interfacial failure between carbon fibre and epoxy resin occurred in the neat epoxy laminate, whereas a combination of interfacial failure and matrix failure occurred in the nanosilica-modified epoxy laminates, especially those with a higher nanosilica concentration (20 wt%). (C) 2011 Elsevier Ltd. All rights reserved