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To investigate the effect of long-term ethanol consumption on learning-memory functions in mice and the mechanisms involved.Thirty male C57BL6/J mice were randomly assigned to 3 groups, with 10 mice in each group. The three groups included a control group in which the mice were given waterMorris water maze test showed that, compared with those of the control group, the times of crossing the platform and the percentage of platform time in the EtOH group and the EtOH+G group were both lower, and the EtOH+G group had the lowest results (Both long-term ethanol consumption and long-term alcoholism can reduce learning-memory functions and long-term alcoholism has the greater impact of the two. The potential mechanism may involve the down-regulation of the expression of SIRT3 protein in the hippocampus, which results in an increased level of pan-acetylation and enhanced expression of oxidative stress protein in the hippocampus, affects the mitochondrial functions of the brain, inhibits the oxidative phosphorylation capacity of mitochondrial complex Ⅱ, reduces the ATP energy supply of the brain tissue, and thus affects the learning-memory function.

Xin-Tian Cai,1 Li-Wei Ji,2 Sha-Sha Liu,1 Meng-Ru Wang,1 Mulalibieke Heizhati,1 Nan-Fang Li1 1Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, National Health Committee Key Laboratory of Hypertension Clinical Research, Urumqi, People’s Republic of China; 2Laboratory of Mitochondrial and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Nan-Fang LiHypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, National Health Committee Key Laboratory of Hypertension Clinical Research, Urumqi, Xinjiang, People’s Republic of ChinaTel +86 991 8564818Email lnanfang2016@sina.comPurpose: The aim of this study was to derivate and validate a nomogram based on independent predictors to better evaluate the 5-year risk of T2D in non-obese adults.Patients and Methods: This is a historical cohort study from a collection of databases that included 12,940 non-obese participants without diabetes at baseline. All participants were randomised to a derivation cohort (n = 9651) and a validation cohort (n = 3289). In the derivation cohort, the least absolute shrinkage and selection operator (LASSO) regression model was used to determine the optimal risk factors for T2D. Multivariate Cox regression analysis was used to establish the nomogram of T2D prediction. The receiver operating characteristic (ROC) curve, C-index, calibration curve, and decision curve analysis were performed by 1000 bootstrap resamplings to evaluate the discrimination ability, calibration, and clinical practicability of the nomogram.Results: After LASSO regression analysis of the derivation cohort, it was found that age, fatty liver, γ-glutamyltranspeptidase, triglycerides, glycosylated hemoglobin A1c and fasting plasma glucose were risk predictors, which were integrated into the nomogram. The C-index of derivation cohort and validation cohort were 0.906 [95% confidence interval (CI), 0.878– 0.934] and 0.837 (95% CI, 0.760– 0.914), respectively. The AUC of 5-year T2D risk in the derivation cohort and validation cohort was 0.916 (95% CI, 0.889– 0.943) and 0.829 (95% CI, 0.753– 0.905), respectively. The calibration curve indicated that the predicted probability of nomogram is in good agreement with the actual probability. The decision curve analysis demonstrated that the predicted nomogram was clinically useful.Conclusion: Our nomogram can be used as a reasonable, affordable, simple, and widely implemented tool to predict the 5-year risk of T2D in non-obese adults. With this model, early identification of high-risk individuals is helpful to timely intervene and reduce the risk of T2D in non-obese adults.Keywords: type 2 diabetes, prediction model, nomogram, risk factor

Developing highly active oxygen evolution reaction (OER) electrocatalysts is crucial and highly desirable to improve the efficiency of water electrolysis for H2 fuel generation. In this work, hiera...

To investigate the regulatory function and mechanism of β-hydroxybutyrate (β-OHB), a ketone body, on the mitochondrial oxidative stress of inflammatory human umbilical vein endothelial cells (HUVECs).Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were used to induce macrophages to release proinflammatory factors, and the culture supernatant was collected as a macrophage-conditioned medium (MCM) to culture HUVECs. A total of 7 groups of cells were used in the study: ①control group, or normal cultured HUVECs; ②MCM group, or the MCM-cultured HUVECs; groups ③ to ⑦ were all HUVECs co-cultured with different reagents, including ③MCM+β-OHB group, ④MCM+N-acetylcysteine (NAC) group, ⑤MCM+β-OHB+NAC group, ⑥MCM+β-OHB+histone deacetylase agonist ITSA1 group, and ⑦MCM+β-OHB+histone deacetylase inhibitor Entinostat group. MitoSOX immunofluorescence staining was conducted to analyzes the mitochondrial superoxide levels, real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was performed to examine the mRNA expression of antioxidant genes, and Seahorse mitochondrial energy analyzer was used to measure mitochondrial aerobic respiration capacity.Compared with the control group, mitochondrial superoxide production was significantly increased in the MCM cultured HUVECs cells, while β-OHB treatment significantly inhibited mitochondrial superoxide production, which was accompanied by an increase in the mRNA expression of antioxidant genes, and significant increase in the basal mitochondrial oxygen consumption rate and respiratory reserve capacity. NAC treatment did not further enhance the protective effect of β-OHB on mitochondrial functions. In addition, ITSA1 treatment could completely offset the antioxidant and mitochondrial protective effects of β-OHB, and these stated effects were still maintained after Entinostat treatment.The ketone body β-OHB attenuates the mitochondrial oxidative stress of vascular endothelial cells through activating the antioxidant pathway and inhibiting histone deacetylase activity.

Although anti-PD-1 immunotherapy is widely used to treat melanoma, its efficacy still has to be improved. In this work, we present a therapeutic method that combines immunotherapy and starvation therapy to achieve better antitumor efficacy. We designed the CMSN-GOx method, in which mesoporous silica nanoparticles (MSN) are loaded with glucose oxidase (GOx) and then encapsulate the surfaces of cancer cell membranes to realize starvation therapy. By functionalizing the MSN's biomimetic surfaces, we can synthesize nanoparticles that can escape the host immune system and homologous target. These attributes enable the nanoparticles to have improved cancer targeting ability and enrichment in tumor tissues. Our synthetic CMSN-GOx complex can ablate tumors and induce dendritic cell maturity to stimulate an antitumor immune response. We performed an in vivo analysis of these nanoparticles and determined that our combined therapy CMSN-GOx plus PD-1 exhibits a better antitumor therapeutic effect than therapies using CMSN-GOx or PD-1 alone. Additionally, we used the positron emission tomography imaging to measuring the level of glucose metabolism in tumor tissues, for which we investigate the effect with the cancer therapy in vivo.

The precise diagnosis of cancer remains a great challenge; therefore, it is our research interest to develop safe, tumor-specific reagents. In this study, we designed nanovesicles derived from erythrocyte membranes; the nanovesicles are capable of recognizing tumor cells for both circulating tumor cell (CTC) capture and tumor imaging. The tumor-targeting molecules folic acid (FA) and fluorescein Cy5 were modified on the nanovesicle surface. The developed nanovesicles exhibit excellent tumor targeting ability both in vitro and in vivo for CTC capture and in tumor imaging. Compared with traditional immunomagnetic beads, the proposed nanovesicles are capable of avoiding non-specific adsorption as a derivative of red blood cells. Combined with a non-invasive means of micromanipulation, the nanometer-sized vesicles show a high purity of CTC capture (over 90%). In vivo, the nanovesicles can also be employed for efficient tumor imaging without obvious toxicity and side effects. In brief, the nanovesicles prepared herein show potential clinical application for integrated diagnosis in vitro and in vivo.

Capturing circulating tumor cells (CTCs) from peripheral blood for subsequent analyses has shown potential in precision medicine for cancer patients. Broad as the prospect is, there are still some challenges that hamper its clinical applications. One of the challenges is to maintain the viability of the captured cells during the capturing and releasing processes. Herein, we have described a composite material that could encapsulate a magnetic Fe3O4 core in a MIL-100 shell (MMs), which could respond to pH changes and modify the anti-EpCAM antibody (anti-EpCAM-MMs) on the surface of MIL-100. After the anti-EpCAM-MMs captured the cells, there was no need for additional conditions but with the acidic environment during the cell culture process, MIL-100 could realize automatic degradation, leading to cell self-release. This self-release model could not only improve the cell viability, but could also reduce the steps of the release process and save human and material resources simultaneously. In addition, we combined clinical patients' case diagnosis with the DNA sequencing and next generation of RNA sequencing technologies in the hope of precision medicine for patients in the future.

The purpose of this note is to clarify the conditions under which the first-order generalize-harmonic representation of the vacuum Einstein evolution system is linearly degenerate.

Filtration of circulating tumor cells (CTCs) in peripheral blood is of proven importance for early cancer diagnosis, treatment monitoring, metastasis diagnosis, and prognostic evaluation. However, currently available strategies for enriching CTCs, such as magnetic activated cell sorting (MACS), face serious problems with purity due to nonspecific interactions between beads and leukocytes in the process of capturing. In the present study, the tumor-targeting molecule folic acid (FA) and magnetic nanoparticles (MNPs) were coated on the surface of red blood cells (RBCs) by hydrophobic interaction and chemical conjugation, respectively. The resulting engineered RBCs rapidly adhered to CTCs and the obtained CTC-RBC conjugates were isolated in a magnetic field. After treatment with RBC lysis buffer and centrifugation, CTCs were released and captured. The duration of the entire process was less than three hours. Cell counting showed that the capture efficiency was above 90% and the purity of the obtained CTCs was higher than 75%. The performance of the proposed method exceeded that of MACS® beads (80% for capture efficiency and 20% for purity) under the same conditions. The obtained CTCs could be successfully re-cultured and proliferated in vitro. Our engineered RBCs have provided a novel method for enriching rare cells in the physiological environment.

Recently, red blood cell (RBC) membrane-coated nanoparticles have attracted much attention because of their excellent immune escapability; meanwhile, gold nanocages (AuNs) have been extensively used for cancer therapy due to their photothermal effect and drug delivery capability. The combination of the RBC membrane coating and AuNs may provide an effective approach for targeted cancer therapy. However, few reports have shown the utilization of combining these two technologies. Here, we design erythrocyte membrane-coated gold nanocages for targeted photothermal and chemical cancer therapy. First, anti-EpCam antibodies were used to modify the RBC membranes to target 4T1 cancer cells. Second, the antitumor drug paclitaxel (PTX) was encapsulated into AuNs. Then, the AuNs were coated with the modified RBC membranes. These new nanoparticles were termed EpCam-RPAuNs. We characterized the capability of the EpCam-RPAuNs for selective tumor targeting via exposure to near-infrared irradiation. The experimental results demonstrate that EpCam-RPAuNs can effectively generate hyperthermia and precisely deliver the antitumor drug PTX to targeted cells. We also validated the biocompatibility of the EpCam-RAuNs in vitro. By combining the molecularly modified targeting RBC membrane and AuNs, our approach provides a new way to design biomimetic nanoparticles to enhance the surface functionality of nanoparticles. We believe that EpCam-RPAuNs can be potentially applied for cancer diagnoses and therapies.

Environment, such as the accretion disk, could modify the signal of the gravitational wave from the astrophysical black hole binaries. In this article, we model the matter field around the intermediate-mass binary black holes by means of an axion-like scalar field and investigate their joint evolution. In details, we consider the equal mass binary black holes surrounded by a shell of axion-like scalar field both in spherical symmetric and non-spherical symmetric cases, and with different strength of the scalar field. Our result shows that the environmental scalar field could essentially modify the dynamics. Firstly, in the spherical symmetric case, with increasing of the scalar field strength, the number of circular orbit of the binary black hole is reduced. It means that the scalar field could significantly accelerate the merger process. Secondly, once the scalar field strength exceeds certain critical value, the scalar field could collapse into a third black hole with its mass being larger than the binary. Consequently, the new black hole collapsed from the environmental scalar field could accrete the binary promptly and the binary collides head-on between each other. In this process, there is almost no any quadrupole signal produced, namely the gravitational wave is greatly suppressed. Thirdly, when the scalar field strength is relatively smaller than the critical value, the black hole orbit could develop eccentricity through the accretion of the scalar field. Fourthly, during the initial stage of the inspire, the gravitational attractive force from the axion-like scalar field could induce a sudden turn in the binary orbits, hence result in a transient wiggle in the gravitational waveform. Finally, in the non-spherical case, the scalar field could gravitationally attract the binary moving toward the mass center of the scalar field and slow down the merger process., Comment: 14 pages, 12 figures

BACKGROUND We evaluated the relationship between the age at first use of oral contraceptives (OC) and breast cancer (BC) risk. METHODS We searched PubMed, Embase, and related reviews published through June 28, 2018, and used summary relative risk (RR) and 95% confidence intervals (CIs) to evaluate the cancer risks, and fixed-effects dose-response meta-analysis to assess potential linear and non-linear dose-response relationships. RESULTS We included 10 studies, with 8585 BC cases among 686,305 participants. The pooled RR for BC was 1.24 (95% CI: 1.10-1.41), with moderate heterogeneities (I = 66.5%, P

Finite difference and pseudo-spectral methods have been widely used in the numerical relativity to solve the Einstein equations. As the third major category method to solve partial differential equations, finite element method is less frequently used in numerical relativity. In this paper, we design a finite element algorithm to solve the evolution part of the Einstein equations. This paper is the second one of a systematic investigation of applying adaptive finite element method to the Einstein equations, especially aiming for binary compact objects simulations. The first paper of this series has been contributed to the constrained part of the Einstein equations for initial data. Since applying finite element method to the Einstein equations is a big project, we mainly propose the theoretical framework of a finite element algorithm together with local discontinuous Galerkin method for the Einstein equations in the current work. In addition, we have tested our algorithm based on the spherical symmetric spacetime evolution. In order to simplify our numerical tests, we have reduced the problem to a one-dimensional space problem by taking the advantage of the spherical symmetry. Our reduced equation system is a new formalism for spherical symmetric spacetime simulation. Based on our test results, we find that our finite element method can capture the shock formation which is introduced by numerical error. In contrast, such shock is smoothed out by numerical dissipation within the finite difference method. We suspect this is partly the reason that the accuracy of finite element method is higher than the finite difference method. At the same time, different kinds of formulation parameters setting are also discussed.

The gravitational collapse of a massless scalar field enclosed with a perfectly reflecting wall in a spacetime with a cosmological constant $\Lambda$ is investigated. The mass scaling for the gapped collapse $ M_{AH}-M_g \propto (\epsilon_c-\epsilon)^\xi$ is confirmed and a new time scaling for the gapped collapse $T_{AH}-T_g\propto(\epsilon_c-\epsilon)^\zeta$ is found. We find that both of these two critical exponents depend on the combination $\Lambda R^2$, where $R$ is the radial position of the reflecting wall. Especially, we find an evolution of the critical exponent $\xi$ from $0.37$ in the confined asymptotic dS case with $\Lambda R^2=1.5$ to $0.7$ in asymptotic AdS case ($\Lambda R^2\rightarrow-\infty$), while the critical exponent $\zeta$ varies from $0.10$ to $0.26$, which shows the new critical behavior for the gapped collapse is essentially different from the one in the Choptuik's case., Comment: 7 pages, 7 figures

The gravitational collapse of a massless scalar field with a self-interaction term $\lambda\phi^4$ in anti-de Sitter space is investigated. We numerically investigate the effect of the self-interaction term on the critical amplitudes, forming time of apparent horizon, stable island and energy transformation. The results show that a positive $\lambda$ suppresses the formation of black hole, while a negative $\lambda$ enhances the process. We define two susceptibilities to characterize the effect of the self-interaction on the black hole formation, and find that near the critical amplitude, there exists a universal scaling relation with the critical exponent $\alpha \approx 0.74$ for the time of black hole formation., Comment: 7 pages, 5 figures