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Background Multiple neonatal exposures to sevoflurane induce neurocognitive dysfunctions in rodents. The lack of cell type–specific information after sevoflurane exposure limits the mechanistic understanding of these effects. In this study, the authors tested the hypothesis that sevoflurane exposures alter the atlas of hippocampal cell clusters and have neuronal and nonneuronal cell type–specific effects in mice of both sexes. Methods Neonatal mice were exposed to 3% sevoflurane for 2 h at postnatal days 6, 8, and 10 and analyzed for the exposure effects at postnatal day 37. Single-nucleus RNA sequencing was performed in the hippocampus followed by in situ hybridization to validate the results of RNA sequencing. The Morris Water Maze test was performed to test neurocognitive function. Results The authors found sex-specific distribution of hippocampal cell types in control mice alongside cell type– and sex-specific effects of sevoflurane exposure on distinct hippocampal cell populations. There were important changes in male but not in female mice after sevoflurane exposure regarding the proportions of cornu ammonis 1 neurons (control vs. sevoflurane, males: 79.9% vs. 32.3%; females: 27.3% vs. 24.3%), dentate gyrus (males: 4.2% vs. 23.4%; females: 36.2% vs. 35.8%), and oligodendrocytes (males: 0.6% vs. 6.9%; females: 5.9% vs. 7.8%). In male but not in female mice, sevoflurane altered the number of significantly enriched ligand–receptor pairs in the cornu ammonis 1, cornu ammonis 3, and dente gyrus trisynaptic circuit (control vs. sevoflurane, cornu ammonis 1–cornu ammonis 3: 18 vs. 42 in males and 15 vs. 21 in females; cornu ammonis 1–dentate gyrus: 21 vs. 35 in males and 12 vs. 20 in females; cornu ammonis 3–dentate gyrus: 25 vs. 45 in males and 17 vs. 20 in females), interfered with dentate gyrus granule cell neurogenesis, hampered microglia differentiation, and decreased cornu ammonis 1 pyramidal cell diversity. Oligodendrocyte differentiation was specifically altered in females with increased expressions of Mbp and Mag. In situ hybridization validated the increased expression of common differentially expressed genes. Conclusions This single-nucleus RNA sequencing study reveals the hippocampal atlas of mice, providing a comprehensive resource for the neuronal and nonneuronal cell type– and sex-specific effects of sevoflurane during development. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

The 4.2 nm α-CsPbI3 quantum dots - polymer composite films with 630 nm emission and high stability have been achieved, which are used for LED displays with color gamut to 96% of the Rec. 2020 standard.

Ultra-stable CsMnX3 nanocrystals embedded glasses with bright and broad red photoluminescence (PL) emission at 649 nm were synthesized as an excellent red phosphor for white light-emitting diode (LED) devices with a high color rendering index (CRI).

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M2 polarization of macrophages is essential for their function in immunologic tolerance, which might promote tumorigenesis. However, the molecular mechanism behind the polarization process is not fully understood. Given that several lines of evidence have suggested that long noncoding RNAs (lncRNAs) could be involved in regulating immune cell differentiation and function, the current study aimed to identify the lncRNAs that specifically modulate M2 macrophage polarization. By utilizing a series of cell-based M2 macrophage polarization models, a total of 25 lncRNAs with altered expression were documented based on lncRNA microarray-based profiling assays. Among them, lncRNA-MM2P was the only lncRNA upregulated during M2 polarization but downregulated in M1 macrophages. Knockdown of lncRNA-MM2P blocked cytokine-driven M2 polarization of macrophages and weakened the angiogenesis-promoting feature of M2 macrophages by reducing phosphorylation on STAT6. Moreover, manipulating lncRNA-MM2P in macrophages impaired macrophage-mediated promotion of tumorigenesis, tumor growth in vivo, and tumor angiogenesis. Collectively, our study identifies lncRNA-MM2P as a modulator required for macrophage M2 polarization and uncovers its role in macrophage-promoted tumorigenesis.

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Alzheimer’s disease (AD) is a neurodegenerative disease, associated with progressive cognitive impairment and memory loss. In the present study, we examined the protective effects of paeoniflorin against memory loss and cognitive decline in lipopolysaccharide (LPS)-induced mice. Treatment with paeoniflorin alleviated LPS-induced neurobehavioral dysfunction, as confirmed by behavioral tests, including the T-maze test, novel-object recognition test, and Morris water maze test. LPS stimulated the amyloidogenic pathway-related proteins (amyloid precursor protein, APP; β-site APP cleavage enzyme, BACE; presenilin1, PS1; presenilin2, PS2) expression in the brain. However, paeoniflorin decreased APP, BACE, PS1, and PS2 protein levels. Therefore, paeoniflorin reverses LPS-induced cognitive impairment via inhibition of the amyloidogenic pathway in mice, which suggests that paeoniflorin may be useful in the prevention of neuroinflammation related to AD.

Manganese doped perovskite nanocrystals (NCs) have been synthesized by a novel two-step hot injection strategy with an unprecedented Mn doping efficiency of 48.5%, bright orange emission under ultraviolet light and X-ray excitation and a photoluminesce (PL) quantum yield of 84.4%, making them excellent luminescent materials.

A novel quaternary ammonium antinomy halide was synthesized and used to construct bright orange LEDs with a luminous efficiency of 24.5 lm W−1, which can run continuously in air for more than 1200 minutes without performance degradation.

Innate immunity is central to controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune responses during viral and bacterial infections.

Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID-19) remain poorly defined. Here, we examined postmortem COVID-19 lung tissues by spatial single-cell transcriptome analysis (SSCTA). We identified 18 major parenchymal and immune cell types, all of which are infected by SARS-CoV-2. Compared to the non-COVID-19 control, COVID-19 lungs have reduced alveolar cells (ACs), and increased innate and adaptive immune cells. Additionally, 19 differentially expressed genes in both infected and uninfected cells across the tissues mirror the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that are correlated with high cell densities (HIHD). The HIHD regions express high levels of SARS-CoV-2 entry-related factors including ACE2, FURIN, TMPRSS2, and NRP1, and co-localized with organizing pneumonia (OP) and lymphocytic and immune infiltration that have increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, echoing the tissue damage and wound healing processes. Sparse non- negative matrix factorization (SNMF) analysis of neighborhood cell type composition (NCTC) features identified 7 signatures that capture structure and immune niches in COVID-19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A progresses with primarily increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B is marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions are marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single-cell RNA-seq data (scRNA-seq) from COVID-19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations primarily consisting of myofibroblasts.Immunofluorescence staining revealed the activation of IL6-STAT3 and TGF-²-SMAD2/3 pathways in these cells, which likely mediate the upregulation of COL1A1 and COL1A2, and excessive fibrosis in the lung tissues. Together, this study provides an SSCTA atlas of cellular and molecular signatures of fatal COVID-19 lungs, revealing the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID-19 lung pathology.

The synthesis of α-CsPbI

Since the report of the first COVID-19 case in 2019, SARS-CoV-2 variants of concern (VOCs) have continued to emerge, manifesting diverse infectivity, evasion of host immunity and pathology. While ACE2 is the predominant receptor of SARS-CoV-2, TMPRSS2, Kim-1, NRP-1, CD147, furin, CD209L, and CD26 have also been implicated as viral entry-related cofactors. To understand the variations in infectivity and pathogenesis of VOCs, we conducted infection analysis in human cells from different organ systems using pseudoviruses of VOCs including Alpha, Beta, Gamma, and Delta. Recombinant spike S1, RBD, ACE2, Kim-1, and NRP-1 proteins were tested for their ability to block infection to dissect their roles in SARS-CoV-2 entry into cells. Compared with wild type SARS-CoV-2 (WT), numerous VOCs had significant increases of infectivity across a wide spectrum of cell types. Recombinant ACE2 protein more effectively inhibited the infection of VOCs including Delta and Omicron (BA.1 and BA.2) than that of WT. Interestingly, recombinant S1, RBD, Kim-1, and NRP-1 proteins inhibited the infection of all pseudoviruses in a manner dependent on the levels of ACE2 expression in different cell types. These results provide insights into the diverse infectivity of SARS-CoV-2 VOCs, which might be helpful for managing the emergence of new VOCs.

In order to achieve high color rendering index (CRI) and low correlated color temperature (CCT) indoor lighting, single component phosphors with broadband dual emission emission are high demanded for white light emitting diodes (WLEDs). However, phosphors with such fluorescent properties are rare at present. Herein, we report a facile solid-state chemical method for the synthesis of single-component phosphor with broadband emission and large Stokes shift that can meet the requirements of future white light sources. These new tetrabutylammonium copper halides phosphors have excellent warm white emission characteristics, and their luminescence peaks located at 494 nm and 654 nm, respectively. The optimized photoluminescence (PL) quantum yield can reach 93.7%. The typical CIE coordinate of the as-fabricated WLED is at (0.3620, 0.3731) with CRI of 89 and low CCT of 4516 K.

Mitogen-activated protein kinases (MAPKs) play critical roles in the induction of numerous cytokines, chemokines, and inflammatory mediators that mobilize the immune system to counter pathogenic infections. Dual-specificity phosphatase-1 (DUSP1) is a member of dual-specificity phosphatases, which inactivates MAPKs through a negative feedback mechanism. Here we report that in response to viral and bacterial infections, not only DUSP1 transcript but also itsN6-methyladenosine (m6A) level rapidly increase together with the m6A reader protein YTHDF2, resulting in enhanced YTHDF2-mediated DUSP1 transcript degradation. Knockdown of DUSP1 promotes p38 and JNK phosphorylation and activation, thus increasing the expression of innate immune response genes including IL1β, CSF3, TGM2 and SRC. Similarly, knockdown of m6A eraser ALKBH5 increases DUSP1 transcript m6A level resulting in accelerated transcript degradation, activation of p38 and JNK, and enhanced expression of IL1β, CSF3, TGM2 and SRC. These results demonstrate that m6A and reader protein YTHDF2 orchestrate optimal innate immune response during viral and bacterial infections by downregulating the expression of a negative regulator DUSP1 of the p38 and JNK pathways that are central to innate immune response against pathogenic infections.IMPORTANCEInnate immunity is central for controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune response during viral and bacterial infections. We have found thatN6-methyladenosine (m6A) and the reader protein YTHDF2 regulate dual-specificity phosphatase-1, a negative regulator of mitogen-activated protein kinases p38 and JNK, to maximize innate immune response during viral and bacterial infections. These results provide novel insights into the mechanism regulating innate immunity, which could help the development of novel approaches for controlling pathogenic infections.

By combing the theoretical framework of contemporary expressive painting and expressive art therapy, this study explores the application and practice of integrating expressive painting into middle school art education in hope to provide new ideas for art education and teaching in contemporary middle schools.

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention. Large-scale screening has revealed many synthetic lethal genetic phenotypes, and relevant small-molecule drugs have also been implemented in clinical practice. Increasing evidence suggests that CDKs, constituting a kinase family predominantly involved in cell cycle control, are synthetic lethal factors when combined with certain oncogenes, such as MYC, TP53, and RAS, which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality. In this review, we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future., Graphical abstract This review summarizes the CDKs-related synthetic lethality cases and the mechanisms, giving a guidance for drug combination antitumor strategies and tumor prediction by specific biomarkers.Image 1

Developing appropriate analytic-function-based constitutive models for new materials with nonlinear mechanical behavior is demanding. For such kinds of materials, it is more challenging to realize the integrated design from the collection of the material experiment under the classical topology optimization framework based on constitutive models. The present work proposes a mechanistic-based data-driven topology optimization (DDTO) framework for three-dimensional continuum structures under finite deformation. In the DDTO framework, with the help of neural networks and explicit topology optimization method, the optimal design of the three-dimensional continuum structures under finite deformation is implemented only using the uniaxial and equi-biaxial experimental data. Numerical examples illustrate the effectiveness of the data-driven topology optimization approach, which paves the way for the optimal design of continuum structures composed of novel materials without available constitutive relations.

SARS-CoV-2 NSP12, the viral RNA-dependent RNA polymerase (RdRp), is required for viral replication and is a therapeutic target to treat COVID-19. To facilitate research on SARS-CoV-2 NSP12 protein, we developed a rat monoclonal antibody (CM12.1) against the NSP12 N-terminus that can facilitate functional studies. Immunoblotting and immunofluorescence assay (IFA) confirmed the specific detection of NSP12 protein by this antibody for cells overexpressing the protein. Although NSP12 is generated from the ORF1ab polyprotein, IFA of human autopsy COVID-19 lung samples revealed NSP12 expression in only a small fraction of lung cells including goblet, club-like, vascular endothelial cells, and a range of immune cells, despite wide-spread tissue expression of spike protein antigen. Similar studies using in vitro infection also generated scant protein detection in cells with established virus replication. These results suggest that NSP12 may have diminished steady-state expression or extensive posttranslation modifications that limit antibody reactivity during SARS-CoV-2 replication.

Background: The mechanisms underlying myocardial ischemia/reperfusion (I/R) injury are not fully understood. This study aims to explore key candidate genes and potential therapeutic targets for treatment of myocardial I/R injury.Methods: The transcriptional profiles of ventricular myocardium during cardiac arrest, ischemia, and reperfusion were obtained from the Gene Expression Omnibus database. Based on the transcriptional data of GSE6381, functional pathway and process enrichment analyses, protein–protein interaction network, and gene set enrichment analyses were conducted. In the animal experiments, we established the myocardial I/R injury model in mice. We validated the mRNA and protein expression of the key genes using the qPCR and western blots. We further assessed the expression and localization of CCL21 and its receptors using immunofluorescence staining experiments.Results: The microarray analyses identified five key genes (CCL21, XCR1, CXCL13, EDN1, and CASR). Myocardial I/R process in mice resulted in significant myocardial infraction, histological damage, and myocardial apoptosis. The results of qPCR and western blots showed that the expression of CCL21 and CXCL13 were increased following myocardial I/R injury in mice. Furthermore, the immunofluorescence staining results revealed that the expression of GPR174/CCR7 (CCL21 receptors), but not CXCR5 (CXCL13 receptor), was elevated following myocardial I/R injury. Moreover, the activated CCL21-GPR174/CCR7 signaling was located on the cardiac fibroblasts of the myocardium with I/R injury.Conclusion: This study revealed several key factors underlying myocardial I/R injury. Of these, the activation of CCL21-GPR174/CCR7 signaling on cardiac fibroblasts was highlighted, which provides potential therapeutic targets for cardioprotection.

SARS-CoV-2 vaccines have contributed to the control of COVID-19 in some parts of the world. However, the constant emergence of variants of concern (VOCs) challenges the effectiveness of SARS-CoV-2 vaccines over time. In particular, Omicron contains a high number of mutations in the spike (S) protein gene, on which most vaccines were developed. In this study, we quantitated neutralizing antibodies in vaccine recipients at various times postvaccination using S protein-based pseudoviruses derived from wild type (WT) SARS-CoV-2 and five VOCs including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). We found that two-dose mRNA-1273 and BNT162b2 vaccines elicited robust neutralizing antibodies against WT, Alpha, Beta, Gamma, and Delta, but wanned after 6 months with a faster decline observed for BNT162b2. Both mRNA-1273 and BNT162b2 elicited weak neutralizing antibodies against Omicron. One dose of Ad26.COV2.S vaccine induced weaker neutralizing antibodies against WT and most VOCs than mRNA-1273 and BNT162b2 did but moderate neutralizing antibodies against Delta and Omicron, which lasted for 6 months. These results support current recommendations of the Centers for Disease Control and Prevention for a booster 5 months after full immunization with an mRNA-based vaccine and the use of an mRNA-based vaccine 2 months after Ad26.COV2.S vaccination.

Body temperature plays a critical role in rehabilitation, and numerous studies proved that the regulation of body temperature contributes to the sensorimotor recovery of patients with brain diseases such as stroke. The hypothalamus plays a key role in thermoregulation. Ultrasound deep brain stimulation (UDBS) can noninvasively modulate deep brain nuclei and have potential applications in the treatment of Parkinson's disease, Alzheimer's disease, and depression, among others. The purpose of this study was to investigate whether ultrasound stimulation of the hypothalamus could regulate body temperature in free-moving mice. Results showed that thermoregulation was related to ultrasonic parameters (pulse repetition frequency (PRF), duty cycle, total time, and acoustic pressure). UDBS of the preoptic area of the anterior hypothalamus at 500 Hz PRF could significantly reduce body temperature ( [Formula: see text] at t = 5 min, [Formula: see text] at t = 10 min, [Formula: see text] at t = 15 min). Meanwhile, UDBS of the dorsomedial hypothalamus at 10 Hz PRF triggered a significant increase in body temperature ( [Formula: see text] at t = 5 min, [Formula: see text] at t = 10 min). These results suggest that UDBS, as a noninvasive neuromodulation tool, may play a key role in the future clinical treatment of malignant hyperthermia and hypothermia.

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple organs. However, the current SLE-related biomarkers still lack sufficient sensitivity, specificity and predictive power for clinical application. Thus, it is significant to explore new immune-related biomarkers for SLE diagnosis and development.MethodsWe obtained seven SLE gene expression profile microarrays (GSE121239/11907/81622/65391/100163/45291/49454) from the GEO database. First, differentially expressed genes (DEGs) were screened using GEO2R, and SLE biomarkers were screened by performing WGCNA, Random Forest, SVM-REF, correlation with SLEDAI and differential gene analysis. Receiver operating characteristic curves (ROCs) and AUC values were used to determine the clinical value. The expression level of the biomarker was verified by RT‒qPCR. Subsequently, functional enrichment analysis was utilized to identify biomarker-associated pathways. ssGSEA, CIBERSORT, xCell and ImmuCellAI algorithms were applied to calculate the sample immune cell infiltration abundance. Single-cell data were analyzed for gene expression specificity in immune cells. Finally, the transcriptional regulatory network of the biomarker was constructed, and the corresponding therapeutic drugs were predicted.ResultsMultiple algorithms were screened together for a unique marker gene, MX2, and expression analysis of multiple datasets revealed that MX2 was highly expressed in SLE compared to the normal group (all P < 0.05), with the same trend validated by RT‒qPCR (P = 0.026). Functional enrichment analysis identified the main pathway of MX2 promotion in SLE as the NOD-like receptor signaling pathway (NES=2.492, P < 0.001, etc.). Immuno-infiltration analysis showed that MX2 was closely associated with neutrophils, and single-cell and transcriptomic data revealed that MX2 was specifically expressed in neutrophils. The NOD-like receptor signaling pathway was also remarkably correlated with neutrophils (r >0.3, P < 0.001, etc.). Most of the MX2-related interacting proteins were associated with SLE, and potential transcription factors of MX2 and its related genes were also significantly associated with the immune response.ConclusionOur study found that MX2 can serve as an immune-related biomarker for predicting the diagnosis and disease activity of SLE. It activates the NOD-like receptor signaling pathway and promotes neutrophil infiltration to aggravate SLE.

The well-known Hartman-Grobman Theorem says that a C1 hyperbolic diffeomorphism F can be locally linearized by a homeomorphism Φ. For parameterized systems Fθ, known results show that the corresponding homeomorphisms Φθ exist uniquely in a functional space equipped with the supremum norm and depend continuously on the parameter θ. In this paper, we further extend the results to Holder dependence of Φθ on θ by Pugh’s strategy, but introducing a kind of special Holder norm instead of the usual supremum norm in the proof to control the linear parts of Fθ. This requires a new Holder linearization result for every Fθ.

Background Coronavirus disease 2019 (COVID-19) patients manifest with pulmonary symptoms reflected by diffuse alveolar damage (DAD), excessive inflammation, and thromboembolism. The mechanisms mediating these processes remain unclear. Methods We performed multicolor staining for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins and lineage markers to define viral tropism and lung pathobiology in 5 autopsy cases. Results Lung parenchyma showed severe DAD with thromboemboli. Viral infection was found in an extensive range of cells including pneumocyte type II, ciliated, goblet, club-like, and endothelial cells. More than 90% of infiltrating immune cells were positive for viral proteins including macrophages, monocytes, neutrophils, natural killer (NK) cells, B cells, and T cells. Most but not all infected cells were angiotensin-converting enzyme 2 (ACE2) positive. The numbers of infected and ACE2-positive cells are associated with extensive tissue damage. Infected tissues exhibited high levels of inflammatory cells including macrophages, monocytes, neutrophils, and NK cells, and low levels of B cells but abundant T cells consisting of mainly T helper cells, few cytotoxic T cells, and no regulatory T cells. Robust interleukin-6 expression was present in most cells, with or without infection. Conclusions In fatal COVID-19 lungs, there are broad SARS-CoV-2 cell tropisms, extensive infiltrated innate immune cells, and activation and depletion of adaptive immune cells, contributing to severe tissue damage, thromboemboli, excess inflammation, and compromised immune responses.

In recent years, two-dimensional (2D) layered tin halide perovskites have attracted much attention due to their excellent luminescence properties compared with their three-dimensional (3D) analogs. Here, we synthesized 2D perovskites of the form (RNH3)2SnBr4 through a facile hot-injection approach without the use of toxic tri-n-octylphosphine (TOP) as the solvent. We found that these compounds have strong photoluminescence (PL) emission with high PL quantum yields (QY) of 35% ((C6H13NH3)2SnBr4), 82% ((C8H17NH3)2SnBr4), 60% ((C12H25NH3)2SnBr4) and 50% ((C18H35NH3)2SnBr4). Among them, ((C6H13NH3)2SnBr4) was synthesized for the first time; however, (C18H36NH3)2SnBr4 perovskites showed the best stability with a PL QY decrease of less than 1% after 30 days under ambient air and humidity conditions. In addition, other 2D (C8H17NH3)2SnX4 (X = Br, I, or mixture) perovskites were prepared by adjusting the halide ratio, resulting in spectral tunability from yellow to red. Interestingly, through Zn2+ doping, the morphology became more uniform, and the PL stability was significantly improved. Finally, we used Zn2+-doped (C8H17NH3)2SnBr4 yellow phosphor to fabricate UV-pumped yellow LEDs. We expect these 2D perovskites to be promising phosphors in future solid-state lighting and display technologies.

Recently, two-dimensional (2D) metal halide perovskite materials with wide application in perovskite-based solar cells have attracted significant attention. Among them, 2D mixed lead–tin perovskites have not been systematically explored. Herein, we synthesize a 2D phenethylammonium (PEA) tin–lead bromide perovskite, PEA2SnxPb1−xBr4, via a simple solution-phase approach without toxic reagents and high temperatures. By tuning the ratio of Sn and Pb, the UV-vis absorption spectra showed unique bandgap bending behaviors. DFT calculations indicate the key effects of spin–orbital coupling (SOC) without the interference of lattice distortion. Moreover, we provided the standard equation with a correction term to introduce the influence of SOC. These results not only provide a step forward towards the bandgap engineering of perovskites, but also help to expand the application of 2D perovskite materials.

The hypothalamus plays an important role in the control of aging. Transcranial ultrasound stimulation (TUS) has been reported as a noninvasive method of neuromodulation. However, the effect of TUS of the hypothalamus on aging remains unclear. Therefore, the aim of this study is to verify whether TUS of the hypothalamus could affect the behaviors of aging mice and the expression level of apoptosis factors and inflammatory cytokines. TUS was delivered to the hypothalamus of mice ( ${n} = {44}$ ) for 14 days (15 min/day) at a fundamental frequency of 1 MHz, pulse repetition frequency of 1 kHz (US1) or 10 Hz (US2), duty cycle of 10%, and acoustic pressure of 0.13 MPa. The effect of TUS on aging was evaluated by the behavioral tests or Western blotting in different stages. The behavioral results showed that mice in the US2 group improved their movement and learning. In addition, there was a significant improvement in the grip strength after TUS in the second behavioral tests (Sham: 0.0351 ± 0.0020 N/g; US1: 0.0340 ± 0.0023 N/g; US2: 0.0425 ± 0.0029 N/g, ${p} = {0.034}$ ). Furthermore, the level of inflammation (TNF- $\alpha $ : Sham: 0.69 ± 0.084; US1: 0.39 ± 0.054; US2: 0.49 ± 0.1, ${p} = {0.021}$ ) and apoptosis (Bax: Sham: 0.47 ± 0.049; US1: 0.42 ± 0.054; US2: 0.18 ± 0.055, ${p} = {0.001}$ ) was significantly reduced after TUS in this stage. We did not see a long-lasting effect of TUS in the third behavioral tests. In addition, we found that TUS is safe according to hematoxylin and eosin (HE) staining. In conclusion, TUS could effectively modulate the hypothalamus, which may provide a new method for controlling aging.

Nucleocytoplasmic transport of signaling modulators is essential for regulating cellular responses to extracellular stimulation and stress, as well as pathogen infection. Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), mediates nuclear export of proteins, rRNAs, snRNAs, and some mRNAs. In this study, we have identified an essential role of XPO1 in regulating Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication during primary infection of primary human umbilical vein endothelial cells. Treatment with an XPO1 inhibitor KPT-8602 and short hairpin RNA (shRNA)-mediated knockdown of XPO1 reduced KSHV lytic replication but had no effect on KSHV entry and trafficking. XPO1 inhibition induced retention of autophagy adaptor protein p62 (SQSTM1) in the nucleus, which enhanced activation of TBK1 and IRF3. As a result, nuclear accumulation of p62 increased expression of innate immune-related genes including IRF7, ISG15, IFIT1, IFIT2, and IFIT3, leading to a reduction of KSHV lytic replication. These results illustrate a novel mechanism by which XPO1 mediates innate immune response and KSHV replication, and identify XPO1 as a potential therapeutic target and KPT-8602 as a promising therapeutic agent for KSHV infection.

BackgroundMultimorbidity has an effect on life expectancy, while its effect on healthy life years is unclear. This study aims to investigate the associations between healthy life years lost due to multimorbidity and living risk.MethodsThe participants of The China Health and Retirement Longitudinal Study (CHARLS) were assessed at four visits between 2011 (baseline) and 2018. At baseline, 13,949 individuals were administered surveys. A combined score based on seven health-related factors was calculated, and the participants were classified into 3 groups based on living risk. We used the adjusted Cox regression methods to examine the associations between living risk groups and multimorbidity. We estimated the healthy life years lost due to multimorbidity using the Sullivan method.ResultsA total of 9,091 adults aged 45 years or older (mean age of 59.55 ± 9.50 years with one disease, 52.60% women) were analyzed in the CHARLS. The probability of no multimorbidity over 7 years decreased from 0.9947 to 0.9697 in the low-risk group, whereas the probability of multimorbidity in low living risk was lower than that of high living risk, ranging from HR 1.253 (95% CI.992–1.581; P = 0.058) to 1.431 (1.05–1.949; P = 0.023) in sex, and ranging from HR 1.340 (95% CI 1.106–1.623; P = 0.003) to 2.002 (1.058–3.787; P = 0.033) in area. At 45 years, the healthy life years lost in men was P < 0.001) in men. In urban areas, participants with diabetes had 3.2 times (95% CI 1.75–5.94, P < 0.001) higher risk of multimorbidity than participants without diabetes.ConclusionsThese findings indicate that a low-risk lifestyle could decrease the loss of healthy life years under multimorbidity. The probability of multimorbidity in women and in urban areas was high. Hypertension was correlated with the hazard risk of multimorbidity.

The laser dazzling effect has always been a crucial issue for the scientific community. Nevertheless, the experiments to study the laser dazzling effect may cost a lot. Therefore, the technology of simulation is promising for this field. Additionally, the effectiveness of the laser dazzling needs to be evaluated by a no reference cost functions. A general model of CCD is proposed in this paper. Additionally, two cost functions are proposed to evaluate the image. The simulation result based on the model shows feasibility of the cost functions. Afterwards an experiment is carried out to testify these cost functions. Different factors include the intensity of the irradiance, the beam radius and the dazzling location of the laser are taken into consideration. The experimental result shows the cost functions have monotonous relationship with the degree of the laser dazzling. This result indicates that the cost functions can be used in the field to measure the degree of the laser dazzling.

The calculation of the real contact area between rough surfaces is an important prerequisite for studying the contact characteristics of mechanical joints. However, it is challenging to accurately calculate the real contact area between rough surfaces by existing theoretical and experimental methods. Therefore, an efficient and practical equivalent calculation method for the real contact area between three-dimensional(3D) rough surfaces based on two-dimensional(2D) profiles is presented in this paper. The main advantage of the presented method as compared with those available in the literature is that the real contact area can be predicted only by the section of the 3D rough surfaces in contact, which greatly reduces the computational cost. The sampling strategy of sections is studied to improve the accuracy of the proposed method. The accuracy of the proposed equivalent calculation method is verified by numerical simulation. The results show that the proposed equivalent calculation method can efficiently predict the real contact area between rough surfaces within the scope of engineering application.