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Yaks live in the Qinghai-Tibet Plateau for a long time where oxygen is scarce, but can ensure the smooth development of testis and spermatogenesis. The key lies in the functional regulation of the Sertoli cells under hypoxia. In this study, we sequenced yak Sertoli cells cultured in normal oxygen concentration (Normoxia) and treated with low oxygen concentration (Hypoxia) by whole transcriptomics, and screened out 194 differentially expressed mRNAs (DEmRNAs), 934 differentially expressed LncRNAs (DELncRNAs) and 129 differentially expressed miRNAs (DEmiRNAs). GO and KEGG analysis showed that these differential genes were mainly concentrated in PI3K-AKT, MAPK, RAS, and other signaling pathways, and were associated with glucose metabolism, tight junction, steroid hormone synthesis, cell fusion, and immunity of yak Sertoli cells. We constructed the gene interaction network of yak Sertoli cells in hypoxia and screened out the relationship pairs related to glucose metabolism and tight junction. The results suggested that the changes in energy metabolism, tight junction, and immune regulation of yak Sertoli cells under hypoxia might provide favorable conditions for spermatogenesis. This study provides data for further study on the role of non-coding RNA in testis development and spermatogenesis of yak. [ABSTRACT FROM AUTHOR]

Porcine epidemic diarrhea virus (PEDV) is a serious disease that poses a significant threat to the pig industry. This study focused on analyzing the Spike protein of PEDV, which harbors crucial antigenic determinants, in identifying dominant epitopes. Immunoinformatics tools were used to screen for B-cell, CD4+ and CD8+ predominance epitopes. These epitopes were then connected to the N-terminal of ferritin to form a self-assembled nanoparticle vaccine. Various physical and chemical properties of the candidate vaccine were analyzed, including secondary structure prediction, tertiary structure modeling, molecular docking, immune response simulation and computer cloning. The results demonstrated that the candidate vaccine was antigenic, soluble, stable, non-allergic, and formed a stable complex with the target receptor TLR-3. Immune simulation analysis showed that the candidate vaccine effectively stimulated both cellular and humoral reactions, leading to increased related cytokines production. Furthermore, efficient and stable expression of the candidate vaccine was achieved through reverse translation in the Escherichia coli K12 expression system following codon optimization and in silico cloning. The developed nanoparticle candidate vaccine in this study holds promise as an effective PEDV vaccine candidate, offering a new approach for the research, development and improvement of vaccines targeting porcine enteric diarrhea coronavirus. [ABSTRACT FROM AUTHOR]

316 L steel-based human implants play an important role in the biomedical field. In order to address the problem of immune rejection of 316 L steel-based human implants and further improve the machining efficiency, the surface roughness (SR) and hydrophilicity of 316 L workpieces are improved by electrical discharge machining milling (EDM-milling) instead of die-sinking electrical discharge machining (EDM) and by the incorporation of nano hydroxyapatite (NHAP) powder into the dielectric. The effects of powder concentration of NHAP, reference voltage, peak current, pulse width, and pulse interval on the material removal rate (MRR), electrode wear rate (EWR), SR, and contact angle (CA) of 316 L workpiece processed by powder mixed EDM-milling with NHAP (NHAP-PMEDM-milling) are investigated by single-factor experiment, and comparisons are done with the powder mixed die-sinking electrical discharge machining with NHAP (NHAP-PMEDM). According to the results, the MRR, EWR, SR, and CA of 316 L by NHAP-PMEDM-milling are varied regularly with the variation of experiment parameters. The addition of NHAP powder into deionized water (DW) can reduce the CA of the surface of 316 L steel workpiece to a great extent, with a maximum reduction of 27.9%, while affecting MRR, EWR, and SR very little. In addition, NHAP-PMEDM-milling can increase MRR by 115.5% and reduce EWR, SR, and CA by 43.2%, 13.2%, and 15.9%, respectively, compared with NHAP-PMEDM. [ABSTRACT FROM AUTHOR]

Pollution from mineral exploitation is an important risk factor affecting surface water environment in mineral regions. It is urgent to construct a simple and accurate model to assess the surface water pollution risk from mineral exploitation in the regional scale. Thus, taking a mining province namely Liaoning in northeastern China as the study area, we proposed a framework to simulate the transport process of pollutants from mineral exploitation points to the surrounding surface water based on the "source-sink" theory. In our framework, we adopted the regional growth method (RGM) to extract the potential polluted water area as the certain "sink" considering the influence of the topography, and then applied Minimum Cumulative Resistance (MCR) model to assess the surface water pollution risk from mineral exploitation. The results revealed that: (1) 9.5% of the water areas were located at the potential impact area of MEPs. (2) The total value of resistance surface in Liaoning is relatively low, and gradually decreased from west to east. (3) MEPs in Liaoning had a high risk and seriously threatened the surface water environment, among 2125 MEPs, 733 MEPs (32.99%) were assessed as extremely high risk level, and about 35% of the MEPs were distributed within 10KM buffer zone of surface water. (4) Water pollution risk of MEPs in Dalian, Tieling, Fuxin and Dandong need to be emphasized. (5) Compared to previous studies, we considered the topographical influence before applying MCR model directly, so the results of water pollution risk were more reliable. This study provides a methodological support and scientific reference for the water environment protection and regional sustainable development. [ABSTRACT FROM AUTHOR]

Landscape stability is a paramount concern within the field of landscape ecology. Indices of landscape patterns not only facilitate an effective analysis of land use transformations but also delve into the mechanisms of landscape disturbances across various spatial and temporal dimensions. Utilizing land use data spanning from 2014 to 2022 for the Shibing and Libo-Huanjiang South China Karst (SCK) World Heritage Sites (WHSs), this study delves into the landscape dynamics of these areas over the past 8 years. This investigation employs landscape pattern indices and a moving window technique to construct a landscape stability evaluation model, incorporating indices such as the Contagion Index, Patch Density, and Total Edge Contrast. Moreover, the study employs Moran's I, a spatial autocorrelation index, to scrutinize the shifts in geographical heterogeneity of landscape stability within the said period. The findings reveal: (1) Between 2014 and 2022, the landscape patterns of the Shibing and Libo-Huanjiang WHSs have undergone significant transformations, with Woodland emerging as the predominant landscape type and its area exhibiting an upward trend in recent years. (2) The level of fragmentation within the research area has decreased, landscape diversity has diminished, and the aggregation index has risen, according to the landscape pattern indices from 2014 to 2022, indicating that conservation measures have significantly influenced the evolution of landscape patterns. (3) Throughout most of the study period, landscape stability predominantly remained at a relatively stable level, albeit with noticeable fluctuations in years heavily impacted by human activities. (4) The areas of high-high agglomeration and the hotspots of the heritage sites were primarily concentrated within the core zones of these sites, suggesting focused areas of conservation and landscape integrity. [ABSTRACT FROM AUTHOR]

Exploring the method for rational design of hierarchical structures such as hollow, sphere, and core–shell structures is a crucial challenge for enhancing the electrochemical performance of supercapacitor electrodes. In this study, we demonstrate a facile method for controllable preparation of hydrangea-shaped CoAl-LDHs/CoF2 composite and used as a positive electrode for supercapacitor. A series of contrast tests are performed to select optimal experiment condition. CoAl-LDHs obtained at a metal ratio of 2:1, reacting 8 h with the addition of NH4F, display optimal performance associated with the hierarchical structure, where NH4F plays a vital role in regulating this uniform generation process. The fabricated working electrode shows a high specific capacitance of 827.8 Fg−1, with excellent capacitance retention of 62.8% after current density increases ten times. At last, an asymmetric supercapacitor using C2A1-8 h sample as positive electrode and activated carbon as negative electrode is assembled and delivers an outstanding energy density of 53.7 Wh kg−1 at a power density of 239.9 kW kg−1, and energy density reaches 27.8 Wh kg−1 at maximum power density of 12,000 W kg−1, indicating C2A1-8 h is a potential candidate for energy storage and conversion systems. [ABSTRACT FROM AUTHOR]

Lysine lactylation (Kla) links metabolism and gene regulation and plays a key role in multiple biological processes. However, the regulatory mechanism and functional consequence of Kla remain to be explored. Here, we report that HBO1 functions as a lysine lactyltransferase to regulate transcription. We show that HBO1 catalyzes the addition of Kla in vitro and intracellularly, and E508 is a key site for the lactyltransferase activity of HBO1. Quantitative proteomic analysis further reveals 95 endogenous Kla sites targeted by HBO1, with the majority located on histones. Using site-specific antibodies, we find that HBO1 may preferentially catalyze histone H3K9la and scaffold proteins including JADE1 and BRPF2 can promote the enzymatic activity for histone Kla. Notably, CUT&Tag assays demonstrate that HBO1 is required for histone H3K9la on transcription start sites (TSSs). Besides, the regulated Kla can promote key signaling pathways and tumorigenesis, which is further supported by evaluating the malignant behaviors of HBO1- knockout (KO) tumor cells, as well as the level of histone H3K9la in clinical tissues. Our study reveals HBO1 serves as a lactyltransferase to mediate a histone Kla-dependent gene transcription. The regulatory mechanism and functional consequence of lysine lactylation remain to be explored. Here, the authors identify HBO1 as a lysine lactyltransferase and suggest a potential role of HBO1 in tumorigenesis through H3K9la-mediated transcription regulation. [ABSTRACT FROM AUTHOR]

This research aimed to investigate effects of different yeast culture (YC) levels on in vitro fermentation characteristics and bacterial and fungal community under high concentrate diet. A total of 5 groups were included in the experiment: control group without YC (CON), YC1 (0.5% YC proportion of substrate dry matter), YC2 (1%), YC3 (1.5%) and YC4 (2%). After 48 h of fermentation, the incubation fluids and residues were collected to analyze the ruminal fermentation parameters and bacterial and fungal community. Results showed that the ruminal fluid pH of YC2 and YC4 groups was higher (P < 0.05) than that of CON group. Compared with CON group, the microbial protein, propionate and butyrate concentrations and cumulative gas production at 48 h of YC2 group were significantly increased (P < 0.05), whereas an opposite trend of ammonia nitrogen and lactate was observed between two groups. Microbial analysis showed that the Chao1 and Shannon indexes of YC2 group were higher (P < 0.05) than those of CON group. Additionally, YC supplementation significantly decreased (P < 0.05) Succinivibrionaceae_UCG-001, Streptococcus bovis and Neosetophoma relative abundances. An opposite tendency of Aspergillus abundance was found between CON and YC treatments. Compared with CON group, the relative abundances of Prevotella, Succiniclasticum, Butyrivibrio and Megasphaera elsdenii were significantly increased (P < 0.05) in YC2 group, while Apiotrichum and unclassified Clostridiales relative abundances were decreased (P < 0.05). In conclusion, high concentrate substrate supplemented with appropriate YC (1%) can improve ruminal fermentation and regulate bacterial and fungal composition. [ABSTRACT FROM AUTHOR]

Pure organic phosphorescence resonance energy transfer is a research hotspot. Herein, a single-molecule phosphorescence resonance energy transfer system with a large Stokes shift of 367 nm and near-infrared emission is constructed by guest molecule alkyl-bridged methoxy-tetraphenylethylene-phenylpyridines derivative, cucurbit[n]uril (n = 7, 8) and β-cyclodextrin modified hyaluronic acid. The high binding affinity of cucurbituril to guest molecules in various stoichiometric ratios not only regulates the topological morphology of supramolecular assembly but also induces different phosphorescence emissions. Varying from the spherical nanoparticles and nanorods for binary assemblies, three-dimensional nanoplate is obtained by the ternary co-assembly of guest with cucurbit[7]uril/cucurbit[8]uril, accompanying enhanced phosphorescence at 540 nm. Uncommonly, the secondary assembly of β-cyclodextrin modified hyaluronic acid and ternary assembly activates a single intramolecular phosphorescence resonance energy transfer process derived from phenyl pyridines unit to methoxy-tetraphenylethylene function group, enabling a near-infrared delayed fluorescence at 700 nm, which ultimately applied to mitochondrial targeted imaging for cancer cells.Phosphorescence resonance energy transfer systems have potential in light-harvesting and bioimaging, but host-guest systems are rarely explored. Here, the authors report the development of a macrocyclic host-guest system for targeted cell imaging. [ABSTRACT FROM AUTHOR]

This paper examines the potential of using ammonia (NH 3 ) as a primary fuel in heavy-duty engines for decarbonization, with some challenges yet to be addressed. It presents a numerical study of a Reactivity Controlled Compression Ignition engine, where pilot diesel is used to ignite the premixed ammonia/air mixture. The numerical model and combustion mechanism are validated against engine experimental results using methanol and iso-octane fuels and ignition delay times of ammonia/n-heptane mixtures measured in a rapid compression machine. The findings show that the engine can effectively operate with up to 50% of the total energy supplied by premixed ammonia, albeit with slightly elevated NO emissions compared to a diesel-fueled engine. Increasing ammonia further leads to lower combustion efficiency. Hydrogen can be utilized in the ammonia engine to enhance ammonia combustion; however, NO emissions increase further. Ammonia leakage primarily originates from regions near the cold wall, the center of the cylinder, and the crevice. N 2 O mainly forms at the ammonia flame front. Emission of N 2 O is therefore mainly due to flame front quenching near the wall. [ABSTRACT FROM AUTHOR]

With the rapid development of intelligent and connected vehicles, the experimental road test for the advanced driving assistance system (ADAS) is dramatically increasing around the world. Considering its high cost and hazardous situations, simulation test based on a dummy model is becoming a promising way for ADAS road test practice to reduce the experiment expanses. This study proposed a methodology for the evaluation of the performance of human and dummies with distinct designed materials based on the data extracted from the Doppler effect of millimeter-wave radar. Echo data of 8 different angles from 0 to 360 degrees, with the an interval of 45 degrees, at the same distance between the test object and the signal source is collected. Meanwhile, the echo energy is collected for correlation modeling and analysis among groups. By evaluating the performance of humans and dummies via statistical analysis, a close correlation was found which results verified the substitutability of the dummy for the ADAS experiment test. The correlation coefficient between human and dummies ranges from 0.75 to 0.93. The support vector machine (SVM) model was developed and fitted to predict the echo energy in diverse environments. The mean average error (MAE) is 5.42–11.42 in the training and testing datasets while root mean square error (RMSE) is 0.43–0.90. The methods developed in the study can simulate the real ADAS road test environment and support future experimental research. [ABSTRACT FROM AUTHOR]

The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection. Cytoskeletal remodeling is known to facilitate mitophagy, but the mechanism is not fully understood. Here, the authors show that damaged mitochondria recruit a RhoA GTPase activating protein that promotes their capture and encasement by autophagosomes. [ABSTRACT FROM AUTHOR]

It has been demonstrated that the ATP-gated ion channel P2X7 receptor is involved in tumor progression and plays an important role in regulating tumor cell growth, invasion, migration and angiogenesis. However, P2X7 receptors have been relatively poorly studied in non-small cell lung cancer (NSCLC) cells. Therefore, the aim of this study was to investigate the effects of P2X7 receptor on A549 cells (NSCLC cell line) migration and invasion and to reveal the molecular mechanisms mediated by it. We detected the expression and function of P2X7 receptor in A549 cells. The effects and mechanisms of P2X7 receptor on A549 cells migration, invasion, and epithelial-mesenchymal transition were detected in vitro and in vivo. The results showed P2X7 receptor expressed by A549 cells had ion channel and macropore formation function. In addition, activation of P2X7 receptor by adenosine triphosphate (ATP) or 2′(3′)-O-(4-Benzoylbenzoyl)-adenosine-5'-triphosphate (BzATP) promoted Epithelial-mesenchymal transition (EMT), migration and invasion of A549 cells, which was attenuated by treatment of cells with P2X7 receptor antagonist A438079 and Oxidized ATP. Furthermore, activation of P2X7 receptor increased phosphorylated protein kinase B (p-Akt) levels, and the phosphatidylinositol-tris–phosphate kinase 3 (PI3K)/protein kinase B (Akt) inhibitor LY294002 blocked migration and invasion of A549 cells induced by ATP or BzATP. At the same time, in vivo results showed that P2X7 receptor could also promote EMT and PI3K/Akt expression in transplanted tumors. Our study indicated that P2X7 receptor promotes A549 cells migration and invasion through the PI3K/Akt signaling pathway, suggesting that P2X7 receptor may be a potential therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]

Due to its exceptional performance, the Ti6Al4V alloy finds extensive use in aviation, biomedical, and petrochemical sectors. Nonetheless, its limited machinability and subpar wear resistance have hindered its widespread application. Therefore, this study underlooks a novel approach by employing nitrogen (N2) gas–assisted electrical discharge machining (NA-EDM) to machine Ti6Al4V. In this context, N2 gas serves a dual purpose. On the one hand, the flow of N2 has a beneficial impact on enhancing the surface properties of the workpiece. On the other hand, N2 reacts with titanium (Ti) to create titanium nitride (TiN), enhancing the component's performance. Also, this study focuses on investigating how peak current, pulse-on time, electrode rotation speed, and gas pressure influence various aspects, including surface morphology, surface roughness, the microstructure of the recast layer, the microhardness of the recast layer, the thickness of the recast layer, and material removal rate (MRR). Experimental findings show that the NA-EDM process results in a smoother surface morphology, a uniform recast layer, and a reduced MRR. The microhardness in NA-EDM exceeds that of EDM by 42.1%, attributed to the formation of TiN and martensite. Ra is decreased by 21.2% compared to EDM. This study offers novel insights into machining Ti6Al4V alloy, opening up possibilities for broader-scale applications. [ABSTRACT FROM AUTHOR]

The HIV-1 Tat protein hijacks the Super Elongation Complex (SEC) to stimulate viral transcription and replication. However, the mechanisms underlying Tat activation and inactivation, which mediate HIV-1 productive and latent infection, respectively, remain incompletely understood. Here, through a targeted complementary DNA (cDNA) expression screening, we identify PRMT2 as a key suppressor of Tat activation, thus contributing to proviral latency in multiple cell line latency models and in HIV-1-infected patient CD4+ T cells. Our data reveal that the transcriptional activity of Tat is oppositely regulated by NPM1-mediated nucleolar retention and AFF4-induced phase separation in the nucleoplasm. PRMT2 preferentially methylates Tat arginine 52 (R52) to reinforce its nucleolar sequestration while simultaneously counteracting its incorporation into the SEC droplets, thereby leading to its functional inactivation to promote proviral latency. Thus, our studies unveil a central and unappreciated role for Tat methylation by PRMT2 in connecting its subnuclear distribution, liquid droplet formation, and transactivating function, which could be therapeutically targeted to eradicate latent viral reservoirs. The mechanisms regulating Tat function for HIV-1 replication remain poorly understood. Here, the authors reveal that the transcriptional activity of Tat is modulated by a PRMT2-licensed switch between its nucleolar sequestration and phase separation into the nucleoplasmic Super Elongation Complex (SEC) droplets. [ABSTRACT FROM AUTHOR]

Underground mining activities can easily trigger surface subsidence and cause damage to surface soil. However, there is still a lack of studies on damaged soil, restricting ecological remediation in mining-induced subsidence regions to a certain degree. Focusing on the particular example of No. 4 Mine in Yili, Xinjiang, China, this study comprehensively combined field sampling, laboratory experiments, and data analysis to investigate the variation rules of basic physical properties and shear characteristics of soil samples. The latter had different subsidence degrees (0, 0–20, 20–40, and above 40 cm) and various depths (0– 10, 10–20, 20– 40, 40–60, and 60–80 cm). The experimental results show that: First, the natural density and dry unit weight of shallow soil in the serious-subsidence region were more significantly affected by mining-induced subsidence than the conditions in the deep layer, which also dropped with the increase in subsidence degree (with a mean drop rate of 7%). Second, serious subsidence could greatly counteract the positive effect of slight and moderate subsidence on the soil shear strength, with a drop rate of up to 30.7%. Third, compared with soil physical indices, mining-induced subsidence more easily affected shear strength indices. In particular, the soil samples taken from 0 to 10 cm depth in the slight subsidence area and 60–80 cm depth in the moderate subsidence area were most significantly affected by mining-induced subsidence, with PCA comprehensive scores of over 1.5. The present study can con-tribute to gaining in-depth knowledge of the damage characteristics of surface soil under mining-induced subsidence and provide a theoretical foundation for formulating reasonable coal mining strategies and ecological protection measures. [ABSTRACT FROM AUTHOR]

Mammalian cardiomyocytes (CMs) undergo maturation during postnatal heart development to meet the increased demands of growth. Here, we found that omentin-1, an adipokine, facilitates CM cell cycle arrest and metabolic maturation. Deletion of omentin-1 causes mouse heart enlargement and dysfunction in adulthood and CM maturation retardation in juveniles, including delayed cell cycle arrest and reduced fatty acid oxidation. Through RNA sequencing, molecular docking analysis, and proximity ligation assays, we found that omentin-1 regulates CM maturation by interacting directly with bone morphogenetic protein 7 (BMP7). Omentin-1 prevents BMP7 from binding to activin type II receptor B (ActRIIB), subsequently decreasing the downstream pathways mothers against DPP homolog 1 (SMAD1)/Yes-associated protein (YAP) and p38 mitogen-activated protein kinase (p38 MAPK). In addition, omentin-1 is required and sufficient for the maturation of human embryonic stem cell-derived CMs. Together, our findings reveal that omentin-1 is a pro-maturation factor for CMs that is essential for postnatal heart development and cardiac function maintenance. [ABSTRACT FROM AUTHOR]

To investigate the involvement of stress induced phosphoprotein 1 (STIP1), heat shock protein (HSP) 70, and HSP90 in ubiquitination of connexin 43 (Cx43) in rat H9c2 cardiomyocytes. Co-immunoprecipitation was used to detect protein-protein interactions and Cx43 ubiquitination. Immunofluorescence was used for protein co-localization. The protein binding, Cx43 protein expression, and Cx43 ubiquitination were reanalyzed in H9c2 cells with modified STIP1 and/or HSP90 expression. STIP1 bound to HSP70 and HSP90, and Cx43 bound to HSP40, HSP70, and HSP90 in normal H9c2 cardiomyocytes. Overexpression of STIP1 promoted the transition of Cx43-HSP70 to Cx43-HSP90 and inhibited Cx43 ubiquitination; knockdown of STIP1 resulted in the opposite effects. Inhibition of HSP90 counteracted the inhibitory effect of STIP1 overexpression on Cx43 ubiquitination. STIP1 suppresses Cx43 ubiquitination in H9c2 cardiomyocytes by promoting the transition of Cx43-HSP70 to Cx43-HSP90. [ABSTRACT FROM AUTHOR]

Wearable electronics with miniaturization and high-power density call for devices with advanced thermal management capabilities, outstanding flexibility, and excellent permeability. However, it is difficult to achieve these goals simultaneously due to the conflict between high thermal conductivity and permeability and flexibility. Here, we report an approach to fabricate flexible, breathable composites with advanced thermal management capability by coating the boron nitride nanosheets (BNNSs) layer with high thermal conductivity on the grids of patterned electrospun thermoplastic polyurethane (TPU) fibrous mats. The composite exhibited a significant enhancement of thermal conductivity and preserved instinctive breathability simultaneously. When the composite was integrated into flexible devices, its saturating operating temperature dropped significantly compared to that of pure Ecoflex packaging. Moreover, the surface temperature fluctuation was less than 0.5 °C during more than 2000 cycles bending-releasing process. Finally, a prototype to fabricate wearable electronics with advanced thermal management capability was proposed. [ABSTRACT FROM AUTHOR]

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity. LKB1 mutations have been associated with primary resistance to immune checkpoint inhibitors in patients with lung cancer. Here the authors show that Lkb1-deficient lung tumors are characterized by defective trafficking and adhesion of T cells and that, by upregulating ICAM1 expression, CDK4/6 inhibitors sensitize LKB1 mutant lung cancer to anti-PD1 blockade. [ABSTRACT FROM AUTHOR]

HER2 belongs to the human epidermal growth factor receptor tyrosine kinase family. Its overexpression or hyperactivation is a leading cause for multiple types of cancers. HER2 functions mainly through dimerization with other family members, such as EGFR. However, the molecular details for heterodimer assembly have not been completely understood. Here, we report cryo-EM structures of the EGF- and epiregulin-bound EGFR/HER2 ectodomain complexes at resolutions of 3.3 Å and 4.5 Å, respectively. Together with the functional analyses, we demonstrate that only the dimerization arm of HER2, but not that of EGFR, is essential for their heterodimer formation and signal transduction. Moreover, we analyze the differential membrane dynamics and transient interactions of endogenous EGFR and HER2 molecules in genome-edited cells using single-molecule live-cell imaging. Furthermore, we show that the interaction with HER2 could allow EGFR to resist endocytosis. Together, this work deepens our understanding of the unique structural properties and dynamics of the EGFR/HER2 complex. [ABSTRACT FROM AUTHOR]

The restriction of structural vibration has assumed great importance in attaining bright emission of luminescent metal nanoclusters (NCs), where tremendous efforts are devoted to manipulating the surface landscape yet remain challenges for modulation of the structural vibration of the metal kernel. Here, we report efficient suppression of kernel vibration achieving enhancement in emission intensity, by rigidifying the surface of metal NCs and propagating as-developed strains into the metal core. Specifically, a layer-by-layer triple-ligands surface engineering is deployed to allow the solution-phase Au NCs with strong metal core-dictated fluorescence, up to the high absolute quantum yields of 90.3 ± 3.5%. The as-rigidified surface imposed by synergistic supramolecular interactions greatly influences the low-frequency acoustic vibration of the metal kernel, resulting in a subtle change in vibration frequency but a reduction in amplitude of oscillation. This scenario therewith impedes the non-radiative relaxation of electron dynamics, rendering the Au NCs with strong emission. The presented study exemplifies the linkage between surface chemistry and core-state emission of metal NCs, and proposes a strategy for brighter emitting metal NCs by regulating their interior metal core-involved motion. The photoluminescence of gold nanoclusters is affected by low-frequency acoustic vibrations. Here, the authors demonstrate that layer-by-layer ligand engineering can suppress such structural vibrations to achieve brighter emissions. [ABSTRACT FROM AUTHOR]

Lysine lactylation (Kla) has recently been reported to participate in regulating transcription in human cells. However, the characterization, regulatory mechanism and functional consequence of Kla in prokaryotes remain unclear. Here, we report that YiaC functions as a lysine lactylase and that CobB serves as a lysine delactylase in the regulation of metabolism. We demonstrate that YiaC catalyzes the addition of Kla, while CobB erases this PTM both in vitro and intracellularly. Moreover, we show that YdiF can catalyze the formation of a lactyl-coenzyme A, which donates lactyl group for Kla. Quantitative proteomic analysis further reveals 446 endogenous Kla sites targeted by CobB and 79 candidates targeted by YiaC in Escherichia coli (E. coli). Furthermore, we present that Kla can influence the functions of metabolic enzymes. Interestingly, we demonstrate that CobB can specifically modulate the activity of PykF by regulating K382la, promoting glycolysis and bacterial growth. Our study identifies the regulatory enzymes and functional network of Kla and reveals a Kla-mediated molecular mechanism catalyzed by CobB for glycolysis regulation in E. coli. The characterization of lysine lactylation (Kla) in prokaryotes remains unclear. Here, the authors identify the regulatory enzymes (YiaC as a lactylase and CobB as a delactylase) and functional network of Kla and reveal a Kla-mediated molecular mechanism for glycolysis regulation in Escherichia coli. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes and is the leading cause of end-stage renal disease (ESRD). Persistent proteinuria is an important feature of DKD, which is caused by the destruction of the glomerular filtration barrier (GFB). Glomerular endothelial cells (GECs) and podocytes are important components of the GFB, and their damage can be observed in the early stages of DKD. Recently, studies have found that crosstalk between cells directly affects DKD progression, which has prospective research significance. However, the pathways involved are complex and largely unexplored. Here, we review the literature on cellular crosstalk of GECs and podocytes in the context of DKD, and highlight specific gaps in the field to propose future research directions. Elucidating the intricates of such complex processes will help to further understand the pathogenesis of DKD and develop better prevention and treatment options. [ABSTRACT FROM AUTHOR]

Objective: We investigated the correlation between zinc levels and Nrf2 expression and potential effects on the clinicopathology of patients with diabetic nephropathy (DN). Methods: We selected 30 patients with DN, diagnosed via renal biopsy at our hospital from March 2018 to November 2019, and enrolled 30 healthy individuals from a medical examination center as the control group. Patients with DN were divided into normal-zinc and low-zinc groups. We detected the levels of zinc, copper, and Nrf2 mRNA in their serum, and collected the clinical and pathological data of DN patients. Results: Serum zinc level and Nrf2 mRNA expression were significantly decreased in patients with DN compared to those of healthy people (P < 0.05). Of the 30 patients, 16 had low zinc (53.3%) and 14 had normal zinc levels (46.7%). There was no significant difference in the blood Nrf2 mRNA expression between the two groups (P > 0.05). However, the expression of Nrf2 in the kidney tissue of the low-zinc group was significantly lower compared to the normal-zinc group (P < 0.05). Diastolic blood pressure and copper levels were significantly higher in the low-zinc group (P < 0.05). In contrast, body mass index, red blood cell count, Hb level, and the ratio of zinc to copper were significantly lower in the low-zinc group (P < 0.05). The pathological classifications of the low-zinc group were more severe (P < 0.05). Conclusion: Patients with DN were more likely to have zinc deficiency and lower expression of Nrf2. Additionally, DN patients with zinc deficiency were prone to have more severe clinical and pathological manifestations. [ABSTRACT FROM AUTHOR]

Sintered NdFeB is widely used due to its excellent magnetic properties, but it is not suitable for machining by conventional machining methods due to its very high brittleness and hardness. Electrical discharge machining (EDM) is deemed to be an important method for machining sintered NdFeB without considering the hardness of the material. To address the problems of poor performance and high cost of EDM machining of sintered NdFeB, in this study, the effect of the EDM-milling process on the surface morphology, cross-section, material removal rate (MRR), surface roughness (SR), and electrode wear rate (EWR) of sintered NdFeB was investigated by varying parameters including current, pulse duration, and pulse interval. Comparative experiments with EDM have shown that the EDM-milling process has better performance on machined surfaces, with large craters of radial size and lower value of SR. Its cross-section has thinner recast layer and smaller range of heat-affected zone. The MRR is enhanced by a maximum of 162%. Moreover, the EWR for EDM and EDM-milling are close to zero. [ABSTRACT FROM AUTHOR]

The sintered NdFeB is widely used in many fields due to its excellent magnetic properties. However, the sintered NdFeB is characterized by its high hardness and brittleness. Therefore, its application has been limited. In order to improve its machining properties by electrical discharge machining (EDM), the deionized water is used as the dielectric medium, and then the sintered NdFeB is processed by the electrical discharge machining milling (EDM-M). The machining properties are studied by the comparative experiments. Changing the set value of the current, get the material removal rate (MRR), the surface roughness (SR) and the tool wear rate (TWR) of the die-sinking EDM in the kerosene-based medium (KEDM), the EDM-M in the kerosene-based medium (KEDM-M), the die-sinking EDM in the deionized water (DEDM), and the EDM-M in the deionized water (DEDM-M), respectively. By the scanning electron microscope (SEM), the influences of current on the material removal mechanism and surface formation mechanism of the DEDM-M are analyzed. Meanwhile, the characteristic of its surface micro-morphology influenced by current is analyzed. Combined SEM with energy-dispersive spectroscopy (EDS), the cross-section of the sintered NdFeB by the DEDM-M is analyzed. It is revealed by the comparative experiments that, for the sintered NdFeB by the DEDM-M, the interval of the machining parameter is wide; the value of SR is lowest obviously under low current set value; the variations of its MRR, SR, and TWR are regular; the controllability is good. The regression equations for the machining properties of the DEDM-M are obtained and its analysis of variance (ANOVA) is good. The analysis on the SEM of its machined surface indicates that the material removal and surface formation of the DEDM-M are effected synthetically by fusion and stress. The change of current leads to the difference in surface micro-morphology by fusion removal, globule, microvoid, microcrack, and surface micro-morphology by stress removal, and then leads to differences in MRR and SR, respectively. The results of analysis on the cross-section reveal that there are four categories from the surface to the matrix. They are recast layer after fusion with plenty of rare earth elements and minor oxygen which is amorphous and sheet, recast layer after fusion with plenty of iron element and minor rare earth elements which is strip and granular, micro-morphology by stress, and heat affected layer that is composed of large grains with thin grain boundaries. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells are critical in providing help for B cells in the germinal center reaction. Tfh cell plasticity, especially with regard to their expression of effector Th cytokines, has been described, but lacks in-depth analysis with genetic approaches. In this study, we systemically compared transcriptomic profiles of Tfh cells derived from various types of immune responses and found gene clusters corresponding to effector Th cells were differentially induced in response to pathogens or immune responses. Of special interest, a subset of Tfh cells producing IFN-γ was generated in an influenza virus infection, partially dependent on the innate cytokine IL-12. Lineage-tracing mouse model revealed unique developmental regulation of IFN-γ+ Tfh cells, while selective ablation of these cells impaired the induction of IgG2c+ germinal center B cells and the control of influenza infection. These results indicate that pathogen-associated Tfh cell plasticity is necessary for host immunity, which has implications in vaccine design. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors. [ABSTRACT FROM AUTHOR]

Copper based ternary and quaternary quantum confined nanostructures have attracted huge attention over recent years due to their potential applications in photonics, photovoltaics, imaging, sensing and other areas. However, anisotropic nanoheterostructures of this type are still poorly explored to date, despite numerous predictions of the distinctive optical properties of these highly fluorescent heavy metal free nanostructures. Here, we report new fluorescent multicomponent Cu–In–(Zn)–S/ZnS nanoheterostructures with a unique anisotropic "ice-cream cone" like morphology. These nanostructures have been prepared with a seeded growth technique and exhibit distinct photophysical properties with maximum emission in the visible range (≈ 640 nm) and long photoluminescence lifetimes (τaverage ≥ 300 ns). In depth time interval studies have been carried out to better understand the step by step growth mechanism of this distinct "ice-cream cone" like geometry. We have demonstrated that the crystal structure evolution from the zinc blende Cu–In–S core to the wurtzite "ice cream cone" like Cu–In–(Zn)–S/ZnS nanocrystals plays a key role in the origin of this morphology. This research opens new possibilities to produce unique fluorescent Cu-based multicomponent anisotropic heteronanostructures, while also offering a distinctive insight into the design of bespoke nanostructures, which could find a range of potential applications. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO), a central protein of erythropoiesis, plays an important role during hypoxia adaptation and is regulated by hypoxia-inducible factor (HIF). However, there is no report on EPO-producing cells and their regulatory mechanisms in yak (Bos grunniens). To understand EPO production and regulation of yak, kidneys from different age of yak were collected and expression of EPO, hypoxia-inducible factor 1 alpha (HIF-1α), and hypoxia-inducible factor 2 alpha (HIF-2α) were detected. Then renal tubule epithelial cells (RTECs) and peritubular interstitial fibroblast-like (RIFs) cells were isolated and cultured to determine their EPO production abilities. Subsequently, the cells were treated with dimethyloxalylglycine (DMOG) and Geldanamycin (GA), which are inhibitors of prolyl-4-hydroxylase domain (PHD) and heat shock protein 90 (HSP90) respectively, and siRNAs of HIF-1α and HIF-2α to explore their effect on EPO production and regulation. The results showed that expressions of EPO, HIF-1α, and HIF-2α were different in the different age groups of yak. High DMOG concentration caused a corresponding increase in the levels of HIF-1α and HIF-2α in RIFs and RTECs, however, EPO levels increased in RIFs only and was not detected at any concentration in RTECs; suggesting that EPO was produced in RIFs. Upon treating RIFs with siRNAs of HIF-1α and HIF-2α, we found that EPO was regulated by PHD through HIF-2α. In addition, increasing GA concentration caused a decrease in expression of HSP90, HIF-1α, HIF-2α, and EPO in RIFs. In conclusion, these findings support our proposition that PHD regulates EPO via HIF-2α in yak RIFs, while HSP90 impelled EPO expression. [ABSTRACT FROM AUTHOR]

A new type SA508-IV reactor pressure vessel steel was irradiated at 290 °C to 3 and 30 displacement per atom (dpa) with 3.5 MeV Fe2+ ions. The focused ion beam was used to cut the samples for the field emission transmission electron microscope (FE-TEM) after irradiation. The microstructure analysis under the scanning transmission electron microscope (STEM) mode of FE-TEM revealed that the heavy ion irradiation produced a large number of matrix defects and Cu-rich clusters. The high dosage of irradiation would also force Mo atoms to relocate to form Cr/Mn/Mo-rich precipitates. Dislocation loops were especially formed in samples irradiated by 30 dpa, which are one of the principal evolving defects in irradiated materials. The nanoindentation test results showed that the nano-hardness increases with the increase of irradiation doses. The semi-plateau stage in 3 dpa irradiation (I3 sample) curve of nano-hardness versus indentation depth corresponds to the saturation of Cu-rich clusters; while the plateau stage in the I30 sample curve should be attributed to the loop coalescence. [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes—S1 and S2—based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC. Proteomics can aid in the identification of molecular subtypes in cancers. Here, the authors perform proteomic profiling of 124 paired oesophageal cancer and adjacent non-tumour tissues and identify two subtypes that are associated with patient survival for therapeutic targeting. [ABSTRACT FROM AUTHOR]

The magnetized sintered NdFeB (MS-NdFeB) permanent magnet material is difficult to machine due to high hardness, brittleness, and magnetic force. In this paper, the electrical discharge machining (EDM) of the MS-NdFeB workpiece is studied to improve the machining process of the MS-NdFeB. In addition to the material removal rate (MRR) and the surface roughness (SR), the change rate of the magnetic flux density (MCR) for the MS-NdFeB is proposed and used as the research index of their machining effect by the EDM process. By orthogonal experiments, using the intuitive analysis method and the analysis of variance (ANOVA) method, study the influences of the peak current, the pulse on time, the pulse off time, and the magnetic field intensity of the processing area (MF) on the MRR, the SR, and the MCR. The scanning electron microscope (SEM) pictures of the machined MS-NdFeB surfaces are obtained based on the experimental design with a one-factor variation. The comparative experiment is performed to reveal the change of the MCR in EDM. The intuitive analysis of the orthogonal experimental result reveals regularities of influences. The ANOVA reveals the significance of influences. The regularities and significance of influences of machining parameters on the machining effects are analyzed assisted by the analysis on these SEM pictures and the comparative experimental results. The optimal combinations of machining parameters for MRR, SR, and MCR are obtained by single-objective optimization. The verification experiments prove the reliability of the single objective optimization results. [ABSTRACT FROM AUTHOR]

Central China, one of the Earth's distinctive ecoregions due to its endemic subtropical biota, has been subjected to enhanced nitrogen deposition and climate warming during recent decades. However, the extent and timescale of ecological changes are largely unexplored. Multiproxy analyses (diatoms, photosynthetic pigments and geochemistry) of 210Pb-dated sediment cores from two shallow ponds within an alpine basin (central China) were used to investigate the response of primary producer communities to external stressors during the last two centuries. The study sites include one drainage pond and one seepage pond. Both ponds exhibited unambiguous changes in production and composition of photoautotrophs since the early twentieth century, which are linked to climate warming, nitrogen deposition and local factors (for example, lake morphometry, desiccation and macrophyte). Although primary producers responded to regional warming and nitrogen deposition, the ecological responses differed among ponds due to local factors. In the deeper seepage pond, light attenuation due to terrestrial organic matter input caused recent decreases in carotenoids and small fragilarioid taxa. In contrast, the co-occurrence of euterrestrial and tychoplanktonic diatoms in the shallower drainage pond was indicative of its hydrological instability. Our results indicate that subtropical montane ponds in the East Asian monsoon region appear to be strongly influenced by a combination of local (for example, catchment-lake connectivity) and regional driving forces (for example, warming and nitrogen deposition). [ABSTRACT FROM AUTHOR]

Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca2+ concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP. [ABSTRACT FROM AUTHOR]

Thiazole ring is an important active molecular skeleton of drugs. Thiazole in natural products and drugs are usually harmlessly eliminated. However, hepatotoxic reactions may occur due to the biological activation of thiazole to produce reactive thioamide. A typical example is hepatotoxic sudoxicam and safety meloxicam. The only structural difference between them is a methyl group on C5 position of thiazole in meloxicam. The molecular basis for the difference remains unknown and the bioactivation mechanism of the thiazole ring is still obscure. Quantum chemical calculations were performed to elucidate the activation mechanism of the thiazole ring under P450 catalysis, and the influence of the substituents on the activation pathways of thiazole ring was also studied. The calculated results show that the activation of thiazole is closely related to the substituents on the thiazole and spin state of Cpd I. The thiazole and substituted thiazole directly open the ring when catalyzed by doublet spin state Cpd I that catalyzed by the quartet spin state Cpd I can open the ring directly or indirectly, which is related to the substituents. Thiazoles modified with electron-donating substituents mainly undergo direct ring opening, while thiazoles modified with electron-withdrawing groups or weak electron-donating groups mainly undergo indirect ring-opening process accompanied by intermediate formation. The research results laid the foundation for the design of thiazole ring drugs, and also laid a theoretical foundation for the study of reducing the toxicity of thiazole ring drugs. [ABSTRACT FROM AUTHOR]

In this study, a virtual-point concept was introduced into fiber-laser photoacoustic tomography to improve the elevational image resolution. The flexible fiber laser was bent into an arc shape to conform to the ultrasound wavefront, which formed an ultrasound focus at the center of the arc. The synthetic aperture focusing technique was utilized to reconstruct the images; as a result, the elevational resolution particularly within the out-of-focus region was considerably improved compared to the resolution of an image retrieved by multiplexing the PA time-resolved signals with sound velocity. The all-optical fiber-laser photoacoustic tomography system with a high spatial resolution has potential for various applications, including biomedical research and preclinical/clinical diagnosis. [ABSTRACT FROM AUTHOR]

A novel flexible zinc oxide nanorods (NRs)/poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) nanocomposite was prepared by electrospinning for fabricating piezoelectric nanogenerator (PNG). The NRs were used as nanofillers of piezoelectric P(VDF-TrFE), which can enhance the electroactive β-crystal ratio as well as the crystallinity of P(VDF-TrFE). It has been found that the addition of different levels of piezoelectric ZnO NRs can improve the overall performance of PNG made with electrospun membranes. The PNG comprised by 10 wt% ZnO NRs/P(VDF-TrFE) nanocomposite demonstrates an outstanding output open-circuit voltage (61 V) and short-circuit current (2.2 μA). It has been concluded that the ion–dipole interaction between NRs and electroactive β-crystals of P(VDF-TrFE) are useful for the construction of the high-performance flexible PNG. Besides, the output power generated from the PNG can directly light 25 commercial light-emitting diodes, and also capable to charge up a capacitor (4.7 μF) and reached 2.1 V in 2 min, which indicates the potential of the PNG for flexible wearable electronic devices. [ABSTRACT FROM AUTHOR]

Genome assemblies provide a powerful basis of comparative multi-omics analyses that offer insight into parasite pathogenicity, host-parasite interactions, and invasion biology. As a unique intracellular nematode, Trichinella consists of two clades, encapsulated and non-encapsulated. Genomic correlation of the distinct differences between the two clades is still unclear. Here, we report an annotated draft reference genome of non-encapsulated Trichinella, T. pseudospiralis, and perform comparative multi-omics analyses with encapsulated T. spiralis. Genome and methylome analyses indicate that, during Trichinella evolution, the two clades of Trichinella exhibit differential expansion and methylation of parasitism-related multi-copy gene families, especially for the DNase II members of the phospholipase D superfamily and Glutathione S-transferases. Further, methylome and transcriptome analyses revealed divergent key excretory/secretory (E/S) genes between the two clades. Among these key E/S genes, TP12446 is significantly more expressed across three life stages in T. pseudospiralis. Overexpression of TP12446 in the mouse C2C12 skeletal muscle cell line could induce inhibition of myotube formation and differentiation, further indicating its key role in parasitism of T. pseudospiralis. This multi-omics study provides a foundation for further elucidation of the mechanism of nurse cell formation and immunoevasion, as well as the identification of pharmacological and diagnostic targets of trichinellosis. Xiaolei Liu, Yayan Feng, et al. report an annotated draft reference genome of the non-encapsulated Trichinella pseudospiralis, and perform comparative multi-omics analyses with encapsulated T. spiralis. Overexpression of TP12446, a key excretory/secretory gene, in a mouse C2C12 skeletal muscle cell line could induce inhibition of myotube formation and differentiation. These results provide insight into the mechanism of nurse cell formation and immunoevasion, as well as the identification of potential pharmacological and diagnostic targets for trichinellosis. [ABSTRACT FROM AUTHOR]

Oligoasthenozoospermia (OA) is one of the most common types of male infertility affecting sperm count and sperm motility. Unfortunately, it is difficult for existing drugs to fundamentally improve the sperm quality of OA patients, because the pathological mechanism of OA has not been fully elucidated yet. Morinda officinalis–Lycium barbarum coupled-herbs (MOLBCH), as traditional Chinese Medicines, has been widely used for treating OA over thousands of years, but its molecular mechanism is still unclear. For this purpose, we adopted a comprehensive approach integrated network pharmacology and molecular docking to reveal the bioactive components and potential targets of MOLBCH against OA. The results showed that MOLBCH alleviated apoptosis, promoted male reproductive function, and reduced oxidant stress in the treatment of OA. Ohioensin-A, quercetin, beta-sitosterol and sitosterol were the key bioactive components. Androgen receptor (AR), Estrogen receptor (ESR1), Mitogen-activated protein kinase 3 (MAPK3), RAC-alpha serine/threonine-protein kinase (AKT1), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were the core potential targets. PI3K/Akt signaling pathway, prostate cancer, AGE-RAGE signaling pathway in diabetic complications were the most representative pathways. Moreover, molecular docking was performed to validate the strong binding interactions between the obtained core components and targets. These observations provide deeper insight into the pathogenesis of OA and can be used to design new drugs and develop new therapeutic instructions to treat OA. [ABSTRACT FROM AUTHOR]

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Introduction: The worldwide prevalence of diabetes has been increasing for decades; diabetes can lead to serious health problems and even death, but the effects of maintaining low fasting blood glucose (FBG) remain controversial. The purpose of this study was to investigate the relationship between FBG levels and all-cause mortality in a long-term follow-up cohort and to find a relatively safe range of FBG levels. Methods: This study included 17,902 adults from a community-based cohort study in rural China who were prospectively followed from 2003 to 2018. Generalized estimating equations were used to evaluate the association between FBG and all-cause mortality, adjusting for pertinent covariates and auto-correlations among siblings. Results: A total of 1053 (5.9%) deaths occurred during 15 years of follow-up. There was a significant U-shaped association between all-cause mortality and FBG. Compared with the reference group (FBG of 5.6 – < 6.1 mmol/l), the risk of death among individuals with FBG levels < 5.6 mmol/l significantly increased by 38% (OR 1.34; 95% CI 1.13–1.59), while the risk of death among individuals with FBG ≥ 6.1 mmol/l or participants with a self-reported history of diabetes significantly increased by 51% (OR 1.49; 95% CI 1.20–1.85). Additionally, the U-shaped association remained steady in any stratification of risk factors. Conclusion: Our study showed a significant U-shaped relationship between FBG levels and risk of all-cause mortality in this rural Chinese population. When FBG was within the range of 5.6 – < 6.1 mmol/l, the risk of all-cause mortality was the lowest. [ABSTRACT FROM AUTHOR]

Patients with pediatric cancers such as neuroblastoma (NB) are often unresponsive to checkpoint blockade immunotherapy. One major factor in pediatric tumor resistance to immunotherapy is considered to be the low mutation rate of pediatric tumors. Another factor may be the overexpression of additional inhibitory pathways. While analyzing the RNA-sequencing database TARGET, we found that human NB tumors overexpress immune checkpoint molecule CD200. To determine its significance and impact on tumor immune microenvironment, we analyzed 49 cases of previously untreated, surgically removed NB tumors using immunohistochemistry and multi-color flow cytometry (FACS). We found that CD200 is overexpressed in more than 90% of NB tumors. In the tumor microenvironment of NB, CD200 is mainly overexpressed in CD45− NB tumor cells, while its cognate receptor (CD200R) is mainly expressed in HLA-DR+CD14+ myeloid cells and CD11c+ dendritic cells. Low-level expression of CD200R is also observed in tumor-infiltrating CD4+ and CD8+ T cells. In NB tumors with higher CD200 expression (CD200high), we observed lower numbers of HLA-DR+CD14+ myeloid cells and less tumor-infiltrating CD4+ and CD8+ T cells. Moreover, we found that CD4+ and CD8+ T cells produced less IFN-γ and/or TNF-α in CD200high NB tumors. Thus, CD200–CD200R pathway appears to downregulate anti-tumor immunity in the tumor microenvironment of NB tumors, and blockade of this pathway may be beneficial for NB patients. [ABSTRACT FROM AUTHOR]

Based on the heterogeneous material model, an integrated analysis method was introduced to predict the service life of propeller. The morphology and distribution characteristic of non-continuous defects (porosity & inclusion) were calculated and mapped into the finite element model by 3D-mapping algorithm, and the fatigue life was predicted based on the heterogeneous material model. In this paper, the coupling analysis of casting process and fatigue prediction of marine propeller was done. The results show that porosity and mass inclusions in blade roots of propeller form serious heterogeneous characteristics in those parts, which increased the maximum stress of the propeller and decreased its theoretical fatigue life by 1/2, indicating that the effect of non-continuous defects on the service performance of casting is notable and cannot be ignored. Based on the integrated analysis method, the inference of the pouring temperature and gating system on the service life of propeller was studied further. The integrated analysis method brings the influence of the casting defects into structural analysis and fatigue analysis, which can improve the accuracy of the fatigue life prediction significantly. [ABSTRACT FROM AUTHOR]