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Triple-negative breast cancer (TNBC) is a severe threat to women’s health because of its aggressive nature, early age of onset, and high recurrence rate. Therefore, in this study, we aimed to evaluate the anti-tumor effects of Gallic acid (GA) on the TNBC HCC1806 cells in vitro. The cell proliferation was detected by MTT and plate clone formation assays, cell apoptosis, cell cycle, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry and Hoechst 33258 staining assays, and the intracellular reactive oxygen species (ROS) accumulation were also investigated. Real-Time PCR and western blot were examined to explore the mechanism of action. The results indicated that GA suppressed HCC1806 cells proliferation and promoted HCC1806 cells apoptosis. Meanwhile, GA treatment changed the morphology of the HCC1806 cells. In addition, GA blocked the HCC1806 cells cycle in the S phase, and it induced cells apoptosis accompanied by ROS accumulation and MMP depolarization. Real-Time PCR results suggested that GA increased Bax, Caspase-3, Caspase-9, P53, JINK and P38 mRNA expression, and decreased Bcl-2, PI3K, AKT and EGFR mRNA expression. Western blotting results suggested that GA increased Bax, cleaved-Caspase-3, cleaved-Caspase-9, P53, P-ERK1/2, P-JNK, P-P38 proteins expression, and decreased Bcl-2, P-PI3K, P-AKT, P-EGFR proteins expression. Furthermore, molecular docking suggested that GA has the high affinity for PI3K, AKT, EGFR, ERK1/2, JNK, and P38. In conclusion, GA could suppress HCC1806 cells proliferation and promote HCC1806 cells apoptosis through the mitochondrial apoptosis pathway and induces ROS generation which further inhibits PI3K/AKT/EGFR and activates MAPK signaling pathways. Our study will provide some new references for using GA in the treatment of TNBC.

Immune checkpoint blockade (ICB) therapy has attracted widespread attention in cancer treatment. Due to the low immunogenicity and immune suppression state in the tumor microenvironment (TME), the therapeutic effects are only moderate. Herein, a TME-activable manganese-boosted catalytic immunotherapy is designed for synergism with ICB therapy to kill tumors efficiently. The tumor cell membrane (CM)-wrapping multienzyme-mimic manganese oxide (MnO

Triple-negative breast cancer (TNBC) is a severe threat to women's health because of its aggressive nature, early age of onset, and high recurrence rate. Therefore, in this study, we aimed to evaluate the anti-tumor effects of Gallic acid (GA) on the TNBC HCC1806 cells

As an important component of the dynamic tumor microenvironment, mesenchymal stem cells (MSCs) can interact with tumor cells to promote tumor growth. Treatment with tumor cell-derived exosomes can change the biological functions of MSCs. We want to study the mechanism by which exosomes derived from gastric cancer cells affect the biological functions of MSCs. After MSCs were treated with adenocarcinoma gastric cells (AGS) cell-derived exosomes, circular RNAs differentially expressed in MSCs were verified using existing RNA microarray results combined with quantitative real-time polymerase chain reaction (qRT-PCR). Then, circular RNAs were knocked down or overexpressed by plasmids, and the functions of circular RNAs were evaluated by Migration and invasion assay. Dual luciferase reporter assay was used to evaluate the potential mechanism of circular RNAs. After treatment with exosomes secreted by AGS, the results showed that some circular RNAs expressed by human adipose-derived MSCs showed significant differences. The elevated circ_0004303 promoted the migration and invasion of human adipose-derived MSCs in vitro. Circ_0004303 upregulated the expression of activated leukocyte cell adhesion molecule (ALCAM) by acting as a miR-148a-3p sponge, thereby enhancing the migration and invasion functions of human adipose-derived MSCs. Therefore, exosomes secreted by AGS can affect the expression of circular RNAs in human adipose-derived MSCs. Hsa_circ_0004303 can regulate the migration and invasion of human adipose-derived MSCs via the miR-148a-3P/ALCAM axis. This study suggests that tumor cells can promote the migration and homing of MSCs in adjacent tissues by secreting exosomes.

BackgroundObservational studies have suggested that peripheral immune disorders are associated with amyotrophic lateral sclerosis (ALS). Previous studies predominantly focused on changes in adaptive immunity. However, emerging evidence showed natural killer (NK) cells, an essential component of innate immunity, were involved in the degeneration of motor neurons. However, the causal relationship between dysregulated NK cells-related immune traits and ALS remains unclear.ObjectiveThis study aimed to explore the causal relationship between NK cells-related immune traits and the risk of ALS.Materials and methodsSingle nucleotide polymorphisms (SNPs) significantly associated with NK cells-related immune traits were selected as instrumental variables to estimate their causal effects on ALS. SNPs from a genome-wide association study (GWAS) on NK cells-related immune traits were used as exposure instruments, including an absolute NK-cells count, absolute HLA-DR+ NK-cells count, NK cells/lymphocytes, NK cells/CD3– lymphocytes, HLA DR+ NK cells/NK cells, HLA DR+ NK cells/CD3– lymphocytes, and the median fluorescence intensities of CD16–CD56+ on NK cells and HLA-DR+ NK cells. Summary-level GWAS statistics of ALS were used as the outcome data. Exposure and outcome data were analyzed using the two-sample Mendelian randomization (MR) method.ResultsEach one standard deviation increase in the expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells were associated with a lower risk of ALS in both the MR-Egger and inverse variance weighted methods (P < 0.05). The results proved robust under all sensitivity analyses. Neither instrumental outliers nor heterogeneity were detected.ConclusionOur results suggest that higher expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells are associated with a lower risk of ALS.

Saiyue Deng,1 Quan Wang,2 Jingjing Fan,3 Xiaoyun Yang,3 Junhua Mei,4 Jiajia Lu,5 Guohua Chen,4 Yuan Yang,1 Wenhua Liu,6 Runsen Wang,7 Yujia Han,7 Rong Sheng,7 Wei Wang,1 Li Ba,1 Fengfei Ding1,8 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China; 3Cardiac Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 4Department of Neurology, Wuhan No.1 Hospital, Wuhan, 430022, People’s Republic of China; 5Cardiac Unit, Wuhan No.1 Hospital, Wuhan, 430022, People’s Republic of China; 6Department of Clinical Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China; 7Huawei Technologies Co, Shenzhen, People’s Republic of China; 8Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of ChinaCorrespondence: Fengfei Ding, Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China, Tel +86 134 7625 5813, Email fengfei_ding@fudan.edu.cn Li Ba, Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China, Tel +86 136 0764 1809, Email bali2015@126.comPurpose: Heart rate variability (HRV) indices have been used as stress indicators. Rare studies investigated the associations of circadian rhythms of the HRV indices with the stress, mood, and sleep conditions in populations under stress.Methods: In total 257 female participants (203 shift workers and 54 non-shift workers) were included. All the participants completed a structured questionnaire to assess the stress, mood, and sleep conditions and performed 24-hour Holter electrocardiogram monitoring on the day away from shifts. Using epochs of 1-min or 5-min beat-to-beat intervals, the HRV indices (SDNN, RMSSD, LF, HF, LF/HF, and LFnu, SD1, SD2, SD1/SD2) were plotted as a function of time and fitted into cosine periodic curves, respectively. Three mathematical parameters based on the cosine periodic curves were extracted, MESOR (M, overall averages of the cosine curve), amplitude (A, amplitude of the peak of the cosine curve), and acrophase (θ, latency to the peak) to quantify the circadian rhythms of the HRV indices. Multivariable linear regression models were used to reveal the associations of these parameters with the clinical assessments of stress, mood, or sleep conditions, as well as with the 24-h averages of the HRV indices.Results: The parameters M and A of SDNN, RMSSD, LF, and HF, and θ of LF/HF and LFnu significantly differ between shift and non-shift workers. The parameter θ of LF/HF positively correlates with the severity of stress and anxiety. The parameter A of LF/HF and LFnu also positively correlates with daytime sleepiness and sleep fragmentation. In addition, the parameters M and A instead of θ of SDNN, RMSSD, LF, LF/HF, and LFnu significantly correlate with the 24-h averages of HRV indices.Conclusion: The circadian rhythms of the HRV indices over 24 hours can, to some extent, predict the severity of stress, emotion and sleep conditions in female populations under stress.Keywords: circadian rhythms, HRV indices, mental health, stress, sleepiness, fatigue, sleep fragmentation

Background Beiging of white fat plays an important role in energy metabolism. Beige adipocytes contribute to the regulation of body weight and body temperature through expenditure of chemical energy to produce heat, and they have therefore recently attracted considerable attention as potential targets for therapeutic approaches in metabolic disorders, including obesity. All adipocytes, including beige adipocytes, differentiate from mesenchymal stem cells (MSCs), which may provide an important path for clinical intervention; however, the mechanism of beiging of human adipose cell-derived MSCs is not fully understood. Here, we provide insights on the role of IRISIN, which is known to be secreted by skeletal muscle and promote beiging of white fat. Results We established an IRISIN-induced mesenchymal stem cell beiging model and found that IRISIN protein interacts with the MSC membrane protein TRPC3. This interaction results in calcium influx and consequential activation of Erk and Akt signaling pathways, which causes phosphorylation of PPARγ. The phosphorylated PPARγ enters the nucleus and binds the UCP1 promoter region. Furthermore, the role of TRPC3 in the beiging of MSCs was largely abolished in Trpc3−/− mice. We additionally demonstrate that the calcium concentration in the brain of mice increases upon IRISIN stimulation, followed by an increase in the content of excitatory amino acids and norepinephrine, while Trpc3−/− mice exhibit the reverse effect. Conclusions We found that TRPC3 is a key factor in irisin-induced beiging of MSCs, which may provide a new target pathway in addressing metabolic disorders. Our results additionally suggest that the interaction of irisin with TRPC3 may affect multiple tissues, including the brain. Graphical abstract

The present study analyzed and identified the chemical constituents from ethyl acetate(EA) extract of Taxilli Herba with UPLC-Q-Exactive-MS and screened active xanthine oxidase(XO) inhibitors with HPLC. The analysis was performed on an Hypersil GOLD C_(18) reversed-phase column(2.1 mm×50 mm, 1.9 μm), with the mobile phase of water containing 1% formic acid(A) and methanol(B) under gradient elution, the flow rate of 0.3 mL·min~(-1), and the injection volume of 5 μL. ESI source was used for MS and the compounds were collected in positive and negative ion modes. Xcalibur 4.1 was used to analyze the retention time, accurate relative molecular weight, and fragmentation of the compounds. The inhibitory activity of some known compounds on XO was screened by HPLC. Thirty chemical constituents were identified, including phenolic acids and flavonoids by experimental data combined with information of standards, data reported previously, and databases, such as MzCloud and ChemSpider. The activities of 10 chemical components were screened. Gallic acid and naringenin chalcone had strong inhibitory activities on XO with IC_(50) of 57 μg·mL~(-1) and 108 μg·mL~(-1). UPLC-Q-Exactive-MS allows the accurate, rapid, and comprehensive identification of main chemical constituents from Taxilli Herba. Gallic acid and naringenin chalcone may be the active components of XO inhibitors.

The combination of photodynamic therapy (PDT) and photothermal therapy (PTT) has attracted much interest in recent years, but non-specific distribution of photosensitizers and intrinsic tumor hypoxic microenvironment have continued to limit its therapeutic efficiency. We herein report a nano-theranostic system, denoted as Ce6-CuS/MSN@PDA@MnO2-FA NPs, which combines PDT, PTT, magnetic resonance (MR) imaging with hypoxia-relieving and tumor-targeting functionalities. Central to this design is the use of mussel-inspired polydopamine (PDA) coating to encapsulate the chlorin e6 (Ce6) and copper sulfide nanoparticles (CuS NPs) loaded mesoporous silica nanoparticle (MSN) core. The PDA coating not only acts as pH sensitive gatekeeper to prevent the premature release of Ce6 under non-acidic tumor microenvironment (TME), but also facilitates post-functionalization so that hypoxia-relieving MnO2 nano-sheets and tumor-targeting ligand folic acid-PEG-thiol (FA-PEG-SH) can be decorated on the outer part of the drug system. In vitro and in vivo measurements clearly demonstrated that all these functionalities worked synergistically as expected. The system, having a low dark cytotoxicity, can be effectively internalized by 4T1 cells and decrease the cell viability to 2% upon 660 nm/808 nm laser irradiation. Tumors in 4T1 tumor-bearing mice can almost be completely destroyed in 2 weeks via combined PDT/PTT. Together with the TME-sensitive MR imaging performance demonstrated, Ce6-CuS/MSN@PDA@MnO2-FA NPs represent a multifunctional prototype which holds great potential to be developed into clinical theranostics.

BackgroundIn this study, we evaluated the prognostic value of the plasma levels of Epstein-Barr virus (EBV) DNA in patients with nasopharyngeal carcinoma (NPC) at different treatment stages.MethodsWe retrospectively analyzed the Data of 206 patients with NPC. Pre-neoadjuvant chemotherapy (pre-NACT), post-NACT, post-radiotherapy, and post-treatment plasma EBV DNA levels were used to establish prognostic nomograms. The concordance index (C-index) and calibration curves were used to compare the prognostic accuracy of the nomograms. The results were confirmed in a validation cohort consisting of patients who were tested for EBV DNA levels at all four stages of treatment. The Kaplan-Meier method was used to calculate the progression-free survival (PFS) and overall survival (OS). Survival differences were calculated using the log-rank test.ResultsEBV DNA-positive patients had worse 3-year PFS and 5-year OS than EBV DNA-negative patients; this was true for pre-NACT (PFS: 82.7% vs. 57.3%, P < 0.001; OS: 90.9% vs. 68.7%, P = 0.08) and post-NACT (PFS: 85.0% vs. 50.6%, P < 0.001; OS: 91.7% vs. 65.7%; P = 0.001) EBV DNA levels but not for post-radiotherapy (PFS: 72.2% vs. 60.9%, P = 0.192; OS: 73.1% vs. 77.2%, P = 0.472) or post-treatment (PFS: 77.3% vs. 59.2%, P = 0.063; OS: 77.5% vs. 79.7%, P = 0.644) levels. Nomograms combining pre-NACT and post-NACT EBV DNA levels had a superior prognostic ability than those of post-radiotherapy and post-treatment EBV DNA levels.ConclusionPre-NACT EBV DNA levels combined with post-NACT EBV DNA levels can more reliably predict survival outcomes in patients with NPC.

Casting roller is equipped with high maintenance frequency and interchangeability in continuous casting machine, viewed as key part during its operation and maintenance. To improve the level of casting roller operation & maintenance management and prolong its service life, a novel framework for remaining useful life prediction of casting roller in continuous casting machine based on digital twin is proposed. First, systematic overview of the proposed framework is described in detail. Second, monitoring and traceability for casting roller are designed based on 3D twin model. Then, multiple failure modes of casting roller are analyzed and its performance degradation is evaluated. After that, the process of remaining useful life prediction based on deep learning together with twin data is given. Finally, a prototype system is developed and implemented, and the results verify the effectiveness and feasibility of proposed framework.

Purpose Assembly is the last step in manufacturing processes. The two-sided assembly line balancing problem (TALBP) is a typical research focus in the field of combinatorial optimization. This paper aims to study a multi-constraint TALBP-I (MC-TALBP-I) that involves positional constraints, zoning constraints and synchronism constraints to make TALBP more in line with real production. For enhancing quality of assembly solution, an improved imperialist competitive algorithm (ICA) is designed for solving the problem. Design/methodology/approach A mathematical model for minimizing the weighted sum of the number of mated-stations and stations is established. An improved ICA is designed based on a priority value encoding structure for solving MC-TALBP-I. Findings The proposed ICA was tested by several benchmarks involving positional constraints, zoning constraints and synchronism constraints. This algorithm was compared with the late acceptance hill-climbing (LAHC) algorithm in several instances. The results demonstrated that the ICA provides much better performance than the LAHC algorithm. Practical implications The best solution obtained by solving MC-TALBP-I is more feasible for determining the real assembly solution than the best solution obtained by solving based TALBP-I only. Originality/value A novel ICA based on priority value encoding is proposed in this paper. Initial countries are generated by a heuristic method. An imperialist development strategy is designed to improve the qualities of countries. The effectiveness of the ICA is indicated through a set of benchmarks.

Aims Insufficient sleep has been found to result in varying degrees of cognitive impairment and emotional changes. Sleep was reported probably responsible for cleaning metabolic wastes in brain by increasing extracellular bulk flow. Herein, we propose that chronic sleep insufficiency in young adult wild‐type mice is also linked with dysfunction of intracellular protein degradation pathways and microglia‐mediated neuroinflammation, which are potentially important mechanisms in the initiation of neurodegeneration. Methods We applied the chronic sleep fragmentation (CSF) model to induce chronic sleep insufficiency in wild‐type mice. After 2 months of CSF, cognitive function, amyloid‐β accumulation, dysfunction of endosome‐autophagosome‐lysosome pathway, and microglia activation were evaluated. Results Following CSF, impairment of spatial learning and memory, and aggravated anxiety‐like behavior in mice were identified by behavioral experiments. Increased intracellular amyloid‐β accumulation was observed in cortex and hippocampus. Mechanistically, CSF could significantly enhance the expression of Rab5 (early endosome marker), Rab7 (late endosome marker), as well as LC3B (autophagosome marker), and autophagy‐positive regulatory factors in brain detected by immunofluorescent staining and Western blot. In addition, activation of microglia was evident by enhanced CD68, CD16/32, and CD206 levels after CSF treatment. Conclusions Chronic sleep fragmentation could initiate pathogenetic processes similar to the early stage of neurodegeneration, including dysfunction of endosome‐autophagosome‐lysosome pathway and microglia‐mediated neuroinflammation. Our findings further strengthen the link between chronic sleep insufficiency and the initiation of neurodegeneration even if lack of genetic predisposition.

This work firstly reported preparation of cobalt-doped CaCu3Ti4O12 (CCCTO) thin film by a sol-gel modified method. It was concluded that a relatively high dielectric constant e' (2326, at 1 kHz), low dielectric loss tan δ (0.012, at 1 kHz) and high nonlinear coefficient α (4.9) were simultaneously obtained in the CaCu2.95Co0.05Ti4O12 thin film at room temperature. The decrease of the dielectric loss was associated with the increase in the density of the insulating grain boundary layer, which was governed by the grain size reduction and densification of CCCTO films due to Co doping. Monovalent cation Cu+ detected by X-ray photoelectron spectroscopy (XPS) of the CaCu2.95Co0.05Ti4O12 thin film decreased leakage current. These excellent electrical properties provided a viable solution to the application of CCTO materials in capacitive-varistors.

Lung squamous cell carcinoma (LUSC) possesses a poor prognosis even for stages I–III resected patients. Reliable prognostic biomarkers that can stratify and predict clinical outcomes for stage I–III resected LUSC patients are urgently needed. Based on gene expression of LUSC tissue samples from five public datasets, consisting of 687 cases, we developed an immune-related prognostic model (IPM) according to immune genes from ImmPort database. Then, we comprehensively analyzed the immune microenvironment and mutation burden that are significantly associated with this model. According to the IPM, patients were stratified into high- and low-risk groups with markedly distinct survival benefits. We found that patients with high immune risk possessed a higher proportion of immunosuppressive cells such as macrophages M0, and presented higher expression of CD47, CD73, SIRPA, and TIM-3. Moreover, When further stratified based on the tumor mutation burden (TMB) and risk score, patients with high TMB and low immune risk had a remarkable prolonged overall survival compared to patients with low TMB and high immune risk. Finally, a nomogram combing the IPM with clinical factors was established to provide a more precise evaluation of prognosis. The proposed immune relevant model is a promising biomarker for predicting overall survival in stage I–III LUSC. Thus, it may shed light on identifying patient subset at high risk of adverse prognosis from an immunological perspective.

Sleep disturbance is generally common in populations as a chronic disease or a complained event. Chronic sleep disturbance is proposed to be closely linked to the pathogenesis of diseases, especially neurodegenerative diseases. We recently found that 2 months of sleep fragmentation initiated Alzheimer's disease (AD)-like behavioral and pathological changes in young wild-type mice. Herein, we present a standardized protocol to achieve chronic sleep fragmentation (CSF). Briefly, CSF was induced by an orbital rotor vibrating at 110 rpm and operating with a repetitive cycle of 10 s-on, 110 s-off, during light-ON phase (8:00 AM-8:00 PM) continuously for up to 2 months. Impairments of spatial learning and memory, anxiety-like but not depression-like behavior in mice as consequences of CSF modeling, were evaluated with Morris water maze (MWM), Novel object recognition (NOR), Open field test (OFT) and Forced swimming test (FST). In comparison with other sleep manipulations, this protocol minimizes the handling labors and maximizes the modeling efficiency. It produces stable phenotypes in young wild-type mice and can be potentially generated for a variety of research purposes.

Background: The systemic immune-inflammation index (SII) and Epstein-Barr virus DNA (EBV DNA) levels has been used as a prognostic marker for nasopharyngeal carcinoma (NPC) patients, but there is no in-depth study in locally advanced NPC patients and no research on the predictive value of their combination. Our study aimed to evaluate the prognostic efficacy of the pretreatment SII, EBV DNA levels and their combination in locally advanced NPC patients receiving induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT). Materials and methods: 319 patients diagnosed with locally advanced NPC receiving IC followed by CCRT were retrospectively reviewed (213 in the training cohort and 106 in the validation cohort). The cut-off value for the SII was determined using receiver operating characteristic (ROC) curve. Correlations between characteristics of patients were assessed using the Pearson correlation coefficient. Survival curves for the SII, EBV DNA levels and their combination were analyzed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed by the Cox proportional hazards regression model to evaluate the prognostic impact on overall survival (OS) and progression-free survival (PFS). A prognostic nomogram was generated and its prediction ability was measured by the concordance index (C-index). Results: The optimal cutoff point for the SII was 402.10. A higher SII and EBV DNA positivity were demonstrated to be related to poorer survival outcomes (P < 0.05). Multivariate analyses showed that a higher SII, EBV DNA positivity and their combination were powerful independent risk factors for OS and PFS (P < 0.05). The SII - EBV DNA had the largest area under the curve (AUC) compared to either score alone. The incorporation of the SII - EBV DNA into established nomogram achieved higher C-index in the prediction of OS and PFS, indicating its superior for predicting survival. All results were found in the training cohort and confirmed in the validation cohort. Conclusions: The pretreatment SII and EBV DNA levels are promising factors for predicting survival in locally advanced NPC patients. The combination of them, which was superior to either score alone, was a complement to the conventional TNM staging system.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by irreversible deterioration of upper and lower motor neurons (MNs). Previously, studies on the involvement of glial cells in the pathogenic process of ALS have mainly revolved around astrocytes and microglia. And oligodendrocytes (OLs) have only recently been highlighted. Grey matter demyelination within the motor cortex and proliferation of the oligodendrocyte precursor cells (OPCs) was observed in ALS patients. The selective ablation of mutant SOD1 (the dysfunctional superoxide dismutase) from the oligodendrocyte progenitors after birth significantly delayed disease onset and prolonged the overall survival in ALS mice model (SOD1

The ultrafine grain with the effective grain size of 1.10 μm was fabricated by intercritical deformation on low-carbon microalloyed steel, which was finer than the deformation induced ferrite transformation (DIFT) at 1.55 μm. During intercritical deformation, the DIFT process was enhanced, showing a colony distribution of the refined grains. Meanwhile, the continuous dynamic recrystallization of pro-eutectoid ferrite was developed by both the subgrains progressively trapping dislocations and the serrated boundary pinching off the elongated grains. These processes were directly observed through the grain average misorientation maps of electron back-scattered diffraction and confirmed by transmission electron microscopy micrographs.

In this study, the effect of pre-deformation at recrystallization and non-recrystallization zone on the grain ultrafining by the subsequent intercritical deformation (ID) was investigated on low-carbon microalloyed steel. The results showed that ultrafine grain microstructure with an average size of ~ 1.0 μm was fabricated through pre-deformation in the recrystallization zone followed by ID. When pre-deformed at the non-recrystallization zone prior to ID, the grain size increased to 1.6 μm with a heterogeneous distribution along with the well-developed dynamic recovery of ferrite. The grain ultrafining mechanism was attributed to the combined action of the deformation-induced ferrite transformation and the continuous dynamic recrystallization. In particular, the continuous dynamic recrystallization process during ID occurred on the pro-eutectoid ferrite as a result of the subgrain rotation mechanism and the absorbing dislocations mechanism.

Imaging-guided photodynamic/photothermal (PDT/PTT) synergetic therapy is important in more precise and efficient cancer treatment. Herein, gadolinium-chelated porphyrin–protein composite based on gold nanorods (GNRs@BPP-Gd) was synthesized through a straightforward and environmentally friendly method. Based on the high longitudinal relaxivity (9.544 mM−1 s−1), GNRs@BPP-Gd can serve as a decent T1-weighted magnetic resonance imaging (MRI) probe to steer treatment. A relevant cellular uptake assay showed that GNRs@BPP-Gd could be internalized into cancer cells effectively with negligible cytotoxicity. Furthermore, MRI-guided PDT/PTT studies in vivo indicated that GNRs@BPP-Gd could efficiently take effect after intravenous injection, leading to almost complete ablation at the tumor site. A single treatment was conducted for comparison with the combined treatment, indicating that synergetic therapy greatly enhanced the anti-tumor effect.

Niemann-Pick disease type C (NPC) is a fatal, neurovisceral lipid storage disease, neuropathologically characterized by cytoplasmic sequestration of glycolipids in neurons, progressive neuronal loss, neurofibrillary tangles (NFTs) formation, and axonal spheroids (AS). Cytoskeletal pathology including accumulation of hyperphosphorylated cytoskeletal proteins is a neuropathological hallmark of the mouse model of NPC (npc mice). With a goal of elucidating the mechanisms underlying the lesion formation, we investigated the temporal and spatial characteristics of cytoskeletal lesions and the roles of cdc2, cdk4, and cdk5 in lesion formation in young npc mice. Cytoskeletal lesions were detectable in npc mice at three weeks of age. Importantly, concomitant activation of cdc2/cyclin B1 kinase and accumulation of a subsequently generated cohort of phospho-epitopes were detected. The activation of cdk4/cyclin D1 and cdk5/p25 kinases was observed during the fourth week of life in npc mice, and this activation contributed to the lesion formation. We concluded that the progression of cytoskeletal pathology in npc mice older than four weeks is accelerated by the cumulative effect of cdc2, cdk4, and cdk5 activation. Furthermore, cdc2/cyclin B1 may act as a key initial player one week earlier. Targeting cell cycle activation may be beneficial to slow down the NPC pathogenesis.

Exosomes represent a new generation of biomarkers for the early diagnosis of hepatic carcinoma. A fluorometric assay is presented that is based on the hybridization chain reaction and magnetic nanoparticles for the highly sensitive determination of exosome (from HepG2 cells). Antibody as the recognition element was modified on the surface of magnetic nanoparticles. Antibody was used to capture the exosome. The Probe 1 was consisted of aptamer sequence and trigger sequence. Aptamer sequence will bind with the surface protein of exosome. The trigger sequence will hybridize with the probe2 (FAM-labeled) and the probe3 (FAM-labeled). So the product of the hybridization chain reaction will present a strong fluorescence signal. The fluorescence product of hybridization chain reaction will link with magnetic nanoparticles through the ‘magnetic nanoparticles-antibody-exosome-aptamer’ structure. The product can be separated from the matrix due to the present of the magnetic nanoparticles. The excitation was set at 490 nm. The fluorescence value of the emission spectra at 519 nm was set as the signal response. The linear range of this assay is from 1000 to 107 particles·mL−1. The detection limit is 100 particles·mL−1. This assay was applied to the determination of exosome from the hepatic carcinoma cells.

Metastasis is the major cause of death in colorectal cancer (CRC) patients. Inhibition of metastasis will prolong the survival of patients with CRC. Cancer cells bring their own soil, cancer-associated fibroblasts (CAFs), to metastasize together, promoting the survival and colonization of circulating cancer cells. However, the mechanism by which CAFs metastasize remains unclear. In this study, CAFs were derived from adipose mesenchymal stem cells (MSCs) after co-culture with CRC cell lines. Transwell assays showed that CAFs have stronger migration and invasion abilities than MSCs. In a nude mouse subcutaneous xenograft model, CAFs metastasized from the primary tumour to the lung and promoted the formation of CRC metastases. The expression of HIF-1α was upregulated when MSCs differentiated into CAFs. Inhibition of HIF-1α expression inhibited the migration and invasion of CAFs. Western blot and ChIP assays were used to identify the genes regulated by HIF-1α. HIF-1α regulated the migration and invasion of CAFs by upregulating miR-210 transcription. Bioinformatics analysis and luciferase reporter assays revealed that miR-210 specifically targeted the 3’UTR of VMP1 and regulated its expression. Downregulation of VMP1 enhanced the migration and invasion of CAFs. In vivo, inhibition of miR-210 expression in CAFs reduced the metastasis of CAFs and tumour cells. Therefore, the HIF-1α/miR-210/VMP1 pathway might regulate the migration and invasion of CAFs in CRC. Inhibition of CAF metastasis might reduce CRC metastasis.

Parkinson’s disease (PD) is the second most widespread neurodegenerative disorder in the world. It has been reported that exosomes derived from mesenchymal stem cells (MSCs) can contribute to the recovery of PD. However, the underlying mechanism remains poorly defined. In this study, proteomics and time-series analysis showed that exosomes derived from MSCs can keep human brain microvascular endothelial cells (HBMECs) in a transcriptionally active state, which may be beneficial for angiogenesis. Next, we found that MSC-derived exosomes can promote the angiogenesis of HBMECs by increasing the expression of ICAM1, and alleviate the damage caused by 1-methyl-4-phenylpyridinium (MPP+) in these cells. Accordingly, when ICAM1 was knocked down, the tube formation ability of HBMECs was obviously decreased. In addition, ICAM1 was found to promote the angiogenesis of HBMECs by activating the SMAD3 and P38MAPK signaling pathways. In a PD mouse model, MSC-derived exosomes were found to contribute to the recovery of PD by promoting ICAM1-related angiogenesis. These findings demonstrate that the exosome-ICAM1-SMAD3/P38MAPK axis can promote the angiogenesis of HBMECs, with possible therapeutic potential for PD.

e16043 Background: To explore whether palliative radiotherapy can further improve overall survival (OS) of patients with metastatic colorectal cancer (mCRC) receiving systemic treatment and analyze its survival prognostic factors. Methods: The demographics, tumor characteristics, and survival outcomes of 484 mCRC patients who underwent systemic treatment with or without palliative radiotherapy from December 2014 to September 2019 were analyzed. A propensity-score model was used to compare the group of patients receiving systemic treatment plus palliative radiotherapy (PR) or simple systemic treatment (ST). Results: There were 334 ST patients and 154 PR patients in total, and 288 cases (144 cases/group) after paired matching. The OS (1 year, 2 years, 3 years) in PR group were 73.6%, 40.3%, 16.0% and, respectively, which were higher than those in ST group (61.1%, 22.9%, 6.9%). The median survival times were 50.8 months and 32.2 months, respectively (P = 0.003). Multivariate analysis showed that the site of primary tumor, patient surgery status, local treatment of metastasis as well as whether or not radiotherapy are independent prognostic factors of survival time. Conclusions: We definitely demonstrated that palliative radiotherapy on the basis of systemic chemotherapy is expected to increase OS in mCRC patients. Left colon, primary surgery, local treatment of metastasis and radiotherapy are the independent prognostic factors of mCRC.

Mounting evidences indicated that long non-coding RNA is dysregulated and involved in the pathology of tumors. However, the role of lncRNAs in colorectal cancer (CRC) progression is not fully determined. Differentially expressed lncRNA profile in CRC was conducted by lncRNA microarray in 15 pairs of CRC tissues and adjacent normal tissues, and validated by real-time PCR analysis in another 106 pairs of tissues. The biological effect of lncRNA ZNFX1-AS1 was evaluated by in vitro and in vivo assays. The regulation between lncRNA ZNFX1-AS1 and miR-144 was evaluated by a series of experiments. We found that lncRNA ZNFX1-AS1 expression was significantly upregulated in CRC tissues and cell lines, and the expression of lncRNA ZNFX1-AS1 was associated with aggressive tumor phenotype and poor prognosis in CRC. Functionally, knockdown of lncRNA ZNFX1-AS1 inhibited cell proliferation, invasion, in vitro and tumorigenesis and metastasis in vivo. Further investigation demonstrated that lncRNA ZNFX1-AS1 functioned as a competing endogenous RNA (ceRNA) for miR-144, thereby leading to the depression of its endogenous target gene Polycomb group protein enhancer of zeste homolog 2 (EZH2). We found that lncRNA ZNFX1-AS1 is significantly upregulated in CRC, and the newly identified lncRNA ZNFX1-AS1-miR-144-EZH2 axis is involved in the regulation of CRC progression, which might be used as potential therapeutic targets for CRC patients.

Background Plasma pituitary adenylate cyclase activating polypeptide (PACAP) concentrations are elevated after traumatic brain injury. We assessed the prognostic value of PACAP for short-term and long-term mortality of acute intracerebral hemorrhage (ICH) patients. Methods A total of 150 patients and 150 age- and gender- matched healthy controls were recruited. The plasma PACAP concentrations were measured using sandwich immunoassays. ICH severity was assessed using hematoma volume and National Institutes of Health Stroke Scale (NIHSS) score. The end points included 1-week mortality and 6-month mortality. The relationships between plasma PACAP concentrations and ICH severity and the end points were analyzed statistically. Results Plasma PACAP concentrations were statistically significantly higher in the ICH patients than in the healthy controls and were correlated positively with hematoma volumes and NIHSS scores using a multivariate linear regression. Multivariate analysis results indicated that plasma PACAP concentration was an independent predictor of 1-week mortality, 6-month mortality and 6-month overall survival. It also had high predictive value based on receiver operating characteristic curve. Conclusions Plasma PACAP concentrations are increased and are highly associated with the severity of ICH; PACAP may be a good predictor of short-term and long-term mortality of ICH.

Objective: The aim of the present study was to examine dynamic changes in serum cholinesterase (ChE) activity during early-stage severe trauma and the clinical significance of these changes. Methods: This prospective, observational study included 81 patients with severe trauma who were treated between October 2011 and April 2013 in the emergency intensive care unit (EICU) of a university-affiliated, tertiary-care, grade A general hospital in China. Serum ChE activity was measured on Days 1, 3, and 7 post-injury. The correlation of dynamic changes in serum ChE activity with trauma severity and prognosis was assessed. Correlations between changes in serum ChE activity after injury and albumin (ALB), prealbumin (PAB), transferrin (TRF), and C-reactive protein (CRP) levels were also analyzed. Results: Serum ChE activity in trauma patients was 42.3%–50.2% lower on Days 1, 3, and 7 compared with the control (P25 subgroup. ChE activity was significantly lower in both the death and the ISS>25 subgroups than in the survival and ISS≤25 subgroups on Days 1, 3, and 7 after injury. Activity was negatively correlated with ISS and acute physiology and chronic health evaluation III (APACHE III) at all time points. When comparing the receiver operating characteristic (ROC) curves for predicting prognosis, the area under the curve (AUC) in the plot of serum ChE was similar to the AUCs in plots of ISS and APACHE III, but significantly smaller than the AUC in the plot of the trauma and injury severity score (TRISS). Serum ChE activity was positively correlated with ALB, PAB, and TRF at all time points post-injury. Activity was not significantly correlated with CRP on Day 1, but was significantly and negatively correlated with CRP on Days 3 and 7. Conclusions: There is a significant decrease in serum ChE activity after severe trauma. Serum ChE may be regarded as a negative acute phase protein (APP) and the dynamic changes in serum ChE may be useful as an auxiliary indicator for evaluating trauma severity and predicting prognosis.

Background Alzheimer’s disease (AD) has high a prevalence rate, high medical costs, and care difficulties, and has become a serious social and economic problem in our aging society. So far, there has not been a reliable and objective diagnostic criteria for AD found. In recent years, there have been many domestic and foreign studies on the biological markers of cerebrospinal fluid in the patients with AD, and high levels of the T-tau, P-tau found in cerebrospinal fluid (CSF) is at this point an indisputable fact. However, the relationship between these markers and the severity of dementia, as well as the development of the disease, should be further studied. Objective Compare the CSF level of total tau (T-tau) and phosphorylated tau at threonine 231 (P-tau231) between patients with moderate to severe Alzheimer’s disease (AD) and those with vascular dementia (VD) at baseline, and 6 month follow-up. Observe the differences between patients with AD and control group, as well as the changes as the disease develops. Methods There were 11 patients with moderate AD (10 ≤ MMSE ≤ 20), 10 patients with severe AD (MMSE ≤ 9), and 7 age-matched patients with severe VD at baseline, among which 7 AD patients and 6 VD patients completed the 6 months follow-up. CSF levels of T-tau, P-tau231 were measured with sandwich ELISA. Result At baseline, the concentrations of the CSF level of T-tau were 470.08 (263.58) pg/mL in the AD group and 208.76 (42.24) pg/mL in the VD group. This difference was statistically significant (Z= -3.369, p

Background Survival benefits of mild hypothermia in animals suffering from uncontrolled hemorrhagic shock (HS) may be influenced by trauma severity. We hypothesized that mild hypothermia would improve early outcomes based on our rabbit model of severe traumatic HS. Materials and methods Fifty male New Zealand rabbits weighing between 1.6 and 2.2 kg were randomized into one of the five groups: group 1 (sham), group 2 (37°C/80 mm Hg), group 3 (37°C/40 mm Hg), group 4 (34°C/80 mm Hg), and group 5 (34°C/40 mm Hg). Under urethane anesthesia, animals that suffered fractures and uncontrolled HS received prehospital fluid resuscitation (aggressive or limited) with temperature controlled at normothermia or mild hypothermia, hemostasis, and hospital resuscitation followed by observation. Results Mild hypothermia significantly improved cardiac systolic function and decreased lung wet-to-dry weight ratios and total injury score compared with normothermia. Group 5 manifested the best results in lung injury. The decreased base excess and pH and increased lactate levels during HS and limited fluid resuscitation were not exacerbated by mild hypothermia. Electrolytes including potassium and calcium and blood glucose levels as well as coagulation were not significantly influenced after mild hypothermia treatment. Seven-hour survival in the hypothermic groups was higher than that in the normothermic groups, although there was no significant difference in survival between groups 5 and 3. Conclusions Therapeutic mild hypothermia improves early outcomes through improving lung and cardiac performance without causing evident homeostasis disturbances in the rabbit model of traumatic uncontrolled HS. Animals may benefit most under the combination treatment with mild hypothermia and limited fluid resuscitation.

With the fiercer competition and more complex environment of manufacturing industry, the service-oriented manufacturing mode integrating manufacture and service has become an inevitable trend. Together with the producer services and product-service system, the development process of service-oriented manufacturing mode was summarized. Compared with the traditional manufacturing mode, a conceptual model of service-oriented manufacturing was proposed. Furthermore, the operational framework of service-oriented manufacturing mode was established based on its operating characteristics. The research paper could provide the manufacturing enterprises with some foundation for implementing the service-oriented manufacturing mode.

To explore the role of Notch signaling pathway and the effect of γ-secretase inhibitor (DAPT) on the apoptosis induced by 1-methyl-4-phenylpyridinium (MPP(+)) in differentiated SH-SY5Y cell.SH-SY5Y cell were incubated with various concentrations (0, 0.5, 1, 1.5, 2 mmol/L) of MPP(+) for 0, 24, 48 and 72 h respectively. Flow cytometry with Annexin V-FITC/PI double staining was used for apoptotic analysis. The protein expressions of Notch-1, Jagged-1 and Hes-1 were detected by Western blot. SH-SY5Y cell were preincubated with 10 µmol/L DAPT for 15 min before 1.5 mmol/L MPP(+) treatment for 48 h. Flow cytometry and Western blot were performed to analyze the cell apoptosis and protein expressions of Notch-1, Jagged-1 and Hes-1.MPP(+) induced the apoptosis of SH-SY5Y cell in a dose (3.20% ± 0.19% vs 10.00% ± 1.72%, 20.60% ± 3.76%, 32.80% ± 5.12%, 46.00% ± 5.06%, all P0.05) and time- (2.80% ± 0.21% vs 12.30% ± 1.82%, 19.60% ± 2.89%, 35.00% ± 4.78%, all P0.05) dependent manner. MPP(+) up-regulated the expressions of Notch-1, Jagged-1 and Hes-1 in a dose- and time-dependent manner in SH-SY5Y cell. DAPT treatment decreased MPP(+)-induced apoptosis (3.10% ± 0.21% vs 35.50% ± 4.98%, 19.20% ± 2.98%, both P0.05) and the expressions of Notch-1, Jagged-1 and Hes-1 in SH-SY5Y cell.The activation of Notch signaling pathway plays an important role in MPP(+)-induced apoptosis of SH-SY5Y cell. DAPT inhibits Notch signaling pathway and protects SH-SY5Y cell from MPP(+)-induced apoptosis.

To study the prevalence rate of upper respiratory tract group A Streptococcus (GAS) carriage in school-age children from Xinjiang Province.A total of 478 children at age of 9-12 years from Tulufan City and Buerjin County of Xinjiang Province were enrolled by random cluster sampling. Throat swab cultures were performed once each season for the determination of presence of GAS.In the 1 827 samples, 196 GAS strains were isolated, with a GAS carrier rate of 10.7%. The prevalence rate of GAS carrier in Tulufan City ranged from 3.7%-16.5% compared with 4.7%-21.4% in Buerjin County (P0.05). The prevalence rate of GAS carrier in winter is the highest, followed by in autumn, spring and summer in both regions. There were significant differences in the GAS carriage rate in autumn between the two regions. There were no significant differences in the GAS carriage rate between boys and girls. Of the 196 GAS strains, 133 from Han, 22 from Uygur and 41 from Hazakh children. There were significant differences in the prevalence rate of GAS carriage among children with different ethic groups.The prevalence rate of GAS carriage is high in school-age children from Tulufan and Buerjin of Xinjiang Province. The GAS carrier rate is associated with the season and ethic group. The children from Buerjin County present a higher GAS carrier rate than those from Tulufan City.

Based on the concept of polychromatic sets (PS), the basic mathematic expression of PS is introduced. According to the entity of PS, PS is classified into two types: disjunctive PS and conjunctive PS. The isolated operation of PS is studied thoroughly and the corresponding problems are analyzed elaborately. Together with manufacturing process system, the information model of conjunctive PS is established, and the machining capacity of local manufacturing resources is evaluated using PS isolated operation. Aiming at the special manufacturing process requirement, the manufacturing resources are allocated optimally. The research results show that the PS isolated operation has stronger modeling and simulating ability in analyzing and synthesizing of complex system.

Chemistry has arrived on the shore of the Island of Stability with the first chemical investigation of the superheavy elements Cn, 113, and 114. The results of three experimental series leading to first measured thermodynamic data and qualitatively evaluated chemical properties for these elements are described. An interesting volatile compound class has been observed in the on-line experiments for the elements Bi and Po. Hence, an exciting chemical study of their heavier transactinide homologues, elements 115 and 116 is suggested., Invited Talk given at the 11th International Conference on Nucleus-Nucleus Collisions (NN2012), San Antonio, Texas, USA, May 27-June 1, 2012. To appear in the NN2012 Proceedings in Journal of Physics: Conference Series (JPCS)

The Trojan Horse Method was applied for the first time to a Radioactive Ion Beam induced reaction to study the reaction $^{18}$F(p,$\alpha$)$^{15}$O via the three body reaction $^{18}$F(d,$\alpha$ $^{15}$O)n at the low energies relevant for astrophysics. The abundance of $^{18}$F in Nova explosions is an important issue for the understanding of this astrophysical phenomenon. For this reason it is necessary to study the nuclear reactions that produce or destroy $^{18}$F in Novae. $^{18}$F(p,$\alpha$)$^{15}$O is one of the main $^{18}$F destruction channels. Preliminary results are presented in this paper., Comment: Talk given by Marisa Gulino at the 11th International Conference on Nucleus-Nucleus Collisions (NN2012), San Antonio, Texas, USA, May 27-June 1, 2012. To appear in the NN2012 Proceedings in Journal of Physics: Conference Series (JPCS)