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Abstract Circulating tumor cells (CTCs) serve as a pivotal foundation for both fundamental oncological research and the precise evaluation of therapeutic interventions. However, the isolation of CTCs from clinical blood samples presents a multitude of sophisticated challenges, predominantly associated with the specificity of biomarkers and the sensitivity of detection techniques. In our previous study, we proposed a novel detection concept for CTCs based on a signature biophysical feature on the surface of cancer cells: a negative charge regulated by glycolytic processes. In this study, we have conducted experiments to ascertain the efficacy of this proposed method in capturing CTCs from clinical blood samples of individuals afflicted with solid tumors and leukemia. Our findings indicate that the method is capable of isolating tens of thousands of viable cancer cells from various metastatic solid cancers and leukemia using a mere 1 mL of blood. These cells were enumerated using cytological imaging that identified morphological characteristics indicative of malignancy. The outcomes of our study suggest that the negatively charged surface of cancer cells is a ubiquitous trait across both cultured cancer cell lines and fresh blood samples derived from cancer patients. Moreover, the capture technology employed in this study demonstrated superior performance in comparison to antecedent methodologies, enhancing the detection and documentation of CTCs for subsequent verification and analysis. This advancement holds significant promise for the improvement of diagnostic accuracy and the monitoring of therapeutic responses in oncology.

Myopia is an increasingly serious health issue among children and adolescents worldwide. This study investigated the situation related to myopia among students in Chengdu, a city in western China, and analyzed the prevalence of myopia spectacle wear and myopia full-correction and their influencing factors to understand the current status of myopia prevention. This school-based cross-sectional study investigated 1582 schools in seven districts of Chengdu City, China, enrolling a total of 417,337 students aged 6–18 years (elementary, middle, and high school) from 2020 to 2022. Examination items included uncorrected visual acuity (UCVA), slit lamp examination and non-cycloplegic autorefraction. Myopia was defined as non-cycloplegic SE ≤ −0.50 D + UCVA> 0 log MAR (age ≥6). The prevalence of myopia spectacle wear is defined as the number of people wearing glasses for myopia/the number of people with myopia (%) within the study population, and myopia full-correction is defined as normal vision after wearing glasses for myopia (≤0 log MAR for 6 years and above). With the support of the government, this programme is conducted 1–2 times a year. Statistical analyses are conducted to determine the association between myopia and various parameters.The average age of the entire survey population was 10.96 ± 3.5 years, and the overall prevalence of myopia was 48.7%, myopia spectacle wear was 65.7%, and myopia full-correction was 50.5%. With increasing age and educational levels, the prevalence of moderate to high myopia, the prevalence of myopia spectacle wear, and the prevalence of myopia full-correction all rise. The prevalence of mild myopia full-correction (46.5%) was higher than that for moderate myopia (47.1%) and even higher than that for high myopia (39.6%). The correct utilization rate of myopic spectacles was 33.17%, increasing with age and education levels, with the highest correct utilization rate of 40.7% among those with moderate myopia. The prevalence of myopia among children and adolescents in Chengdu is relatively low, and the prevalence of myopia spectacle wear and myopia full-correction need to be improved, and it was found that with the increase of myopia, the prevalence of myopia full-correction among adolescents decreased instead.

Abstract Background Due to the great heterogeneity of gastric cancer (GC), the prognosis of patients within a stage is very different. Therefore, it is necessary to identify the high risk factors for postoperative recurrence and metastasis and take appropriate therapeutic strategies to improve the prognosis of patients. In this study, we aimed to explore the prognostic significance of preoperative and postoperative serum carcinoembryonic antigen (CEA), carbohydrate antigen 19 − 9 (CA19-9) and carbohydrate antigen 72 − 4 (CA72-4) in patients with stage I, II and III GC who underwent radical gastrectomy. Methods A total of 580 patients who underwent curative surgical resection and had not received neoadjuvant chemotherapy were included in this study. The relationship between clinicopathological features and recurrence was analysed. Survival analysis was performed by Kaplan–Meier curve. Univariate and multivariate Cox regression analyses were performed to determine prognostic factors in GC patients. Results Among patients with stage III GC, the recurrence free survival (RFS) and overall survival (OS) of patients with CA19-9>35 U/mL were significantly lower than those with CA19-9 ≤ 35 U/mL; CA19-9 was always a significant independent marker. CEA and CA72-4 were sometime useful to predict RFS or OS alternatively in the pre- or postoperative period. The only other independent significant factors for prognosis in our study were lymph node metastases for RFS and postoperative adjuvant chemotherapy for OS. Conclusion Preoperative and postoperative CA19-9 values are independent risk factors for predicting prognosis in stage III GC after curative gastrectomy.

Abstract Background Circular RNAs (circRNAs) play important roles in the occurrence and development of cancer and chemoresistance. DNA damage repair contributes to the proliferation of cancer cells and resistance to chemotherapy-induced apoptosis. However, the role of circRNAs in the regulation of DNA damage repair needs clarification. Methods RNA sequencing analysis was applied to identify the differentially expressed circRNAs. qRT-PCR was conducted to confirm the expression of hsa_circ_0007919, and CCK-8, FCM, single-cell gel electrophoresis and IF assays were used to analyze the proliferation, apoptosis and gemcitabine (GEM) resistance of pancreatic ductal adenocarcinoma (PDAC) cells. Xenograft model and IHC experiments were conducted to confirm the effects of hsa_circ_0007919 on tumor growth and DNA damage in vivo. RNA sequencing and GSEA were applied to confirm the downstream genes and pathways of hsa_circ_0007919. FISH and nuclear-cytoplasmic RNA fractionation experiments were conducted to identify the cellular localization of hsa_circ_0007919. ChIRP, RIP, Co-IP, ChIP, MS-PCR and luciferase reporter assays were conducted to confirm the interaction among hsa_circ_0007919, FOXA1, TET1 and the LIG1 promoter. Results We identified a highly expressed circRNA, hsa_circ_0007919, in GEM-resistant PDAC tissues and cells. High expression of hsa_circ_0007919 correlates with poor overall survival (OS) and disease-free survival (DFS) of PDAC patients. Hsa_circ_0007919 inhibits the DNA damage, accumulation of DNA breaks and apoptosis induced by GEM in a LIG1-dependent manner to maintain cell survival. Mechanistically, hsa_circ_0007919 recruits FOXA1 and TET1 to decrease the methylation of the LIG1 promoter and increase its transcription, further promoting base excision repair, mismatch repair and nucleotide excision repair. At last, we found that GEM enhanced the binding of QKI to the introns of hsa_circ_0007919 pre-mRNA and the splicing and circularization of this pre-mRNA to generate hsa_circ_0007919. Conclusions Hsa_circ_0007919 promotes GEM resistance by enhancing DNA damage repair in a LIG1-dependent manner to maintain cell survival. Targeting hsa_circ_0007919 and DNA damage repair pathways could be a therapeutic strategy for PDAC.

Abstract Background Lipid metabolism has a crucial role in neural repair in neurodegenerative diseases. We recently revealed that lipogenesis-mediated interleukin-33 (IL-33) upregulation lead to blood–brain barrier (BBB) repair after ischemic stroke. However, manipulating the key enzyme fatty acid synthase (FASN) to enhance lipogenesis was very challenging. Glyceryl triacetate (GTA) was used as a donor of acetate and precursor of acetyl coenzyme A, the key substrate for de novo lipogenesis catalyzed by FASN. Therefore, we hypothesized that GTA would promote lipogenesis the peri-infarct after ischemic stroke and contribute to the BBB repair through IL-33. Methods Middle cerebral artery occlusion (MCAO) was performed on C57BL mice and GTA was gavage administrated (4 g/kg) on day 2 and 4 after MCAO. Lipogenesis was evaluated by assessment of the protein level of FASN, lipid droplets, and fatty acid products through liquid chromatography-mass spectrometry in the peri-infarct area on day 3 after MCAO, respectively. BBB permeability was determined by extravasation of Evans blue, IgG and dextran, and levels of tight junction proteins in the peri-infarct area on day 7 after MCAO, respectively. Infarct size and neurological defects were assessed on day 7 after MCAO. Brain atrophy on day 30 and long-term sensorimotor abilities after MCAO were analyzed as well. The inhibitor of FASN, C75 and the virus-delivered FASN shRNA were used to evaluate the role of FASN-driven lipogenesis in GTA-improved BBB repair. Finally, the therapeutic potential of recombinant IL-33 on BBB repair and neurological recovery was evaluated. Results We found that treatment with GTA increased the lipogenesis as evidenced by lipid droplets level and lauric acid content, but not the FASN protein level. Treatment with GTA increased the IL-33 level in the peri-infarct area and decreased the BBB permeability after MCAO. However, infarct size and neurological defect score were unchanged on day 7 after MCAO, while the long-term recovery of sensorimotor function and brain atrophy were improved by GTA. Inhibition of lipogenesis using C75 or FASN shRNA reversed the beneficial effect of GTA. Finally, exogenous IL-33 improved BBB repair and long-term functional recovery after stroke. Conclusion Collectively, we concluded that treatment with GTA improved the BBB repair and functional recovery after ischemic stroke, probably by the enhancement of lipogenesis and IL-33 expression. Graphical Abstract

Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.

Effect of Ti/Y/O element on helium (He) clustering in vacancy (Vac) defect of vanadium (V) alloy were investigated using first-principles calculations. We first calculated the formation and binding energies of Hen clusters in Vac–X (X = O/O–Ti/O–4Ti/O–3Ti–Y) configurations, the values for O–3Ti–Y configuration are obviously reduced by 0.2–1.6 eV with respect to those of alone Vac. In the presence of O, He still favors the octahedral interstitial site at a Vac. The formation energies of Hen clusters in Vac–O–Ti and Vac–O–4Ti defects are close to those of Vac–O with n = 1–5 (n represents the number of He), which are higher than those of Vac by 3 %. 3Ti–Y considerably increases the formation energies of Hen clusters in Vac–O–3Ti–Y complex over 20 %. The nth He binding energy with Vac–X–Hen−1 shows a decreasing fluctuant trend, the attraction of Vac–O–3Ti–Y to He is the smallest among all considered configurations. The presence of Ti-O/Y-Ti-O/O obviously reduce the stability of Vac–He clusters. In addition, we discussed the de-trapping behaviors of He from the Vac–X–Hen complexes and found Hen clusters more easily de-trapped from the Vac–X configuration. The present results show that the formation of Vac–X complex reduces vacancy-trapping ability for more He impurities, leading to lots of small Vac–X–He cluster formation, hindering the formation of larger Hen clusters (He bubbles) in V alloys under irradiation.

V-4Cr-4Ti alloy is one of the candidate structural materials for future fusion reactors due to its desirable characteristics. In our previous research, MAX-phase-dispersion-strengthened vanadium alloy (V-4Cr-4Ti-1.5Y-0.3Ti3SiC2), prepared through mechanical alloying, showed excellent thermal stability and creep resistance and was expected to have good radiation resistance. This study investigates the effects of 2.5 MeV V2+ ion irradiation on V-4Cr-4Ti-1.5Y-0.3Ti3SiC2 and V-4Cr-4Ti alloys at 500 °C, with peak damage of 0.8, 3.5, and 6.1 dpa. Transmission electron microscopy and nanoindentation were used to examine the changes in microstructure and hardness before and after irradiation. The microscopic analysis reveals that dispersed nanoparticles maintained good stability under irradiation. Defect clusters grow with increasing irradiation doses in both materials. The nanoindentation results show that V-4Cr-4Ti-1.5Y-0.3Ti3SiC2 has higher initial hardness and lower irradiation hardening, indicating better resistance to radiation hardening than V-4Cr-4Ti. This research serves as a valuable reference for the assessment of the irradiation resistance of Ti3SiC2-dispersion-strengthened V-4Cr-4Ti alloy.

Abstract Monoclonal antibodies are at the vanguard of the most promising cancer treatments. Whereas traditional therapeutic antibodies have been limited to extracellular antigens, T cell receptor mimic (TCRm) antibodies can target intracellular antigens presented by cell surface major histocompatibility complex (MHC) proteins. TCRm antibodies can therefore target a repertoire of otherwise undruggable cancer antigens. However, the consequences of off-target peptide/MHC recognition with engineered T cell therapies are severe, and thus there are significant safety concerns with TCRm antibodies. Here we explored the specificity and safety profile of a new TCRm-based T cell therapy for hepatocellular carcinoma (HCC), a solid tumor for which no effective treatment exists. We targeted an alpha-fetoprotein peptide presented by HLA-A*02 with a highly specific TCRm, which crystallographic structural analysis showed binds directly over the HLA protein and interfaces with the full length of the peptide. We fused the TCRm to the γ and δ subunits of a TCR, producing a signaling AbTCR construct. This was combined with an scFv/CD28 co-stimulatory molecule targeting glypican-3 for increased efficacy towards tumor cells. This AbTCR + co-stimulatory T cell therapy showed potent activity against AFP-positive cancer cell lines in vitro and an in an in vivo model and undetectable activity against AFP-negative cells. In an in-human safety assessment, no significant adverse events or cytokine release syndrome were observed and evidence of efficacy was seen. Remarkably, one patient with metastatic HCC achieved a complete remission after nine months and ultimately qualified for a liver transplant.

Background: Although circular RNAs (circRNAs) have recently garnered interest as disease markers, they have been relatively poorly studied as a biomarker in colorectal cancer (CRC). In this study, we aimed to screen the exosome-derived circRNAs in CRC and explore their potential as diagnostic and prognostic biomarkers of CRC Methods: Exosomes were extracted from the plasma using a kit and validated by immunoblotting, transmission electron microscopy, and particle size analysis. The microarray datasets were employed to identify differentially-expressed circRNAs from plasma exosomes. Real-time quantitative reverse transcription PCR (RT-qPCR) verified the results of the microarray analysis, and Receiver operating characteristic (ROC) curve revealed the diagnostic ability of a single circRNA. The Starbase combined with microT, miRmap, and RNA22 were used to establish a circRNA-miRNA-mRNA network. Gene ontology, Kyoto Encyclopedia of Genes, Genomes pathway enrichment analysis, and Gene Set Enrichment Analysis were applied to determine potential functions of the identified mRNAs Results: Comparing the microarray of plasma exosome-derived circRNAs and the microarray downloaded from the GEO database, 15 candidate circRNAs with up-regulated expression were identified. RT-qPCR verified that hsa_circ_0003270 (circGAPVD1) was upregulated in CRC plasma exosomes. ROC analysis showed that circGAPVD1 in plasma exosomes has potential diagnostic value for CRC. The sensitivity and specificity of circGAPVD1 in the diagnosis of CRC were found to be 75.64 and 71.79%, respectively (area under ROC = 0.7662). Furthermore, the lymph node metastasis and TNM staging of patients were positively correlated with high expression of circGAPVD1. Combined with the ENCORI database and GEO datasets, we identified the circGAPVD1-related ceRNA network. The enrichment analysis revealed that key nodes in the ceRNA network participate in many important signaling pathways such as protein post-translational modifications Conclusion: Our results revealed the diagnostic efficiency of circGAPVD1 in plasma exosomes. The highly expressed circGAPVD1 is expected to be a novel diagnostic marker for CRC.

The clustering behaviors and stable configurations of vacancies with the size up to 30 in vanadium were studied by first-principles investigations. The average formation energies per vacancy of vacancy clusters decreases with the sizes. When Vn cluster with the odd size forms Vn+1 cluster, the average formation energy per vacancy has a lager reduction relative to the case of even size. The stabilities of vacancy clusters increase with the sizes in terms of the total binding energy (n = 2–30), the incremental binding energies of vacancy clusters show an increasing trend of fluctuation with the sizes, which can be explained by both the size characteristics and terrace-ledge-kink model. We also estimated the relationship between vacancy formation/incremental binding energy and Wigner-Seitz area. Finally, we established a machine learning model based on Linear-SVM to predict formation energies of larger vacancy clusters. These results deepened the understanding of the formation and evolution of nanovoids in vanadium metal under irradiation.

As a crucial component for temporary blocking of layer segments in the segmental fracturing process, bridge plugs are difficult to unseal by conventional methods and may cause major downhole accidents if not handled properly. In this paper, a nanofluidic self-heating unsealing rubber cylinder is designed, which is equipped with a nanofluidic self-heating unsealing sandwich inside the conventional rubber cylinder, consisting of a nanofluidic system and an annular flexible heater. When unsealing, the nanofluidic self-heating unsealing sandwich is heated by the annular flexible heater, and the nanofluidic system can help the bridge plug rubber cylinder shrink in volume and unseal smoothly by the characteristics of heat shrinkage and cold expansion. The nanofluidic system, consisting of porous carbon with an exceptionally large specific surface area and glycerol, serves as a prime example for filling the sandwich layer, and the design parameters calculation was carried out. The sealing performance of the designed nanofluidic self-heating unsealing rubber cylinder was analyzed based on the Mooney–Rivlin principal structure by finite element modeling. The results show that the maximum contact stress between the nanofluidic self-heating unsealing rubber cylinder and the casing wall increases by 9.73%, the compression distance reduces by 24.47%, and the maximum equivalent force decreases by 12.17% on average compared with a conventional rubber cylinder under the same seating load. The designed nanofluidic self-heating unsealing rubber cylinder can satisfy the requirements of pressure-bearing capacity and sealing performance and performs better than a conventional rubber cylinder.

We systemically investigated helium (He) interacting with 27 substitutional solute elements in vanadium by first-principles calculations. The interactions between early three 3d/4d/5d transition solutes and He are attractive while they are repulsive for other solute elements, He still favors tetrahedral sites. We predicted the influence of substitutional solutes on He effective diffusivity, Sc/Ti/Y/La can obviously reduce He diffusivity while other solutes show little effect. Moreover, we studied the synergistic interactions of the defect complex with He, solute and vacancy. The binding of group IIIB/IVB solution elements and vacancy reduce vacancy capturing for He, inhibiting He clustering in vacancies. The presence of He increases the stability of solute–vacancy clusters. The results can help to understand the effect of solute elements on He accumulation and embrittlement in vanadium alloys under irradiation.

Aiming at the problem of matching and optimization of the power transmission system of two-speed electric vehicles， according to the design parameters and target requirements of the whole vehicle， the power matching of the core components such as the drive motor， power battery， and transmission of the pure electric vehicle is carried out through theoretical calculations， and by using the Cruise simulation software， the vehicle model of the target vehicle is established， and the matching result is simulated and verified. On the premise that the dynamic performance meets the design requirements， in order to further improve the economy， a joint simulation model of Cruise and Isight is built， and an improved non-dominated sorting genetic algorithm （NSGA-Ⅱ） is adopted to optimize the transmission ratio of the transmission system with multiple objectives to achieve the best solution for power and economy. The optimization results show that the power consumption under the optimized NEDC （New european driving cycle） cycle is reduced by 0.38 kWh/100 km， and the economy is increased by 2.4%. The acceleration time of 0~100 km/h is reduced by 0.95 s compared with that before the optimization， and the power performance increased by 7.5%.

Soil cation exchange property (SCEP) is important in soil development and environmental buffering. However, the variations in SCEP and its correlation with soil-forming factors in subsurface soil are not fully understood. In this study, we quantified the surface and subsurface SCEP variations as a function of parent material, vegetation, hillslope position, and soil type. Fifty upland soil profiles from mid-subtropical China were selected. The cation exchange capacity (CEC) and effective CEC (ECEC) of subsurface soil were significantly higher in soils derived from slate, Quaternary red clay (QRC), and limestone than in soils derived from granite and sandstone. The subsurface soils derived from limestone had the highest base saturation (BS) and the sum of base cations, and the lowest aluminum (Al) saturation. The SCEP in surface soil significantly varied with vegetation and hillslope position. The surface soil CEC was the highest in mixed-forest vegetation, whereas the ECEC and exchangeable acidity (EA) were the highest in arable vegetation. Exchangeable potassium (K+) was lowest and the EA was highest in soil orders at the strong development phase. Exchangeable calcium (Ca2+), magnesium (Mg2+), CEC, and BS were the highest in soil orders at the intermediate development phase. The prediction accuracy of soil CEC using the random forest model was higher than that obtained using multiple stepwise regression, with the best results (R2 = 0.92) obtained in the surface soil. Our study indicated that the SCEP in surface and subsurface soils was controlled by different soil-forming factors and could be effectively predicted by soil properties in subtropical China.

Abstract Background Glioblastoma (GBM) is a highly malignant brain tumor with poor survival and prognosis. Randomized trials have demonstrated that chemotherapy improves survival in patients with GBM. This study aims to examine the clinical characteristics that are potentially associated with the efficacy of chemotherapy and the risk factors of GBM. Methods A total of 25,698 patients diagnosed with GBM were identified between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER). The clinical and demographic variables between groups were examined by Student’s t-test and Pearson’s chi-square test. GBM-specific survival (GBMSS) and overall survival (OS) were evaluated using the Kaplan-Meier method with the log-rank test. Univariable and multivariable analyses were also performed using the Cox proportional hazards model to identify statistically significant prognostic factors. Results Patients who received chemotherapy had better overall survival (median OS 13 vs. Three months, HR = 1.9224, 95%CI 1.8571–1.9900, p

Background: Exopolysaccharides (EPSs) secreted from lactic acid bacteria are carbohydrate polymers with reported biological activities. In this study, we extracted and characterized the composition as well as antioxidant and biofilm-inhibitory properties of EPS from Lactobacillus coryniformis NA-3 isolated from northeast Chinese sauerkraut (Suan Cai). Methods: Lactobacillus coryniformis NA-3 was identified with 16S rDNA amplification and Neighbor Joining (NJ) phylogenetic analysis. EPS derived from Lactobacillus coryniformis NA-3 (EPS-NA3) was analyzed, including compositions by high-performance liquid chromatography (HPLC), functional groups by Fourier-transform infrared spectroscopy (FT-IR) and glycosidic bond configuration by Hydrogen-1 Nuclear Magnetic Resonance (1H NMR). Antioxidant activity of EPS was evaluated with hydroxyl and superoxide radical-scavenging. Anti-biofilm activities of EPS-NA3 were checked through inhibition and dispersion. Results: The monosaccharide composition of EPS included α-rhamnose, α-mannose, α-galactose, and α-glucose in a ratio of 2.6:1.0:5.0:3.3. The free radical-scavenging abilities of EPS-NA3 were 37.77% ± 1.56% and 78.87% ± 3.07% on hydroxyl and superoxide reactive oxygen species respectively. Moreover, EPS-NA3 attenuated the formation of Bacillus cereus and Salmonella typhimurium biofilms by inhibition ratios of approximately 80% and 40% respectively. Additionally, treatment with EPS-NA3 dispersed established biofilms of B. cereus and S. typhimurium by approximately 90% and 20% respectively. Conclusion: These results suggest that EPS-NA3 may be developed as antioxidant and anti-biofilm agents for industrial and clinical applications due to its capacity of scavenging free radicals, inhibition of bacterial biofilm formation, and dispersion of established biofilms.

Thyroid-associated ophthalmopathy (TAO), also known as thyroid eye disease (TED) or Graves’ orbitopathy (GO), is a complex autoimmune condition causing visual impairment, disfigurement, and harm to patients’ physical and mental health. The pathogenesis of TAO has not been fully elucidated, and the mainstream view is that coantigens shared by the thyroid and orbit trigger remodeling of extraocular muscles and orbital connective tissues through an inflammatory response. In recent years, cytokines and the immune responses they mediate have been crucial in disease progression, and currently, common evidence has shown that drugs targeting cytokines, such as tocilizumab, infliximab, and adalimumab, may be novel targets for therapy. In this review, we summarize the research development of different cytokines in TAO pathogenesis in the hope of discovering new therapeutic targets.

The accurate, simple, and efficient measurement of the concentration of single-stranded DNA (ssDNA) is important for many analytical applications, such as DNA adsorption, biosensor design, and disease diagnosis, but it is still a challenge. Herein, we studied a cationic conjugated polymer (CCP)-based ssDNA assay taking advantage of the obvious fluorescence change of CCPs upon binding ssDNA. Poly(3-(3′-N,N,N-triethylamino-1′-propyloxy)-4-methyl-2,5-thiophene hydrochloride) (PMNT) achieved an apparent dissociation constant (Kd) of 57 ± 4 nM for ssDNA, indicating a very high binding affinity between PMNT and ssDNA. This allowed us to develop a CCP-based ssDNA biosensor with a detection limit of 0.6 nM, similar to the fluorescence-dye-based method using SYBR Green I and SYBR Gold. Our CCP-based biosensor produced smaller differences among ssDNA samples with different base compositions. In addition, the existence of double-stranded DNA (dsDNA) at different concentrations did not interfere with the fluorescence of PMNT, indicating that our CCP-based biosensor was more suitable for the measurement of ssDNA. Compared with fluorescence-intensity-based quantification, our CCP system allowed ratiometric quantification, which made the calibration easier and more robust. We then applied our method to the quantification of ssDNA on AuNPs using both unmodified and thiolated ssDNA, and the accurate quantification of ssDNA was achieved without any fluorophore modification. This method provides an alternative approach for the measurement of ssDNA.

Engineered cementitious composites (ECC) exhibit ultra-high ductility and post-cracking resistance, which makes it an attractive material in civil engineering. First, a monotonic uniaxial tensile test was performed, considering the effects of polyvinyl alcohol (PVA) fiber volume content and water-binder ratio. Then, the effects of the above variables on the tensile characteristics including the tensile stress–strain relationship, deformation capacity, and fracture energy were investigated based on test results; and when the water-binder ratio is 0.28 and the fiber volume content is 2%, the deformation performance of ECC is improved most significantly. Next, combined with damage mechanics theory, the damage evolution mechanism of ECC in monotonic uniaxial tension was revealed, based on which the damage factor and damage evolution equation of ECC were developed and the expressions of model parameters were proposed. Moreover, the comparison between the proposed model and test results demonstrated the accuracy of the proposed model. Finally, to further verify the feasibility of the proposed model, a finite element (FE) simulation analysis of the tensile performance of high-strength stainless steel wire rope (HSSWR) reinforced ECC by adopting the proposed model was compared with test results and the simulation analysis results by using anther existing model, the “trilinear model of ECC”. The comparison shows that the proposed model in this paper can predict more accurately.

To understand the role of α-Fe/TaC interface on the clustering behavior of helium (He) atoms inside castable nanostructured alloys under irradiation, we built two models (Ta13C14@Fe215 and {100} 〈110〉 Fe//{100} 〈100〉 TaC interface) and perform systemical ab initio calculations to investigate the energetics of point defects (vacancy, anti-site defect and He), substitutional defect clusters CrFem (1 ≤ m ≤ 4), and Hen (1 ≤ n ≤ 4) clusters, the migration behavior of He atom as well as the effect of Cr atoms and vacancies on the stability of Hen clusters. Vacancy and He at the α-Fe/TaC interface of the Ta13C14@Fe215 are more stable than that in Ta13C14 cluster and Fe matrix. Ta atom at this interface escapes from the lattice site more easily than C atom. In addition, the Cr atoms substituting Fe sites are more stable than Fe vacancies, which reduces the formation energies of Hen clusters in α-Fe/TaC on the Ta13C14@Fe215. Both formation energy and migration energy of He atom in {100} 〈110〉 Fe//{100} 〈100〉 TaC interface are lower than those in bulk TaC and α-Fe. Hence, {100} 〈110〉 Fe//{100} 〈100〉 TaC interface as a sink can trap more helium atoms and vacancies than α-Fe matrix.

BackgroundNOD-like receptors (NLR) are intracellular sensors of the innate immune system, with the NLRP3 being a pro-inflammatory member that modulates cardiac ischemia-reperfusion injury (IRI) and metabolism. No information is available on a possible role of anti-inflammatory NLRs on IRI and metabolism in the intact heart. Here we hypothesize that the constitutively expressed, anti-inflammatory mitochondrial NLRX1, affects IRI and metabolism of the isolated mouse heart.MethodsIsolated C57Bl/6J and NLRX1 knock-out (KO) mouse hearts were perfused with a physiological mixture of the essential substrates (lactate, glucose, pyruvate, fatty acid, glutamine) and insulin. For the IRI studies, hearts were subjected to either mild (20 min) or severe (35 min) ischemia and IRI was determined at 60 min reperfusion. Inflammatory mediators (IL-6, TNFα) and survival pathways (mito-HKII, p-Akt, p-AMPK, p-STAT3) were analyzed at 5 min of reperfusion. For the metabolism studies, hearts were perfused for 35 min with either 5.5 mM 13C-glucose or 0.4 mM 13C-palmitate under normoxic conditions, followed by LC-MS analysis and integrated, stepwise, mass-isotopomeric flux analysis (MIMOSA).ResultsNLRX1 KO significantly increased IRI (infarct size from 63% to 73%, end-diastolic pressure from 59 mmHg to 75 mmHg, and rate-pressure-product recovery from 15% to 6%), following severe, but not mild, ischemia. The increased IRI in NLRX1 KO hearts was associated with depressed Akt signaling at early reperfusion; other survival pathways or inflammatory parameters were not affected. Metabolically, NLRX1 KO hearts displayed increased lactate production and glucose oxidation relative to fatty acid oxidation, associated with increased pyruvate dehydrogenase flux and 10% higher cardiac oxygen consumption.ConclusionDeletion of the mitochondrially-located NOD-like sensor NLRX1 exacerbates severe cardiac IR injury, possibly through impaired Akt signaling, and increases cardiac glucose metabolism.

Ketamine inhibits neural stem/progenitor cell (NSPC) proliferation and disrupts normal neurogenesis in the developing brain. 17β-Estradiol alleviates neurogenesis damage and enhances behavioral performance after ketamine administration. However, the receptor pathway of 17β-estradiol that protects NSPCs from ketamine-induced injury remains unknown. In the present study, we investigated the role of estrogen receptor α (ER-α) and estrogen receptor β (ER-β) in 17β-estradiol’s protection against ketamine-exposed NSPCs and explored its potential mechanism. The primary cultured NSPCs were identified by immunofluorescence and then treated with ketamine and varying doses of ER-α agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) or ER-β agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) for 24 h. NSPC proliferation was analyzed by 5-bromo-2-deoxyuridine incorporation test. The expression of phosphorylated glycogen synthase kinase-3β (p-GSK-3β) was quantified by western blotting. It was found that treatment with different concentrations of PPT did not alter the inhibition of ketamine on NSPC proliferation. However, treatment with DPN attenuated the inhibition of ketamine on NSPC proliferation at 24 h after their exposure (P < 0.05). Furthermore, treatment with DPN increased p-GSK-3β expression in NSPCs exposed to ketamine. These findings indicated that ER-β mediates probably the protective effects of 17β-estradiol on ketamine-damaged NSPC proliferation and GSK-3β is involved in this process

This paper presents a comparison of P-Delta effects on the nonlinear seismic behavior of the steel moment-resisting frame structures (MRFs) subjected to near-fault and far-fault ground motions. The 3-, 9- and 20-story MRFs designed for the American SAC Phase II Steel Project are used as benchmark models. The 40 near-fault ground motions with large velocity pulses, as well as ten typical far-fault ground motions, are selected and scaled for the nonlinear time-history analysis. The P-Delta effect is quantified based on peak inter-story drift ratio (PIDR) demands. The displacement demands of the whole structure and the distortion of the structural components are compared and analyzed. It was found that, at each floor, the P-Delta effect under near-fault ground motions is more significant than that under the far-fault ground motions. The P-Delta effect under near-fault ground motions also increases more rapidly with decreasing structure height even for low-rise structures or low earthquake intensity. It was also found that the P-Delta effect cause the PIDR demands to increase by 10% for all three structures subjected to far-fault ground motions. In contrast, considering the P-Delta effect, the PIDR demands rapidly increase by 45% for the high-rise building subjected to near-fault ground motions. Note that the increasing PIDR demands occur at the weakest floor and with the stronger earthquake intensity. However, the P-Delta effect does not change the location of the weakest floor and the yield sequence of components. The seismic behaviors under far-fault and near-fault ground motions are significantly different, because near-fault ground motions not only have velocity pulse but also possibly trigger structural higher vibration modes. In addition, the P-Delta effect may change the distortion direction of the components so that the prediction of the structural collapse direction may be affected. In addition, it was found that if the structure’s period is near the pulse period, the P-Delta effect becomes more significant with the increase of earthquake intensity, and accordingly, it should not be ignored. Moreover, the P-Delta effect cannot be neglected either for the structures susceptible to near-fault ground motions, even if those structures are not tall or the earthquake intensity is not strong.

Abstract Hybrid heterojunction solar cells (HHSCs) have gained extensive research and attention due to simple device structure and low-cost technological processes. Here, HHSCs are presented based on a highly transparent conductive polymer poly(3,4ethylenedioxythiophene):poly(styrenesulfonate)(PEDOT:PSS) directly spin-coated on an n-type crystalline silicon with microscale surface textures, which are prepared by traditional chemical etching. We have studied interface properties between PEDOT:PSS and textured n-Si by varying coating conditions. Final power conversion efficiency (PCE) could arrive at 8.54% by these simple solution-based fabrication processes. The high conversion efficiency is attributed to the fully conformal contact between PEDOT:PSS film and textured silicon. Furthermore, the reflectance of the PEDOT:PSS layer on textured surface is analyzed by changing film thickness. In order to improve the performance of the device, silver nanowires were employed as electrodes because of its better optical transmittance and electrical conductivity. The highest PCE of 11.07% was achieved which displayed a 29.6% enhancement compared with traditional silver electrodes. These findings imply that the combination of PEDOT:PSS film and silver nanowire transparent electrodes pave a promising way for realizing high-efficiency and low-cost solar cells.

Generation of midbrain dopaminergic (mDA) neurons from human pluripotent stem cells provides a platform for inquiry into basic and translational studies of Parkinson’s disease (PD). However, heterogeneity in differentiation in vitro makes it difficult to identify mDA neurons in culture or in vivo following transplantation. Here, we report the generation of a human embryonic stem cell (hESC) line with a tyrosine hydroxylase (TH)-RFP (red fluorescent protein) reporter. We validated that RFP faithfully mimicked TH expression during differentiation. Use of this TH-RFP reporter cell line enabled purification of mDA-like neurons from heterogeneous cultures with subsequent characterization of neuron transcriptional and epigenetic programs (global binding profiles of H3K27ac, H3K4me1, and 5-hydroxymethylcytosine [5hmC]) at four different stages of development. We anticipate that the tools and data described here will contribute to the development of mDA neurons for applications in disease modeling and/or drug screening and cell replacement therapies for PD.

Ketamine exposure disturbed normal neurogenesis in the developing brain and resulted in subsequent neurocognitive deficits. 17β-estradiol provides robust neuroprotection in a variety of brain injury models in animals of both sexes and attenuates neurodegeneration induced by anesthesia agents. In the present study, we aimed to investigate whether 17β-estradiol could attenuate neonatal ketamine exposure-disturbed neurogenesis and behavioral performance. We treated 7-day-old (Postnatal day 7, PND 7) Sprague-Dawley rats and neural stem cells (NSCs) with either normal saline, ketamine, or 17β-estradiol before/after ketamine exposure, respectively. At PND 14, the rats were decapitated to detect neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunofluorescence staining. The proliferation, neuronal differentiation, and apoptosis of NSCs were assessed by immunohistochemistry method and TUNEL assay, respectively. The protein levels of cleaved caspase-3 in vivo in addition to GSK-3β and p-GSK-3β in vitro were examined by western blotting. Spatial learning and memory abilities were assessed by Morris water maze (MWM) test at PND 42–47. Ketamine exposure decreased cell proliferation in the SVZ and SGZ, inhibited NSC proliferation and neuronal differentiation, promoted NSC apoptosis and led to adult cognitive deficits. Furthermore, ketamine increased cleaved caspase-3 in vivo and decreased the expression of p-GSK-3β in vitro. Treatment with 17β-estradiol could attenuate ketamine-induced changes both in vivo and in vitro. For the first time we showed that 17β-estradiol alleviated ketamine-induced neurogenesis inhibition and cognitive dysfunction in the developing rat brain. Moreover, the protection of 17β-estradiol was associated with GSK-3β.

Understanding the properties of defects is crucial to design higher performance semiconductor materials because they influence the electronic and optical properties significantly. Using ab initio calculations, the dynamics properties of nitrogen interstitial in GaN material, including the configuration, migration, and interaction with vacancy were systematically investigated in the present work. By introducing different sites of foreign nitrogen atom, the most stable configuration of nitrogen interstitial was calculated to show a threefold symmetry in each layer and different charge states were characterized, respectively. In the researches of migration, two migration paths, in-plane and out-of-plane, were considered. With regards to the in-plane migration, an intermediated rotation process was observed first time. Due to this rotation behavior, two different barriers were demonstrated to reveal that the migration is an anisotropic behavior. Additionally, charged nitrogen Frenkel pair was found to be a relatively stable defect complex and its well separation distance was about 3.9 Å. Part of our results are in good agreement with the experimental results, and our work provides underlying insights of the identification and dynamics of nitrogen interstitial in GaN material. This study of defects in GaN material is useful to establish a more complete theory and improve the performance of GaN-based devices.

Cell-cell interaction as one of the niche signals plays an important role in the balance of stem cell quiescence and proliferation or differentiation. In order to address the effect and the possible mechanisms of cell-cell connection on neural stem/progenitor cells (NSCs/NPCs) proliferation and differentiation, upon passaging, NSCs/NPCs were either dissociated into single cell as usual (named Group I) or mechanically triturated into a mixture of single cell and small cell clusters containing direct cell-cell connections (named Group II). Then the biological behaviors including proliferation and differentiation of NSCs/NPCs were observed. Moreover, the expression of gap junction channel, neurotrophic factors and the phosphorylation status of MAPK signals were compared to investigate the possible mechanisms. Our results showed that, in comparison to the counterparts in Group I, NSCs/NPCs in Group II survived well with preferable neuronal differentiation. In coincidence with this, the expression of connexin 45 (Cx45), as well as brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in Group II were significantly higher than those in Group I. Phosphorylation of ERK1/2 and JNK2 were significantly upregulated in Group II too, while no change was found about p38. Furthermore, the differences of NSCs/NPCs biological behaviors between Group I and II completely disappeared when ERK and JNK phosphorylation were inhibited. These results indicated that cell-cell connection in Group II enhanced NSCs/NPCs survival, proliferation and neuronal differentiation through upregulating the expression of gap junction and neurotrophic factors. MAPK signals- ERK and JNK might contribute to the enhancement. Efforts for maintaining the direct cell-cell connection are worth making to provide more favorable niches for NSCs/NPCs survival, proliferation and neuronal differentiation.

AbstractIt has been suggested that ketamine cause injury during developing brain. Minocycline could prevent neuronal cell death through the activation of cell survival signals and the inhibition of apoptotic signals in models of neurodegenerative diseases. Here we investigated the protective effect of minocycline against ketamine-induced injury in neural stem cell(NSC) from neonatal rat. Ketamine (100μM/L) significantly inhibited NSC proliferation, promoted their differentiation into astrocytes and suppressed neuronal differentiation of NSCs. Moreover, the apoptotic level was increased following ketamine exposure. Minocycline pretreatment greatly enhanced cell viability, decreased caspase-3-like activity, even reversed the differentiation changes caused by ketamine. To elucidate a possible mechanism of minocycline’ neuroprotective effect, we investigated the phosphoinositide3- kinase pathway using LY294002, a specific PI3K inhibitor. Immunoblotting revealed that minocycline enhanced the phosphorylation/activation of Akt and phosphorylation/inactivation of glycogen synthase kinase-3beta (Gsk-3β).Our results suggest that PI3K/Akt and Gsk-3β pathway are involved in the neuroprotective effect of minocycline.

Large-scale binary integer programs occur frequently in many real-world applications. For some binary integer problems, finding an optimal solution or even a feasible solution is computationally expensive. In this paper, we develop a discrete meta-control procedure to approximately solve large-scale binary integer programs efficiently. The key idea is to map the vector of n binary decision variables into a scalar function defined over a time interval [0; n] and construct a linear quadratic tracking (LQT) problem that can be solved efficiently. We prove that an LQT formulation has an optimal binary solution, analogous to a classical bang-bang control in continuous time. Our LQT approach can provide advantages in reducing computation while generating a good approximate solution. Numerical examples are presented to demonstrate the usefulness of the proposed method.

Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics might cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment. Using an in vitro model consisting of dissociated primary cultured mouse neurons, we demonstrate abnormal pre- and post-synaptic marker expression after a clinically-relevant isoflurane anesthesia exposure is conducted during neuron development. We find that pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) pathway can reverse the observed changes. Isoflurane exposure increases expression of phospho-S6, a marker of mTOR pathway activity, in a concentration-dependent fashion and this effect occurs throughout neuronal development. The mTOR 1 complex (mTORC1) and the mTOR 2 complex (mTORC2) branches of the pathway are both activated by isoflurane exposure and this is reversible with branch-specific inhibitors. Upregulation of mTOR is also seen with sevoflurane and propofol exposure, suggesting that this mechanism of developmental anesthetic neurotoxicity may occur with all the commonly used GAs in pediatric practice. We conclude that GAs disrupt the development of neurons during development by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.

Many people suffer from high mental workload which may threaten human health and cause serious accidents. Mental workload estimation is especially important for particular people such as pilots, soldiers, crew and surgeons to guarantee the safety and security. Different physiological signals have been used to estimate mental workload based on the n-back task which is capable of inducing different mental workload levels. This paper explores a feature weight driven signal fusion method and proposes interactive mutual information modeling (IMIM) to increase the mental workload classification accuracy. We used EEG and ECG signals to validate the effectiveness of the proposed method for heterogeneous bio-signal fusion. The experiment of mental workload estimation consisted of signal recording, artifact removal, feature extraction, feature weight calculation, and classification. Ten subjects were invited to take part in easy, medium and hard tasks for the collection of EEG and ECG signals in different mental workload levels. Therefore, heterogeneous physiological signals of different mental workload states were available for classification. Experiments reveal that ECG can be utilized as a supplement of EEG to optimize the fusion model and improve mental workload estimation. Classification results show that the proposed bio-signal fusion method IMIM can increase the classification accuracy in both feature level and classifier level fusion. This study indicates that multi-modal signal fusion is promising to identify the mental workload levels and the fusion strategy has potential application of mental workload estimation in cognitive activities during daily life.

Edaravone is clinically used for treatment of patients with acute cerebral infarction. However, the effect of double application of edaravone on neurogenesis in the hippocampus following ischemia remains unknown. In the present study, we explored whether pre- and posttreatment of edaravone had any effect on neural stem/progenitor cells (NSPCs) in the subgranular zone of hippocampus in a rat model of transient global cerebral ischemia and elucidated the potential mechanism of its effects. Male Sprague-Dawley rats were divided into three groups: sham-operated ( n = 15), control ( n = 15), and edaravone-treated ( n = 15) groups. Newly generated cells were labeled by 5-bromo-2-deoxyuridine. Immunohistochemistry was used to detect neurogenesis. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling was used to detect cell apoptosis. Reactive oxygen species (ROS) were detected by 2,7-dichlorofluorescien diacetate assay in NSPCs in vitro . Hypoxia-inducible factor-1α (HIF-1α) and cleaved caspase-3 proteins were quantified by western blot analysis. Treatment with edaravone significantly increased the number of NSPCs and newly generated neurons in the subgranular zone ( p