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The nonlinear, time correlation, and non-Gaussian features in data present significant challenges for effective fault detection. While the Gate Recurrent Unit (GRU) network is renowned for its capacity to manage time correlation, it falls short in capturing non-Gaussian features in process data, which can likely lead to suboptimal monitoring results. To address this limitation, the Enhancement Gate Recurrent Unit (ENGRU) is developed to perfect the fault detection accuracy of the network. Specifically, The ENGRU effectively extracts high order statistics information by employing the overcompleted independent component analysis method, thereby augmenting its ability to capture non-Gaussian properties. The extracted features information are then entered into the ENGRU model further to uncover additional hidden features beyond what the GRU can achieve. The ENGRU network, which is built upon the extracted characteristic information, even farther enhances the accuracy of the fault detection. The merits of the proposed model are demonstrated by comparing it with excellent fault detection algorithms on a benchmark platform. [ABSTRACT FROM AUTHOR]

Process monitoring models play an increasingly indispensable role in promptly differentiating faults within the wastewater treatment process to maintain a safe state. The accuracy and time overhead are crucial indicators in judging whether models results are excellent or not. In terms of accuracy, deep learning methods excel, because of their generalized approximation and strong learning capabilities that enable them to infinitely approach an ideal level of monitoring accuracy. Meanwhile, they also have large computational loads that generates significant time overhead, which poses challenges for real-time monitoring of the wastewater treatment process. Hence, a novel process monitoring method called Time-Stacked Broad Learning System (Time-SBLS) is developed to alleviate these concerns in an effective and accurate manner. Time-SBLS leverages the efficiency of the BLS while incorporating the residual mechanism and time lag idea to capture necessary nonlinear features and time correlation associated with the fault detection accuracy better. Furthermore, another advantage of Time-SBLS is its inherited efficiency from BLS regarding time overhead, which is minimized by utilizing the pseudo-inverse technique to calculate weight parameters. Experimental findings on the Benchmark platform reveal that Time-SBLS offers considerable advantages in terms of accuracy and network time overhead compared to other state-of-the-art approaches. • Time-SBLS is applied for the first time to the wastewater treatment process. • Time-SBLS model can achieve satisfactory monitoring accuracy. • Time-SBLS overcomes the limitations of some deep learning networks. • Time-SBLS is compatible with accuracy and time overhead simultaneously. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Se doping MWCNTs-graphene hybrids are prepared and used for supporting substrate. • Y-shaped DNA-aided target recycling signal amplification and hemin/G-quadruplex is used for signal amplification. • The biosensor used for PDGF-BB detection shows linear range of 0.1 pM-10 nM and detection limit of 27 fM. Abstract A highly sensitive electrochemical biosensor for detection of platelet-derived growth factor-BB (PDGF-BB) is developed by using Se-doped multi-walled carbon nanotubes (MWCNTs)-graphene hybrids as electrode supporting substrate, hemin/G-quadruplex as trace labels and Y-shaped DNA-aided target recycling as signal magnifier. The aptamer-containing hairpin probes were first immobilized on the electrode. When target PDGF-BB was added, the aptamer binded PDGF-BB to trigger catalytic assembly of two other hairpins to form many G-quadruplex Y-junction DNA structures, which released PDGF-BB to again bind the intact aptamer to initiate another assembly cycle. G-quadruplex/hemin complexes were produced when hemin was added to generate substantially amplified current output. The developed assay showed a linear range toward PDGF-BB from 0.1 pM to 10 nM with a detection limit of 27 fM (S/N = 3). The method showed excellent specificity and repeatability, and could be expediently applied for sensitive detection of other molecules by simply changing the aptamers. [ABSTRACT FROM AUTHOR]

In this work, a sandwich-type electrochemical biosensing platform is developed based on carbon sphere-MoS 2 (CS-MoS 2 ) and target recycling amplification of catalyzed hairpin assembly (CHA) strategy for ultrasensitive determination of microRNA (miRNA). The CS-MoS 2 is prepared and used as sensing substrate, which shows high specific surface area, enhanced stability and good dispersibility. The capture probe is first modified on Au nanoparticles/CS-MoS 2 modified glassy carbon electrode through Au-S band, and hairpin DNA1 (H1) then reacts with it and unfolds its loop domain by hybridizing with target miRNA-21. The opened H1 subsequently assembles with biotin labeled hairpin DNA 2 (H2) to displace the target. The liberated miRNA-21 is free and backs to the original solution to proceed next circulation, resulting in the generation of large amounts of H1–H2 duplex. Massive signal indicators horseradish peroxidase are then immobilized on electrode, and catalyze hydrogenperoxide + hydroquinone (H 2 O 2  + HQ) system to produce a strong electrochemical response. The proposed assay benefits from advantages of sandwich-type structure, favorable electrochemical properties of CS-MoS 2 and CHA target recycling amplification strategy. Therefore, it exhibits a wide linear relation between 1 × 10 −16 and 1 × 10 −10  M with a low detection limit of 1.6 × 10 −17  M for miRNA-21 detection. [ABSTRACT FROM AUTHOR]

T and B cell compartmentalization is a hallmark of secondary lymphoid organs and is maintained by chemokine-expressing stromal cells. How this stromal cell network initially develops and differentiates into two distinct subsets is poorly known, especially for the splenic white pulp (WP). Here, we show that perivascular fibroblast precursors are triggered by LTα1β2 signals to expand, express CCL19/21, and then differentiate into two functionally distinct fibroblast subsets responsible for B and T cell clustering and WP compartmentalization. Failure to express or sense CCL19 leads to impaired T zone development, while lack of B cells or LTα1β2 leads to an earlier and stronger impairment in WP development. We therefore propose that WP development proceeds in multiple steps, with LTα1β2+ B cells acting as major inducer cells driving the expansion and gradual differentiation of perivascular fibroblasts into T and B zone organizer cells. [ABSTRACT FROM AUTHOR]

Crack initiation and propagation are key scientific questions influencing rock failure. To study crack initiation and propagation during rock failure, CT scanning tests were performed on the sandstone samples. The initiation and propagation stages of sandstone cracks were analysed based on a reconstructed three-dimensional crack structure model. The types of crack initiation and propagation in minerals and the effects of mineral composition heterogeneity on crack initiation and propagation were studied using microscopic analytical techniques. The effect of mineral granularity on crack initiation and propagation was analysed using statistical methods. The results show that crack initiation and propagation can be divided into four stages: microcrack inoculation, mesocrack initiation, mesocrack evolution to macrocrack, and macrocrack penetration. Four cracks are formed at different locations, extending along the mineral edge, deflecting at the mineral edge, bifurcating at the mineral edge, and penetrating through the mineral. The poikilitic texture formed by quartz debris and cement makes it easy for cracks to extend along the mineral edges. In quartz debris with high crystallinity, the crack tends to deflect and bifurcate at the edge of quartz debris. The symbiotic structure of altered quartz and clay minerals easily causes cracks to propagate through the minerals. Furthermore, the distribution of mineral granularity affects crack initiation and propagation. The inhomogeneity of mineral granularity can easily cause the initiation and propagation of cracks. The size of the mineral granularity affects the width of the secondary crack. These research results can provide a basis and reference for predicting and evaluating the stability of rock masses. [ABSTRACT FROM AUTHOR]

Background: The potential role of whole grain in preventing various mortality outcomes has been inconsistently reported in a wealth of prospective observational studies. Objective: We evaluated the relations between whole-grain intake and risks of dying from any cause, cardiovascular disease (CVD), and cancer through a meta-analytic approach. Design: Relevant studies were identified by searching PubMed and EMBASE databases and bibliographies of retrieved full publications. Summary RRs with 95% CIs were calculated with a random-effects model. Results: Thirteen studies on total mortality (104,061 deaths), 12 on CVD mortality (26,352 deaths), and 8 on cancer mortality (34,797 deaths) were included. Three studies reported whole-grain intake, and the remaining studies reported whole-grain product intake. In the dose-response analysis in which the intake of whole-grain products was converted to the amount of whole grain, the summary RRs for an increment in whole-grain intake of 50 g/d were 0.78 (95% CI: 0.67, 0.91) for total mortality, 0.70 (95% CI: 0.61, 0.79) for CVD mortality, and 0.82 (95% CI: 0.69, 0.96) for cancer mortality. A similar reduction was observed for the mortality from ischemic heart disease (RR: 0.68; 95% CI: 0.55, 0.84) but not from stroke (RR: 0.93; 95% CI: 0.54, 1.62). There was evidence of nonlinear associations of whole-grain intake with total (P-nonlinearity < 0.001) and CVD mortality (P-nonlinearity <0.001), but not with cancer mortality (P-nonlinearity = 0.12), with the curves for the associations appearing slightly steeper at lower ranges (<35 g/d) of the intake than at higher ranges. Conclusions: Our findings suggest significant inverse relations between whole-grain intake and mortality due to any cause, CVD, or cancer. The findings support the recommendation of increasing whole-grain intake to improve public health. [ABSTRACT FROM AUTHOR]

Previous studies suggested that blood fatty acids (FAs) might affect blood pressure (BP), but the findings have been inconclusive. This study evaluated the cross-sectional and prospective associations of erythrocyte FAs with BP in middle-aged and elderly Chinese individuals. Between 2008 and 2010, 1834 participants (1364 women and 470 men) aged 57 ± 5 y had baseline measurements taken of their erythrocyte FAs and BP. A total of 1477 participants (1103 women and 374 men) had their BP measured again after 3.09 ± 0.32 y (range: 2.91-3.26 y). In the cross-sectional analyses (n = 1834), the erythrocyte saturated FA (SFA) content was positively associated with BP, whereas total cis polyunsaturated FAs (PUFAs), their subtypes cis n-3 (ω-3) PUFAs and cis n-6 (ω-6) PUFAs, and the PUFA-to-SFA ratio were inversely associated with BP (all P-trends < 0.05). The longitudinal results (n = 1477) showed marginally inverse associations between cis n-3 PUFAs and the n-3:n-6 PUFA ratio and BP. For individual cis n-3 PUFAs, higher contents of 20:5n-3, 22:5n-3, and 22:6n-3 were significantly associated with reduced increases in SBP over time (the mean change range between quartile 4 and quartile 1 was -0.917 to -0.749 mm Hg for SBP; all P-trends < 0.01), and 20:5n-3 was inversely associated with DBP change (the mean change between quartile 4 and quartile 1 was -0.631; P-trend < 0.001). Path analyses suggested that the associations between cis n-3 PUFAs and BP might be mediated by decreasing serum triglycerides (TGs) and body mass index (BMI). Our findings revealed that a higher content of cis n-3 PUFAs (mainly very long-chain cis n-3 PUFAs) may benefit BP progress, probably mediated by decreasing serum TGs and BMI. [ABSTRACT FROM AUTHOR]

• Chinese financial marketization has been fast and deep but its breadth has been heterogeneous. • We examine the degree of financial marketization and its interaction with provincial real effective exchange rates. • We also show how these real effective exchange rates and financial marketization interact with regard to export performance. A lot of research has been undertaken on the relationship between exchange rate fluctuation and export. On this basis, this paper considers the moderating effect of financial marketization on the relationship between them, and shifts the research perspective to the provincial level. Using quarterly inter-provincial panel data from 2006 to 2017, this paper focuses on whether financial marketization can weaken the negative effect of exchange rate volatility on export. The conclusions are as follows: at the national level, the depreciation of the inter provincial effective exchange rate in the current period can promote export growth in the next period, while exchange rate volatility will inhibit the next period exports. Financial marketization can mitigate the negative effect of exchange rate volatility on exports. We do however find regional differences in the intensity of these relationships. This study provides empirical evidence for accelerating the reform of financial marketization, steadily promoting the formation mechanism of RMB exchange rate and balancing the development of regional trade. [ABSTRACT FROM AUTHOR]

• An experiment for comparison of three different current limiting topologies is conducted. For the same tape consumption of 17 m, the limiting rates of R-SFCL, FC-SFCL and H-SFCL are 10 %, 28 % and 58 % respectively within the DC voltage range of 240–440 V. Both FC-SFCL and H-SFCL have good current limiting effect. Compared with FC-SFCL, the H-SFCL has stronger flexibility and adaptability, and there is no quenching recovery time, which makes it better cooperate with the DC circuit breaker to realize automatic reclosing. Therefore, H-SFCL is the most suitable superconducting current limiter for MVDC SPS. • This paper puts forward an optimal allocation method of H-SFCL on MVDC SPS. To solve the problem of optimizing the number and position of current limiters, a dual objective hierarchical optimization configuration method is proposed with the goal of minimizing the maximum allowable current and inductance energy of circuit breakers. The optimization of the number, position, and internal component parameters of current limiters is achieved on a four-terminal system. The results show that the proposed hierarchical optimization configuration method can effectively achieve the optimization of position and component parameters. • An improved four objective optimal allocation method suitable for circuit breakers and H-SFCLs is proposed to address the issue of the breaking sequence between the internal switch in H-SFCL and the external circuit breaker. The results showed that the maximum effective individual ratio within the first 20 generations of improvement was 88%; The improved iteration speed has significantly increased, and the effective individual ratio in the 5th generation can reach 100%, effectively improving the effective individual ratio in the optimization iteration process and achieving overall optimization of isolation and current limiting equipment. Medium voltage direct current shipboard power system (MVDC SPS) is the development trend of navy in the future. At present, one of the bottlenecks restricting the development of MVDC SPS is that the short fault. There is a lack of effective means to limit short fault current to protect MVDC SPS. This paper presents a method of applying a hybrid type superconducting fault current limiter (H-SFCL) to MVDC SPS protection. The architecture and system modeling of MVDC SPS are introduced, and the mechanism of bipolar DC short fault is analyzed. The topology and working principle of H-SFCL are introduced. The small-scale prototype experiment is done, the current limiting effect of H-SFCL is compared with resistive type superconducting fault current limiter (R-SFCL) and flux-coupling type superconducting fault current limiter (FC-SFCL) in the prototype test, so as to verify the superiority of H-SFCL. A dual objective hierarchical optimization configuration method is proposed, and the number and position of H-SFCLs are verified on a four-terminal system, as well as multi-objective optimization for H-SFCLs. A fault isolation and H-SFCL optimal allocation evaluation model is proposed; An improved method suitable for fault isolation and multi-objective optimal allocation of H-SFCLs is proposed to address the issue of breaking timing between internal switches in H-SFCLs and external circuit breakers in the optimization process. The research results indicate that the proposed optimal allocation method can optimize the inductance, resistance, and switch breaking time inside the current limiter, and can match the timing with the external circuit breaker; The proposed multi-objective optimization configuration method has a maximum effective individual ratio of 88% in the first 20 generations of improvement, and the improved iteration speed has significantly increased. In the 5th generation, the effective individual ratio can reach 100%. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces. [ABSTRACT FROM AUTHOR]

This work aims to study the free and forced transverse vibrations of a nanowire on elastic substrate, in a systematic way. To this end, the governing equations are obtained from an updated mechanical model integrating the effects of surface and elastic substrate. The Winkler, Pasternak and Generalized substrate models are taken into consideration to characterize various substrates. The characteristic equations, mode shapes and effective Young’s moduli are determined for nanowires with three typical boundary conditions: simply supported, clamped-clamped and clamped-free. The Laplace transform is employed to derive the exact solutions for forced vibrations of the three typical nanowires. Numerical calculations are performed to validate the proposed solutions and to analyze the effects of surface and elastic substrates on the free and forced vibrations. [ABSTRACT FROM AUTHOR]

The glucagon receptor (GCGR) is a potential target for diabetes therapy. Several emerging GCGR antagonism-based therapies are under preclinical and clinical development. However, GCGR antagonism, as well as genetically engineered GCGR deficiency in animal models, are accompanied by α-cell hyperplasia and hyperglucagonemia, which may limit the application of GCGR antagonism. To better understand the physiological changes in α cells following GCGR disruption, we performed single cell sequencing of α cells isolated from control and gcgr-/- (glucagon receptor deficient) zebrafish. Interestingly, beyond the α-cell hyperplasia, we also found that the expression of gcga, gcgb, pnoca, and several glucagon-regulatory transcription factors were dramatically increased in one cluster of gcgr-/- α cells. We further confirmed that glucagon mRNA was upregulated in gcgr-/- animals by in situ hybridization and that glucagon promoter activity was increased in gcgr-/-;Tg(gcga:GFP) reporter zebrafish. We also demonstrated that gcgr-/- α cells had increased glucagon protein levels and increased granules after GCGR disruption. Intriguingly, the increased mRNA and protein levels could be suppressed by treatment with high-level glucose or knockdown of the pnoca gene. In conclusion, these data demonstrated that GCGR deficiency not only induced α-cell hyperplasia but also increased glucagon expression in α cells, findings which provide more information about physiological changes in α-cells when the GCGR is disrupted. [ABSTRACT FROM AUTHOR]

Sensitive detection of ochratoxin A (OTA) plays an important role in the field of food safety control. In this study, we are reporting for the first time an electrochemical biosensor which employs the integration of MoSe 2 nanoflowers, Au nanoparticles (AuNPs), aptamer and the guanine-rich complementary DNA sequence for the sensitive detection of OTA. MoSe 2 nanoflowers are prepared by a simple hydrothermal method and used as a promising sensing platform based on its large surface area. The methylene blue is used as a tracer and a guanine-rich complementary DNA sequence is designed to bind with the unbound OTA aptamer for signal amplification. The aptamer is immobilized on the AuNPs/MoSe 2 modified electrode surface through Au–S interaction. Since OTA can competitively bind with the aptamer due to their high affinity, the presence of OTA will induce the decrease of guanine-rich DNA on the electrode surface, in turn reduces the signal of methylene blue which can specifically adsorb to the guanine units of DNA. The proposed assay shows a good linear relationship within the range of 0.0001–1 nM with a detection limit of 0.08 pM for OTA. The developed biosensor has been applied to determine OTA concentration in wine samples. [ABSTRACT FROM AUTHOR]

Objective: Whey protein (WP) has been reported to reduce body weight gain and improve glucose metabolism in obese individuals. This study aims to assess and compare the effects of WP and its hydrolysate-leucine (Leu) supplementation in non-obese, insulin-resistant (IR) rat models, particularly the effects on insulin sensitivity, lipid profile, and antioxidant activity. Methods: Wistar rats were fed a diet consisting of 38.5% fat for 12 wk and 51.3% fat for an additional 4 wk to establish non-obese IR rats. The IR rats were then switched to regular A1N-93 diet containing 0% WP, 5% WP, 15% WP or 1.6% Leu for 8 wk. The Leu content was the same in the 15% WP and 1.6% Leu groups based on high-performance liquid chromatography. The IR rats' body weight, fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance were measured before and after supplementation. An oral glucose tolerance test was performed after supplementation. Body composition, plasma concentrations of the lipids profile, and antioxidant index also were analyzed. Results: No significant difference was observed in body weight, energy intake, and fasting blood glucose in the non-obese IR rats at the end of the experiment. Compared with the 0% WP group, the fasting insulin and homeostasis model assessment-insulin resistance significantly decreased in the 15% WP and 1.6% Leu groups. Furthermore, the blood glucose area under the curve of the oral glucose tolerance test was significantly less in the 15% WP and 1.6% Leu groups. There were no differences in the lipids profile, except for the increase in the high-density lipoprotein cholesterol in the 15% WP and 1.6% Leu groups. For the antioxidant index, the 15% WP group had significantly increased plasma levels for total antioxidation capacity, superoxide dismutase, and glutathione, and a decreased malondialdehyde concentration. The 1.6% Leu group was shown to have the same effect as the 15% WP group, except for the glutathione. Conclusion: Our findings demonstrate that the supplementation of WP and Leu may improve IR and antioxidant stress without resulting in changes in body weight and energy intake in non-obese IR rats. [ABSTRACT FROM AUTHOR]

Necrophagous flies, comprising the first wave of insects present in a cadaver, provide a great potential for more accurate determination of the late postmortem interval (PMI) based on their age. Cuticular hydrocarbons (CHs) are a promising age indicator in some insect species, especially for the larvae of necrophagous flies. Gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) were used to characterize the age-dependent, quantitative changes in CHs of larval Aldrichina grahami (Aldrich) (Diptera: Calliphoridae) at 24 8C. The majority of low-molecular-weight alkanes (⩽C25) and almost all of the alkenes decreased in abundance with larval development. By contrast, the abundance of high-molecular-weight alkanes of chain length greater than C25 gradually increased with age. For several peaks, including peak 28 (pentacosene a), peak 31 (n-C25), peak 43 (n-C27) and peak 68 (n-C31), a highly significant correlation was found between peak ratio (n-C29 divided by each chromatographic peak) and chronological age of the larvae. A mathematical model, derived from multivariate linear regression analysis, was developed for determining age of the larvae based on age-dependent changes in CHs. The estimated larval age based on the CHs had a good linear correlation with the chronological age (R2 > 0.9). These results indicate that CHs has a great potential for determining the age of fly larvae, and concomitantly for the PMI in forensic investigation. [ABSTRACT FROM AUTHOR]

Dysregulation of the circadian rhythm is associated with many diseases, including diabetes, obesity, and cancer. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (Arntl or Bmal1) is the only clock gene whose loss disrupts circadian locomotor behavior in constant darkness. BMAL1 levels are affected by proteasomal inhibition and by several enzymes in the ubiquitin--proteasome system, but the exact molecular mechanism remains unclear. Here, using immunoprecipitation and MS analyses, we discovered an interaction between BMAL1 and ubiquitin-conjugating enzyme E2 O (UBE2O), an E3-independent E2 ubiquitin--conjugating enzyme (i.e. hybrid E2/E3 enzyme). Biochemical experiments with cell lines and animal tissues validated this specific interaction and uncovered that UBE2O expression reduces BMAL1 levels by promoting its ubiquitination and degradation. Moreover, UBE2O expression/ knockdown diminished/increased, respectively, BMAL1-mediated transcriptional activity but did not affect BMAL1 gene expression. Bioluminescence experiments disclosed that UBE2O knockdown elevates the amplitude of the circadian clock in human osteosarcoma U2OS cells. Furthermore, mapping of the BMAL1-interacting domain in UBE2O and analyses of BMAL1 stability and ubiquitination revealed that the conserved region 2 (CR2) in UBE2O significantly enhances BMAL1 ubiquitination and decreases BMAL1 protein levels. A Cys-to-Ser substitution experiment identified the critical Cys residue in theCR2domain responsible for BMAL1 ubiquitination. This work identifies UBE2O as a critical regulator in the ubiquitin--proteasome system, which modulates BMAL1 transcriptional activity and circadian function by promoting BMAL1 ubiquitination and degradation under normal physiological conditions. [ABSTRACT FROM AUTHOR]

Targeting of Mycobacterium tuberculosis (MTB) PE/PPE antigens that induce type 1 helper T cell (Th1) and Th17 responses represents a crucial strategy for the development of tuberculosis (TB) vaccines. However, only a few PE/PPE antigens induce these responses. Here, we sought to determine how the cell wall–associated antigen PPE60 (Rv3478) activates dendritic cell (DC) maturation and T-cell differentiation. We observed that PPE60 induces DC maturation by augmenting the protein expression of cluster of differentiation 80 (CD80) and CD86 and major histocompatibility complex (MHC) class I and MHC class II on the cell surface. PPE60 also stimulated the production of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, IL-12p70, and IL-23p19 but not IL-10. This induction was mediated by Toll-like receptor 2 (TLR2) and followed by activation of p38, c-Jun N-terminal kinase (JNK), and NF-κB signaling. PPE60 enhanced MHC-II expression and promoted antigen processing by DCs in a TLR2-dependent manner. Moreover, PPE60-stimulated DCs directed naïve CD4+ T cells to produce IFN-γ, IL-2, and IL-17A, expanding the Th1 and Th17 responses, along with activation of T-bet and RAR-related orphan receptor C (RORγt) but not GATA-3. Moreover, PPE60 activated the NLRP3 inflammasome followed by caspase-1–dependent IL-1β and IL-18 synthesis in DCs. Of note, pharmacological inhibition of NLRP3 activation specifically attenuated IFN-γ and IL-17A secretion into the supernatant from CD4+ T cells cocultured with PPE60-activated DCs. These findings indicate that PPE60 induces Th1 and Th17 immune responses by activating DCs in a TLR2-dependent manner, suggesting PPE60's potential for use in MTB vaccine development [ABSTRACT FROM AUTHOR]

Understanding the mechanism underlying the physiological divergence of species is a long-standing issue in evolutionary biology. The circadian clock is a highly conserved system existing in almost all organisms that regulates a wide range of physiological and behavioral events to adapt to the day-night cycle. Here, the interactions between hCK1ε/δ/DBT (Drosophila ortholog of CK1δ/ε) and serine-rich (SR) motifs from hPER2 (ortholog of Drosophila per) were reconstructed in a Drosophila circadian system. The results indicated that in Drosophila, the SR mutant form hPER2S662G does not recapitulate the mouse or human mutant phenotype. However, introducing hCK1δ (but not DBT) shortened the circadian period and restored the SR motif function. We found that hCK1δ is catalytically more efficient than DBT in phosphorylating the SR motif, which demonstrates that the evolution of CK1δ activity is required for SR motif modulation. Moreover, an abundance of phosphorylatable SR motifs and the striking emergence of putative SR motifs in vertebrate proteins were observed, which provides further evidence that the correlated evolution between kinase activity and its substrates set the stage for functional diversity in vertebrates. It is possible that such correlated evolution may serve as a biomarker associated with the adaptive benefits of diverse organisms. These results also provide a concrete example of how functional synthesis can be achieved through introducing evolutionary partners in vivo. [ABSTRACT FROM AUTHOR]

The thalassospiramide lipopeptides have great potential for therapeutic applications; however, their structural and functional diversity and biosynthesis are poorly understood. Here, by cultivating 130 Rhodospirillaceae strains sampled from oceans worldwide, we discovered 21 new thalassospiramide analogues and demonstrated their neuroprotective effects. To investigate the diversity of biosynthetic gene cluster (BGC) architectures, we sequenced the draft genomes of 28 Rhodospirillaceae strains. Our family-wide genomic analysis revealed three types of dysfunctional BGCs and four functional BGCs whose architectures correspond to four production patterns. This correlation allowed us to reassess the "diversity-oriented biosynthesis" proposed for the microbial production of thalassospiramides, which involves iteration of several key modules. Preliminary evolutionary investigation suggested that the functional BGCs could have arisen through module/domain loss, whereas the dysfunctional BGCs arose through horizontal gene transfer. Further comparative genomics indicated that thalassospiramide production is likely to be attendant on particular genes/pathways for amino acid metabolism, signaling transduction, and compound efflux. Our findings provide a systematic understanding of thalassospiramide production and new insights into the underlying mechanism. [ABSTRACT FROM AUTHOR]

This study numerically investigated the effects of different bolt pre-loadings on the performance of the gas diffusion layer (GDL) in a bolted proton exchange membrane fuel cell (PEMFC). Firstly, a complete three-dimensional finite element model of a PEMFC bolted by 12 bolts with a reactive area of 5 cm by 5 cm was established using the commercial software SolidWorks. Then, a pre-loading of 1 MPa to 7 MPa on each bolt was applied, increasing in increments 1 MPa, and the corresponding deformation and stress fields of each component of the fuel cell were obtained using the commercial software ANSYS 15.0/Workbench. Finally, the effects of the bolt pre-loading variations on the performance of the GDL were discussed. The results showed that the compression ratio of the GDL increased linearly with the magnitude of bolt pre-loading, and improving the performance of the GDL. However, when the pre-loading on each bolt reached 7 MPa, the compression ratio exceeded 15%, degrading the efficiency of the PEMFC. Also, by comparing the relationships between bolt pre-loading and conductivity and porosity of GDL, in order to obtain the maximum performance of GDL, an optimum value of 4 MPa for bolt preloading was recommended. [ABSTRACT FROM AUTHOR]

Cu–Cu ultrasonic bonding is a highly promising technology for advanced interconnect technology for a 3D integrated circuit micro bump. The interface kinetic friction characteristic is also a key factor in determining the level of bonding for this technology. This study uses molecular dynamics simulation to determine the effects of different temperatures on the material kinetic friction characteristics of Cu substrates in single-crystal and polycrystalline structures. The Taguchi method is used to optimize the simulation, in order to confirm that the convergent kinetic friction coefficients are not affected by size effect. A comparison between the results obtained in the present study and those of previous studies shows good agreement between these two sets of results for kinetic friction coefficients. In order to thoroughly understand the effect of temperature on material characteristics, this study uses the central symmetry parameter to monitor defected atoms and to determine the kinetic friction characteristics at various temperatures. The results show that in single-crystal structures, because the generation of dislocations is not restricted to grain boundaries, the normal force does not change significantly but the tangential force decreases as the temperature increases. Therefore, the kinetic friction coefficient for single-crystal Cu decreases as temperature increases. Because the generation of dislocations in polycrystalline structures is restricted to grain boundaries between 293 K and 650 K, the tangential force and the normal force do not decrease significantly as the temperature increases. Consequently, the kinetic friction coefficient for polycrystalline Cu remains stable and is unaffected by any increase in temperature. Between 825 K and 1000 K, although the generation of dislocations in polycrystalline structures is still restricted to grain boundaries, high temperatures soften the material, which leads to a significant decrease in the tangential force and the normal force. Therefore, the kinetic friction coefficient of polycrystalline Cu does not decrease significantly. Finally, at temperatures of less than 850 K, the kinetic friction coefficient for single-crystal Cu is greater than that for polycrystalline Cu. At 850 K, the kinetic friction coefficient for single-crystal Cu is equal to that for polycrystalline Cu, but at 1000 K, the kinetic friction coefficient for single-crystal Cu is less than that for polycrystalline Cu. The results of the simulation show that lattice structures have a significant effect on the kinetic friction coefficient at different temperatures. [ABSTRACT FROM AUTHOR]

Aims To investigate the effects of sevoflurane inhalation on β-amyloid (Aβ)-induced cognitive disorders and hippocampal oxidative stress in rat models. Materials and methods Cognitive dysfunction is induced by hippocampal injection of Aβ 1–40 (10 μg in 2 μl) for 22 days. To explore the effect of sevoflurane inhalation on Aβ 1–40 induced cognitive disorder, two doses of sevoflurane inhalation are used: 1.3% (Aβ + S1) and 2.6% (Aβ + S2). Sham operation (Sham, for operation control), saline injection (Control, for injection control) and 30% oxygen inhalation after Aβ 1–40 injection (Aβ + O 2 , for inhalation control) were used as controls. All rats were further tested in electrical Y-maze and Morris water maze. Serum S100β levels, hippocampal superoxide dismutase (SOD) activity, S100β expression and malonyldialdehyde (MDA) concentrations were further quantified. Key findings Rats in Aβ + O 2 , Aβ + S1 and Aβ + S2 groups had lower number of correct actions in the electrical Y maze task, longer escape latencies, less time exploring the original platform, elevated serum S100β levels, depressed hippocampal SOD activity, S100β expression and higher MDA concentrations compared to control group (p < 0.05). Such difference was not significant between Aβ + S1 and Aβ + O 2 rats. Rats in Aβ + S2 group, however, showed significantly impaired performances compared to those in Aβ + S1 group (p < 0.05). Significance Sevoflurane (2.6%) can aggravate the Aβ-induced cognitive dysfunction, possibly via the intracerebral oxidative stress response. [ABSTRACT FROM AUTHOR]

Alcohol abuse can result in significant alterations to the structure of the brain and ultimately to behavioral dysfunctions. Epidemiological studies have shown that alcoholism is closely associated with impaired memory and judgment. However, the degree of deficit (brain injury) depends on factors such as the age of onset, duration of heavy drinking, continuous versus periodic (binge) drinking and the typical amount consumed per session. In recent years, neuroinflammation has been proposed as one of the alcoholism-induced neuropathological mechanisms, since increased levels of microglial markers are observed in the brains of both post-mortem human alcoholics and various alcohol-treated animals, from newborn or adolescent rodents to adult rodents. Many studies have investigated how microglia modulate alcohol-induced behavioral changes such as cognitive deficits, abnormal locomotor activity, motor impairment and mood disturbance. Importantly, we try to characterize and compare the distinct features in different ethanol (EtOH)-induced neurodegenerative disease (NDD) models. Moreover, mounting evidence indicates that in response to certain environmental toxins, microglia can become over-activated under oxidative stress, releasing pro-inflammatory mediators that cause central nervous system (CNS) disease. The molecular mechanisms involve free radical formation and the release of pro-inflammatory cytokines that are detrimental to neighboring neurons and interfere with the molecules regulating cell–cell interactions. The identification and understanding of the cellular and molecular mechanisms of microglial activation are described, as well as multiple downstream targets, in different alcohol-treated animal models. This review might contribute to the development of treatments and/or therapeutic agents that can reduce or eliminate the deleterious effects of alcohol-induced NDD. [ABSTRACT FROM AUTHOR]

In the current study, zirconia (ZrO2) and its composite, magnesia-zirconia (MgO-ZrO2), were prepared as the hydrophilic interaction chromatographic (HILIC) stationary phases (SPs). Different experimental variables including water content, pH and buffer concentration in the mobile phase (MP) as well as column temperature were systematically studied to permit an in-depth understanding of the chromatographic properties of the mentioned SPs and to explore the retention mechanism further on. The results were compared with a native SiO2 column. Adsorption was demonstrated as the main retention mechanism on the two ZrO2-based SPs. The transferring of the analytes from the MP to the ZrO2-based SPs was endothermic and high column temperature would facilitate the retention. In addition, the MgO-ZrO2 SP exhibited superior resolution, column efficiency as well as stronger retention in comparison to the bare ZrO2 SP, which demonstrated that the introduction of MgO could improve the structure and properties of the material. In conclusion, MgO-ZrO2 was a promising material for HILIC applications. [ABSTRACT FROM AUTHOR]

The titanium dioxide (TiO2) micromesh surface was obtained by a solution-dipping template strategy. A deposition mask was formed on the silicon substrates by the self-assembly of monolayer polystyrene colloidal particles with a diameter of 1 μm, then the TiO2 film was deposited on the mask using a TiO2 sol, and the micromesh structure was produced by high temperature heat treatment (HTT) and ultrasonic cleaning. The structure was investigated by scanning electron microscopy (SEM) and X-ray diffraction (XRD), and the wettability was evaluated by water contact angle measurement. The blood platelets adhesion test was also performed to study the hemocompatibility of the micromesh structure. The XRD result showed that the TiO2 film prepared by sol-dipping method was composed of anatase phase. The water contact angle measurement showed that the TiO2 micromesh surface was more hydrophobic than the flat TiO2 surface. The platelets adhesion test showed that the TiO2 micromesh surface could effectively inhibit platelets adhesion. It is highlighted that this TiO2 micromesh surface may have potential application for the blood contact implanted devices. [ABSTRACT FROM AUTHOR]

Patients suffering from chronic neuropathic pain are at high risk of co-morbid depression, which burdens healthcare. This work aimed to investigate the effects of resveratrol, a phenolic monomer enriched in red wine and grapes, on pain-related and depressive-like behaviors in mice with mononeuropathy, and explored the mechanism(s). Mice received chronic constriction injury (CCI) of sciatic nerves, and sequentially developed pain-related and depressive-like behaviors, as evidenced by sensory hypersensitivity (thermal hyperalgesia in Hargreaves test and mechanical allodynia in von Frey test) and behavioral despair (prolonged immobility time in forced swim test). Chronic treatment of neuropathic mice with resveratrol (30 mg/kg, p.o., twice per day for three weeks) normalized their thermal hyperalgesia (but not mechanical allodynia) and depressive-like behaviors, and these actions were abolished by chemical depletion of central serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. The anti-hyperalgesia and anti-depression exerted by resveratrol may be pharmacologically segregated, since intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of methysergide, a non-selective 5-HT receptor antagonist, separately abrogated the two actions. Furthermore, the antihyperalgesic action of resveratrol was preferentially counteracted by co-administration of the 5-HT7 receptor antagonist SB-258719, while the anti-depression was abrogated by 5-HT1A receptor antagonist WAY-100635. These results confirm that chronic resveratrol administration exerts curative-like effects on thermal hyperalgesia and co-morbid depressive-like behaviors in mice with mononeuropathy. Spinal and supraspinal serotonergic systems (coupled with 5-HT7 and 5-HT1A receptors, respectively) are differentially responsible for the antihyperalgesic and antidepressant-like properties of resveratrol. [ABSTRACT FROM AUTHOR]

Transgenic mice expressing mutations in tau have yielded essential discoveries for Alzheimer's disease. One of the most commonly used tau mouse models is the tet-off Tg(tauP301L)4510 model that expresses P301L human tau driven by the calcium-calmodulin kinase IIα (CaMKIIα) promoter system. Tau expression in this model is regulatable, allowing for suppression of mutant tau expression until adulthood and prevention of possible developmental alterations resulting from P301L tau expression during development. Here, we compared the effect and sample sizes needed for three learning and memory tasks in mice with adult-onset P301L tau expression. Our findings indicate that the Incremental Repeated Acquisition (IRA) and trace fear conditioning tasks, neither of which have previously been published with these mice, were highly sensitive to P301L tau expression, whereas the Morris water maze, the most commonly used task with this model, was the least sensitive. Memory deficits were observed at a time when tau pathology was subtle and prior to readily detectable neuronal loss. Thus, we provide essential information (effect and sample sizes needed) for establishing experimental designs at a time point when memory deficits are likely to go undetected if inadequate sample sizes are used. Our work also suggests the tet-off Tg4510 model provides a way to avoid mutant tau expression during the perinatal and early postnatal stages, thereby preventing possible developmental alterations unrelated to Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objective To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level. Design Databases were searched for the related English-language literature published up to March 1, 2014. Only papers in peer-reviewed journals are cited. Setting Not applicable. Patient(s) Not applicable. Intervention(s) Melatonin treatment, alterations of the normal light:dark cycle and light exposure at night. Main Outcome Measure(s) Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs. Result(s) The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ. Conclusion(s) Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset at night disrupts the master circadian clock and suppresses elevated nocturnal melatonin levels, light at night should be avoided. [ABSTRACT FROM AUTHOR]