New two-dimensional nanocomposites combined with target-induced strategy in an electrochemical aptasensor for sensitive determination of sulfadimethoxine.

Ni-Zn bimetallic organic framework nanosheets (NiZn-MOF NSs) were modified onto PEI-functionalized MXene for the first time. The combination of the two kinds of nanosheets forms a sensing platform with superior conductivity and biocompatibility. On this basis, a highly sensitive biosensor was developed for the determination of sulfadimethoxine (SDM). Furthermore, Au and Mn nanoparticles decorated reduced graphene oxide (Au-Mn/rGO) was introduced as a signal hindering molecule under the target-induced amplification strategy. When the Au-Mn/rGO-labelled SDM-binding aptamer (Au-Mn/rGO-SBA) specifically bound to target SDM, it detached from the electrode, thereby further amplifying the electrochemical signal of [Fe(CN)6]3-/4-. The developed aptasensor for SDM showed excellent response signals in the range 1 pg mL-1 to 100 ng mL-1, with a limit of detection (LOD) as low as 0.22 pg mL-1. Significantly, the proposed sensor also showed satisfactory results in milk samples with recoveries ranging from 87.0 to 96.4% and RSD from 1.5 to 5.1%, which is believed to be useful in food safety assays.

The Associations between Evacuation Movements and Children's Physiological Demands Analyzed via Wearable-Based Sensors.

During fire evacuations, crawling is recommended to prevent harm from toxic smoke and to access more breathable air. Few studies have evaluated the physiological burden of crawling, especially for children. The method of using wearable sensors to collect data (e.g., electrodermal activity, EDA; skin temperature, SKT) was used to evaluate the effects of different locomotive postures on children's velocity and physiological demands. Twenty-eight (28) children (13 boys and 15 girls), aged 4 to 6 years old, traveled up to 22.0 m in different postures: Upright walking (UW), stoop walking (SW), knee and hand crawling (KHC). The results showed that: (1) Gender and age had significant impacts on children's velocity (p < 0.05): Boys were always faster than girls in any of the three postures and the older the child, the faster the velocity for KHC. (2) Physiological results demonstrated that KHC was more physically demanding than bipedal walking, represented by higher scores of the EDA and SKT indicators, similar to the findings of adults. (3) Gender and age had significant impacts on children's physiological demands (p < 0.05). The physiological demands were greater for boys than girls. In addition, the higher the age, the less physiological demands he/she needs. Overall, the findings suggest that children are unnecessarily required to choose crawling precisely as adults as the best posture to respond to emergency scenarios. In a severe fire, stoop walking is suggested, as there is more respired air and children could move quickly and avoid overworking physiological burdens. The results of this study are expected to be considered in the evaluation of current evacuation recommendations and for the safety guide of preparedness to improve the effectiveness of risk reduction for children.

The Role of Macrophages in Lung Fibrosis and the Signaling Pathway.

Lung fibrosis is a dysregulated repair process caused by excessive deposition of extracellular matrix that can severely affect respiratory function. Macrophages are a group of immune cells that have multiple functions and can perform a variety of roles. Lung fibrosis develops with the involvement of pro-inflammatory and pro-fibrotic factors secreted by macrophages. The balance between M1 and M2 macrophages has been proposed to play a role in determining the trend and severity of lung fibrosis. New avenues and concepts for preventing and treating lung fibrosis have emerged in recent years through research on mitochondria, Gab proteins, and exosomes. The main topic of this essay is the impact that mitochondria, Gab proteins, and exosomes have on macrophage polarization. In addition, the potential of these factors as targets to enhance lung fibrosis is also explored. We have also collated the functions and mechanisms of signaling pathways associated with the regulation of macrophage polarization such as Notch, TGF-ß/Smad, JAK-STAT and cGAS-STING. The goal of this article is to explain the potential benefits of focusing on macrophage polarization as a way to relieve lung fibrosis. We aspire to provide valuable insights that could lead to enhancements in the treatment of this condition.

Surface-Activated Ti3C2Tx Adsorption of Acetylene Black Coupled with Polyaniline as a Signal Tag for the Detection of the ESAT-6 Antigen of Mycobacterium tuberculosis.

Early secretory antigenic target-6 (ESAT-6) is regarded as the most immunogenic protein produced by Mycobacterium tuberculosis, whose detection is of great clinical significance for tuberculosis diagnosis. However, the detection of the ESAT-6 antigen has been hampered by the expensive cost and complex experimental procedures, resulting in low sensitivity. Herein, we developed a titanium carbide (Ti3C2Tx)-based aptasensor for ESAT-6 detection utilizing a triple-signal amplification strategy. First, acetylene black (AB) was immobilized on Ti3C2Tx through a cross-linking reaction to form the Ti3C2Tx-AB-PAn nanocomposite. Meanwhile, AB served as a conductive bridge, and Ti3C2Tx can synergistically promote the electron transfer of PAn. Ti3C2Tx-AB-PAn exhibited outstanding conductivity, high electrochemical signals, and abundant sites for the loading of ESAT-6 binding aptamer II (EBA II) to form a novel signal tag. Second, N-CNTs were adsorbed on NiMn layered double hydride (NiMn LDH) nanoflowers to obtain NiMn LDH/N-CNTs, exhibiting excellent conductivity and preeminent stability to be used as electrode modification materials. Third, the biotinylated EBA (EBA I) was immobilized onto a streptavidin-coated sensing interface, forming an amplification platform for further signal enhancement. More importantly, as a result of the synergistic effect of the triple-signal amplification platform, the aptasensor exhibited a wide detection linear range from 10 fg mL-1 to 100 ng mL-1 and a detection limit of 4.07 fg mL-1 for ESAT-6. We envision that our aptasensor provides a way for the detection of ESAT-6 to assist in the diagnosis of tuberculosis.

Influence of Cathode Channel Parameters and Fan Duty Ratio on Low Power Forced-Convection Open-Cathode Proton Exchange Membrane Fuel Cell Stack.

The open-cathode forced-convection proton exchange membrane fuel cell has emerged as a viable option for portable energy sources. The forced-convection open-cathode mode, however, makes the cell's performance sensitive to changes in the cathode channel and fan parameters. In this study, small fuel cell stacks with varying cathode channel depths, widths, and width-rib ratios were assembled, and the effects of different cathode channel parameters and fan duty ratios on cell performance were investigated. The experimental results show that changing the cathode channel parameters has a significant impact on oxidant supply. When the channel width is increased, the cell performance increases first, then decreases. The cell performance decreases as the channel width-rib ratio increases. The performance of the cell improves as the cathode channel depth increases. Furthermore, the experimental results show that decreasing the duty ratio of the fan and using moderate heating improves cell performance.

Effect of FTY-720 on Pulmonary Fibrosis in Mice via the TGF-ß1 Signaling Pathway and Autophagy.

We investigated whether FTY-720 might have an effect on bleomycin-induced pulmonary fibrosis through inhibiting TGF-ß1 pathway, and up-regulating autophagy. The pulmonary fibrosis was induced by bleomycin. FTY-720 (1 mg/kg) drug was intraperitoneally injected into mice. Histological changes and inflammatory factors were observed, and EMT and autophagy protein markers were studied by immunohistochemistry and immunofluorescence. The effects of bleomycin on MLE-12 cells were detected by MTT assay and flow cytometry, and the related molecular mechanisms were studied by Western Blot. FTY-720 considerably attenuated bleomycin-induced disorganization of alveolar tissue, extracellular collagen deposition, and α-SMA and E-cadherin levels in mice. The levels of IL-1ß, TNF-α, and IL-6 cytokines were attenuated in bronchoalveolar lavage fluid, as well as protein content and leukocyte count. COL1A1 and MMP9 protein expressions in lung tissue were significantly reduced. Additionally, FTY-720 treatment effectively inhibited the expressions of key proteins in TGF-ß1/TAK1/P38MAPK pathway and regulated autophagy proteins. Similar results were additionally found in cellular assays with mouse alveolar epithelial cells. Our study provides proof for a new mechanism for FTY-720 to suppress pulmonary fibrosis. FTY-720 is also a target for treating pulmonary fibrosis.

JTE-013 Alleviates Pulmonary Fibrosis by Affecting the RhoA/YAP Pathway and Mitochondrial Fusion/Fission.

Pulmonary fibrosis may be due to the proliferation of fibroblasts and the aggregation of extracellular matrix, resulting in the stimulation of inflammation damage, destroying lung tissue structure, seriously affecting the patient's respiratory function, and even leading to death. We investigated the role and mechanism of JTE-013 in attenuating bleomycin (BLM)-induced pulmonary fibrosis. BLM-induced pulmonary fibrosis was established in mice. Type 2 alveolar epithelial cells (MLE-12) were stimulated with sphingosine monophosphate (S1P) in vitro. JTE-013, an S1PR2 (sphingosine 1-phosphate receptor 2) antagonist, and Verteporfin were administered in vivo and in vitro. IL-4, IL-5, TNF-α, and IFN-γ were measured by ELISA. IL-4 and IFN-γ positive cells were detected by flow cytometry. Inhibition of S1PR2 with JTE-013 significantly ameliorated BLM-induced pathological changes and inflammatory cytokine levels. JTE-013 also significantly reduced the expression of RHOA/YAP pathway proteins and mitochondrial fission protein Drp1, apoptosis, and the colocalization of α-SMA with YAP, Drp1, and Tom20, as detected by immunohistochemistry, immunofluorescence staining, TUNEL, and Western blot. In vitro, S1PR2 and YAP knockdown downregulated RHOA/YAP pathway protein expression, Drp1 phosphorylation, and Drp1 translocation, promoted YAP phosphorylation and phenotypic transformation of MFN2, and inhibited the up-regulation of mitochondrial membrane potential, reactive oxygen species production, and cell apoptosis (7.13% vs. 18.14%), protecting the integrity of the mitochondrial dynamics. JTE-013 also inhibited the expression of fibrosis markers α-SMA, MMP-9, and COL1A1, and alleviated the symptoms of pulmonary fibrosis. Conclusively, JTE-013 has great anti-pulmonary fibrosis potential by regulating RHOA/YAP and mitochondrial fusion/fission.

Discovery of NLRP3 inhibitors using machine learning: Identification of a hit compound to treat NLRP3 activation-driven diseases.

NLRP3 is vital in developing many human diseases as one of the most critical inflammasomes. Developing related inhibitors has been instrumental in advancing the development of therapies for associated diseases. To date, there are no NLRP3 inhibitors on the market. This study identified a series of NLRP3 inhibitors using the self-developed machine learning model. Among them, CSC-6 was validated as the hit molecule with optimal activity and significantly inhibited IL-1ß secreted by PMA-THP-1 cells (IC50 = 2.3 ± 0.38 µM). The results show that CSC-6 specifically binds NLRP3 and inhibits NLRP3 activation by blocking ASC oligomerization during NLRP3 assembly. In vivo experiments have demonstrated that CSC-6 effectively reduces the symptoms of NLRP3 overactivation-mediated sepsis and Gout in mouse models. Importantly, CSC-6 has lower cytotoxicity and exhibits better stability in human-derived liver microsomes, which is more favorable for the drug to maintain its efficacy in vivo for longer. The discovery of CSC-6 may contribute to the design and discovery of related NLRP3 inhibitors.

Aptasensor for Mycobacterium tuberculosis antigen MPT64 detection using anthraquinone derivative confined in ordered mesoporous carbon as a new redox nanoprobe.

Rapid and sensitive tuberculosis (TB) diagnoses remain big challenges to current detection tools. In this work, a sensitive electrochemical aptasensor was constructed for the determination of Mycobacterium tuberculosis antigen MPT64 using a new redox nanoprobe. We found that anthraquinone derivative, anthraquinone-2-carboxylic acid (AQCA), a redox mediator, could be confined in ordered mesoporous carbon material of CMK-3. Due to the large loading amount of AQCA, as well as the confined space and electron transfer promotion effect of CMK-3, the obtained AQCA/CMK-3 nanohybrid with mass ratio of 2:1 showed excellent electroactivity and was employed as a new redox nanoprobe for signal amplification for the first time. Additionally, urchin-like Ce-MOFs were used to load a large amount of deposited gold nanocrystals (dep-Au), leading to dense immobilization of capture probe. The proposed electrochemical aptasensor for MPT64 detection showed a good linear relationship in the range from 100 fg/mL to 10 ng/mL with a low detection limit of 67.6 fg/mL. Besides, the aptasensor was utilized to detect MTP64 in human serum samples for TB diagnosis and presented satisfactory results.

Discovery of 9,11-Seco-Cholesterol Derivatives as Novel FXR Antagonists.

The farnesoid X receptor (FXR) plays an important role in the regulation of bile acid, lipid, and glucose homeostasis. Recent findings have shown that the inhibition of FXR is beneficial to improvement of related metabolic diseases and cholestasis. In the present work, 9,11-seco-cholesterol derivatives were designed and synthesized by cleaving the C ring of cholesterol and were identified as novel structures of FXR antagonists. Compound 9a displayed the best FXR antagonistic activity at the cellular level (IC50 = 4.6 µM) and decreased the expression of the target genes of FXR in vivo.

Design and Simulation of Air-Breathing Micro Direct Methanol Fuel Cells with Different Anode Flow Fields.

The design of the anode flow field is critical for yielding better performance of micro direct methanol fuel cells (µDMFCs). In this work, the effect of different flow fields on cell performance was investigated by the simulation method. Compared with grid, parallel and double-serpentine flow fields, a single-serpentine flow field can better improve the mass transfer efficiency of methanol and the emission efficiency of the carbon dioxide by-product. The opening ratio and channel length also have important effects on the cell performance. The cells were manufactured using silicon-based micro-electro-mechanical system (MEMS) technologies and tested to verify the simulation results. The experimental results show that the single-serpentine flow field represents a higher peak power density (16.83 mWcm-2) than other flow fields. Moreover, the results show that an open ratio of 47.3% and a channel length of 63.5 mm are the optimal parameters for the single-serpentine flow field.

An Ergonomic Assessment of Different Postures and Children Risk during Evacuations.

Crawling is recommended for avoiding high heat and toxic fumes and for obtaining more breathable air during evacuations. Few studies have evaluated the effects of crawling on physical joints and velocity, especially in children. Based on motion capture technology, this study proposes a novel method of using wearable sensors to collect exposure (e.g., mean duration, frequency) on children's joints to objectively quantify the impacts of different locomotion methods on physical characteristics. An on-site experiment was conducted in a kindergarten with 28 children (13 boys and 15 girls) of different ages (4-6 years old) who traveled up to 22 m in three different postures: upright walking (UW), stoop walking (SW), and knee and hand crawling (KHC). The results showed that: (1) The level of joint fatigue for KHC was heavier than bipedal walking (p < 0.05), which was evidenced by higher mean duration and frequency. There was no significant difference between UW and SW (p > 0.05). (2) The physical characteristics of the children in the different postures observed in this study were different (p < 0.05). The ankle was more fatigued than other joints during bipedal walking. Unlike infants, the wrists and hips of the children became fatigued while crawling. The key actions flexion/extension are more likely to induce joint fatigue vs. other actions. (3) Crawling velocity was significantly slower than the bipedal velocities, and UW was 10.6% faster than SW (p < 0.05). The bipedal walking velocity started to decrease after the children had travelled up to 13 m, while the KHC velocity started to decrease after traveling up to 11.6 m. (4) In a severe fire, the adoption of SW is suggested, as the evacuees can both evacuate quickly and avoid overworking their joints. (5) There were no significant differences in the age (p > 0.05) and gender (p > 0.05) of the children on the joints in any of the three postures. To conclude, KHC causes more damage to body joints compared to bipedal walking, as evidenced by higher exposure (mean duration, frequency), whereas UW and SW are similar in terms of the level of joint fatigue. The above findings are expected to provide a useful reference for future applications in the children's risk assessment and in the prevention design of buildings.

A Trilaminar-Catalytic Layered MEA Structure for a Passive Micro-Direct Methanol Fuel Cell.

A membrane electrode assembly (MEA) with a novel trilaminar-catalytic layered structure was designed and fabricated for a micro-direct methanol fuel cell (µ-DMFC). The trilaminar-catalytic layer comprises three porous layers. The medial layer has a lower porosity than the inner and outer layers. The simulation results predicted a lower water content and a higher oxygen concentration in the trilaminar-catalytic layer. The novel trilaminar-catalytic layer enhanced the back diffusion of water from the cathode to the anode, which reduces methanol crossover and improves oxygen mass transportation. The electrochemical results of the half-cell test indicate that the novel MEA has a greatly increased cathode polarization and a slightly increased anode polarization. Thus, this novel µ-DMFC structure has a higher power density and a longer discharging time, and hence may be used in portable systems.

Effects of Different Staircase Design Factors on Evacuation of Children from Kindergarten Buildings Analyzed via Agent-Based Simulation.

Staircase design is critical to the evacuation of children. Through an agent-based simulation, this study focused on the relationship between staircase design factors and evacuation efficiency in a multi-story kindergarten. A quantitative study was conducted on three critical architectural design factors: stair flight width, positional relationship, and design pattern of the juncture between the staircase and the corridor. The findings were as follows. (1) When the stair flight width ranges from 0.7 to 1.0 m, an increase in this width can improve evacuation efficiency significantly; when the width ranges from 1.1 to 1.4 m, evacuation efficiency is improved continuously, but an increase in this width range has a diminishing effect on evacuation efficiency; when the width is greater than 1.7 m, a further increase has an adverse effect on evacuation efficiency, because such a staircase space allows overtaking behaviors. (2) Under the same stair flight width conditions, evacuation efficiency is higher when the staircase and corridor are perpendicular to each other than when they are parallel, because the natural steering angle of the children was preserved during their evacuation. (3) The cut corner and rounded corner designs between the staircase and corridor improved evacuation efficiency and alleviated the congestion at bottleneck positions; the evacuation efficiency continued to rise with an increase in the cutting angle. These findings are expected to provide a useful reference for the evacuation design of kindergarten buildings and for emergency evacuation management.

The Relationship between Different Types of Alarm Sounds and Children's Perceived Risk Based on Their Physiological Responses.

Due to differences in cognitive ability and physiological development, the evacuation characteristics of children are different from those of adults. This study proposes a novel method of using wearable sensors to collect data (e.g., electrodermal activity, EDA; heart rate variability, HRV) on children's physiological responses, and to continuously and quantitatively evaluate the effects of different types of alarm sounds during the evacuation of children. In order to determine the optimum alarm for children, an on-site experiment was conducted in a kindergarten to collect physiological data for responses to different types of alarm sounds during the evacuation of 42 children of different ages. The results showed that: (1) The alarm sounds led to changes in physiological indicators of children aged 3-6 years, and the effects of different types of alarm sounds on EDA and HRV activities were significantly different (p < 0.05). Skin conductance (SC), skin conductance tonic (SCT) and skin conductance level (SCL) can be used as the main indicators for analysing EDA of children in this experiment (p < 0.05), and the indicators of ultralow frequency (ULF) and very low frequency (VLF) for HRV were not affected by the type of alarm sounds (p > 0.05). (2) Unlike adults, kindergarten children were more susceptible to the warning siren. The combined voice and warning alarm had optimal effects in stimulating children to perceive risk. (3) For children aged 3-6 years, gender had a significant impact on children's reception to evacuation sound signals (p < 0.05): Girls are more sensitive than boys in receiving evacuation sound signals, similar to findings of studies of risk perception of adult males and females. In addition, the higher the age, the greater the sensitivity to evacuation sound signals, which accords with results of previous studies on the evacuation dynamics of children.

Multi-View Maximum Entropy Clustering by Jointly Leveraging Inter-View Collaborations and Intra-View-Weighted Attributes.

As a dedicated countermeasure for heterogeneous multi-view data, multi-view clustering is currently a hot topic in machine learning. However, many existing methods either neglect the effective collaborations among views during clustering or do not distinguish the respective importance of attributes in views, instead treating them equivalently. Motivated by such challenges, based on maximum entropy clustering (MEC), two specialized criteria-inter-view collaborative learning (IEVCL) and intra-view-weighted attributes (IAVWA)-are first devised as the bases. Then, by organically incorporating IEVCL and IAVWA into the formulation of classic MEC, a novel, collaborative multi-view clustering model and the matching algorithm referred to as the view-collaborative, attribute-weighted MEC (VC-AW-MEC) are proposed. The significance of our efforts is three-fold: 1) both IEVCL and IAVWA are dedicatedly devised based on MEC so that the proposed VC-AW-MEC is qualified to effectively handle as many multi-view data scenes as possible; 2) IEVCL is competent in seeking the consensus across all involved views throughout clustering, whereas IAVWA is capable of adaptively discriminating the individual impact regarding the attributes within each view; and 3) benefiting from jointly leveraging IEVCL and IAVWA, compared with some existing state-of-the-art approaches, the proposed VC-AW-MEC algorithm generally exhibits preferable clustering effectiveness and stability on heterogeneous multi-view data. Our efforts have been verified in many synthetic or real-world multi-view data scenes.

Down-regulation of Rictor enhances cell sensitivity to PI3K inhibitor LY294002 by blocking mTORC2-medicated phosphorylation of Akt/PRAS40 in esophageal squamous cell carcinoma.

PI3K/Akt/mTOR signaling pathway plays a vital role in regulating cell survival, differentiation, metabolism and migration, which is frequently hyperactive in a number of cancers, including esophageal squamous cell carcinoma (ESCC). As the core subunit of mTORC2, Rictor is shown to be amplified in ESCC patients' tissues and plays an important role in regulation of Akt. The objective of this study is to evaluate the effects of Rictor knockdown on cell sensitivity to PI3K inhibitor LY294002 in ESCC cells and ESCC xenografts as well as its mechanisms. We found LY294002 obviously restrained cell proliferation in dose-dependent and time-dependent manners by inhibiting PI3K/Akt/mTOR/p70S6K signaling pathway, whereas triggered mTORC2-medicated phosphorylation of Akt (Ser473)/PRAS40 (Thr246) in ECa109 and EC9706 cells. Stable knockdown of Rictor by shRNA enhanced the inhibitory effects of LY294002 on cell proliferative, migration and colony formation, as well as promoted its effects on cell cycle arrest and cell apoptosis in vitro. Furthermore, stable knockdown of Rictor enhanced the antitumor effects of LY294002 by inhibiting tumor growth and promoting cell apoptosis in vivo. Mechanistic assay revealed that knockdown of Rictor could attenuate LY294002-induced phosphorylation of Akt (Ser473)/PRAS40 (Thr246). Our results provide rationale that combined inhibition of Rictor/mTORC2 and PI3K for the treatment of ESCC.