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Background: Electronic cigarette (e-cig) vaping has increased in the past decade in the US, and e-cig use is misleadingly marketed as a safe cessation for quitting smoking. The main constituents in e-liquid are humectants, such as propylene glycol (PG) and vegetable glycerine (VG), but different flavoring chemicals are also used. However, the toxicology profile of flavored e-cigs in the pulmonary tract is lacking. We hypothesized that menthol and tobacco-flavored e-cig (nicotine-free) exposure results in inflammatory responses and dysregulated repair in lung fibroblast and epithelium. Method: We exposed lung fibroblast (HFL-1) and epithelium (BEAS-2B) to Air, PG/VG, menthol flavored, or tobacco-flavored e-cig, and determined the cytotoxicity, inflammation, and wound healing ability in 2D cells and 3D microtissue chip models. Results: After exposure, HFL-1 showed decreased cell number with increased IL-8 levels in the tobacco flavor group compared to air. BEAS-2B also showed increased IL-8 secretion after PG/VG and tobacco flavor exposure, while menthol flavor exposure showed no change. Both menthol and tobacco-flavored e-cig exposure showed decreased protein abundance of type 1 collagen α 1 (COL1A1), α-smooth-muscle actin (αSMA), and fibronectin as well as decreased gene expression level of αSMA (Acta2) in HFL-1. After tobacco flavor e-cig exposure, HFL-1 mediated wound healing and tissue contractility were inhibited. Furthermore, BEAS-2B exposed to menthol flavor showed significantly decreased tight junction gene expressions, such as CDH1, OCLN, and TJP1. Conclusion: Overall, tobacco-flavored e-cig exposure induces inflammation in both epithelium and fibroblasts, and tobacco-flavored e-cig inhibits wound healing ability in fibroblasts. [ABSTRACT FROM AUTHOR]

Quick Access Recorders (QARs) provide an important data source for Flight Operation Quality Assurance (FOQA) and flight safety. It is generally characterized by large volume, high-dimensionality and high frequency, and these features result in extreme complexities and uncertainties in its usage and comprehension. In this study, we proposed a Time-Feature Attention (TFA)-based Convolutional Auto-Encoder (TFA-CAE) network model to extract essential flight features from QAR data. As a case study, we used the QAR data landing at the Kunming Changshui International Airport and Lhasa Gonggar International Airport as the experimental data. The results show that (1) the TFA-CAE model performs the best in extracting representative flight features in comparison to some traditional or similar approaches, such as Principal Component Analysis (PCA), Convolutional Auto-Encoder (CAE), Self-Attention-based CAE (SA-CAE), Gate Recurrent Unit based Auto-Encoder (GRU-AE) and TFA-GRU-AE models; (2) flight patterns corresponding to different runways can be recognized; and (3) anomalous flights can effectively deviate from many observations. Overall, the TFA-CAE model provides a well-established technique for further usage of QAR data, such as flight risk detection or FOQA. [ABSTRACT FROM AUTHOR]

Covalent organic framework (COF) membranes show great potential for gas separation, but their large pore size make it hard to effectively separate gases with similar kinetic diameters. A promising strategy is to cover the surface of COF membranes with an ultrathin film of ionic liquids (ILs) to improve the selectivity of gas permeation. Here, we investigated the CO 2 /CH 4 separation performance of composite membranes composed of COF (CTF-1) and 20 kinds of ILs, respectively, using molecular simulations. The [C 4 mim][PF 6 ]/COF membrane is found to exhibit the best separation performance, with CO 2 permeability up to 7.93 × 104 GPU and CO 2 /CH 4 selectivity of 12.33 when the IL thickness is 8 Å. By studying the microstructure of the composite membrane, it was found that there is a relatively dispersed distribution of cations and anions on the COF surface, which is beneficial to the diffusion of gas molecules. The gas permeation process results reveal that CO 2 rapidly achieves equilibrium in both the adsorption and dissolution layers simultaneously, thereby enhancing the permeation rate of gas molecules. The analysis of interaction energy and PMF indicates that the improved selectivity is due to the stronger interaction between IL and CO 2 than that for CH 4. [Display omitted] • 20 types of ultrathin IL-covered COF membranes for separating CO 2 /CH 4 were proposed. • [C 4 mim][PF 6 ]/COF membrane exhibits the highest separation performance. • The dispersed and uniform ionic distribution on the COF surface permits rapid gas diffusion. • The stronger IL-CO 2 interaction compared to CH 4 enhances selectivity. [ABSTRACT FROM AUTHOR]

Mitochondrial quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase during mitophagy. The exact mechanism that operates the interaction of Miro1 with mitophagy machinery and their role in cigarette smoke (CS)-induced mitochondrial dysfunction that often results in lung inflammation is unclear. We hypothesized that Miro1 plays an important role in regulating mitophagy machinery and the resulting lung inflammation by CS exposure to mice. The lung epithelial Rhot1fl/fl (WT) and Rhot1CreCC10 mice were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils that are associated with inflammatory mediators. Chronic exposure showed increased infiltration of neutrophils versus air controls. The effects of acute and chronic CS exposure were augmented in the Rhot1CreCC10 group, indicating that epithelial Miro1 ablation led to the augmentation of inflammatory cell infiltration with alteration in the inflammatory mediators. Thus, Rhot1/Miro1 plays an important role in regulating CS-induced lung inflammatory responses with implications in mitochondrial quality control. [ABSTRACT FROM AUTHOR]

Unlike standalone embedded devices, behaviors of a cyber-physical system (CPS) are highly dynamic. Many parameter values (e.g., those related to nature environment and third party black box functions) are unknown offline. Furthermore, distributed sub-CPSs may exchange data online. In this article, we first propose the concept of parametric hybrid automata (PHA) to describe such complex CPSs. As some PHA parameter values are unknown until runtime, conventional offline model checking is infeasible. Instead, we propose to carry out PHA model checking online, as a fault prediction mechanism. However, this usage is challenged by the high time cost of state reachability verification, which is the conventional focus of model checking. To address this challenge, we propose that the model checking shall focus on online scenario reachability validation instead. Furthermore, we propose a mechanism to compose/decompose scenarios. Our scenario reachability validation can exploit linear programming to achieve polynomial time cost. Evaluations on a state-of-the-art train control system show that our approach can cut online model checking time cost from over 1 h to within 200 ms. [ABSTRACT FROM AUTHOR]

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner. [ABSTRACT FROM AUTHOR]

Nicotine inhalation via electronic cigarettes (e‐cigs) is an emerging concern. However, little is known about the acute toxicity in the lungs following inhalation of nicotine‐containing e‐cig aerosols. We hypothesized that acute exposure to aerosolized nicotine causes lung toxicity by eliciting inflammatory and dysregulated repair responses. Adult C57BL/6J mice were exposed 2 hours daily for 3 days to e‐cig aerosols containing propylene glycol (PG) with or without nicotine. Acute exposure to nicotine‐containing e‐cig aerosols induced inflammatory cell influx (neutrophils and CD8a+ T lymphocytes), and release of pro‐inflammatory cytokines in bronchoalveolar lavage fluid in a sex‐dependent manner. Inhalation of e‐cig aerosol containing PG alone significantly augmented the lung levels of various homeostasis/repair mediators (PPARγ, ADRP, ACTA2, CTNNB1, LEF1, β‐catenin, E‐cadherin, and MMP2) in a sex‐dependent manner when compared to air controls. These findings were accompanied by an increase in protein abundance and altered gene expression of lipogenic markers (PPARγ, ADRP) and myogenic markers (fibronectin, α‐smooth muscle actin and β‐catenin), suggesting a dysregulated repair response in mouse lungs. Furthermore, exposure to nicotine‐containing e‐cig aerosols or PG alone differentially affected the release of pro‐inflammatory cytokines in healthy and COPD human 3D EpiAirway tissues. Overall, acute exposure to nicotine‐containing e‐cig aerosols was sufficient to elicit a pro‐inflammatory response and altered mRNA and protein levels of myogenic, lipogenic, and extracellular matrix markers in mouse lung in a sex‐dependent manner. Thus, acute exposure to inhaled nicotine via e‐cig leads to dysregulated repair and inflammatory responses, which may lead to airway remodeling in the lungs. [ABSTRACT FROM AUTHOR]

Background: Disulfidptosis and the disulfidptosis-related gene SLC7A11 have recently attracted significant attention for their role in tumorigenesis and tumour management. However, its association with adrenocortical carcinoma (ACC) is rarely discussed. Methods: Differential analysis, Cox regression analysis, and survival analysis were used to screen for the hub gene SLC7A11 in the TCGA and GTEx databases and disulfidptosis-related gene sets. Then, we performed an association analysis between SLC7A11 and clinically relevant factors in ACC patients. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic value of SLC7A11 and clinically relevant factors. Weighted gene coexpression analysis was used to find genes associated with SLC7A11. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and the LinkedOmics database were used to analyse the functions of SLC7A11-associated genes. The CIBERSORT and Xcell algorithms were used to analyse the relationship between SLC7A11 and immune cell infiltration in ACC. The TISIDB database was applied to search for the correlation between SLC7A11 expression and immune chemokines. In addition, we performed a correlation analysis for SLC7A11 expression and tumour mutational burden and immune checkpoint-related genes and assessed drug sensitivity based on SLC7A11 expression. Immunohistochemistry and RT‒qPCR were used to validate the upregulation of SLC7A11 in the ACC. Results: SLC7A11 is highly expressed in multiple urological tumours, including ACC. SLC7A11 expression is strongly associated with clinically relevant factors (M-stage and MYL6 expression) in ACC. SLC7A11 and the constructed nomogram can accurately predict ACC patient outcomes. The functions of SLC7A11 and its closely related genes are tightly associated with the occurrence of disulfidptosis in ACC. SLC7A11 expression was tightly associated with various immune cell infiltration disorders in the ACC tumour microenvironment (TME). It was positively correlated with the expression of immune chemokines (CXCL8, CXCL3, and CCL20) and negatively correlated with the expression of immune chemokines (CXCL17 and CCL14). SLC7A11 expression was positively associated with the expression of immune checkpoint genes (NRP1, TNFSF4, TNFRSF9, and CD276) and tumour mutation burden. The expression level of SLC7A11 in ACC patients is closely associated withcthe drug sensitivity. Conclusion: In ACC, high expression of SLC7A11 is associated with migration, invasion, drug sensitivity, immune infiltration disorders, and poor prognosis, and its induction of disulfidptosis is a promising target for the treatment of ACC. [ABSTRACT FROM AUTHOR]

A wireless electrocardiogram case study suggests that current CDMA2000 cellular technology has considerable potential in medical telemetry. Modifications to the network protocol stack ensure the highest data integrity and lowest service delay. [ABSTRACT FROM PUBLISHER]

Global Positioning System (GPS) stations installed in and around the epicenter of the Lushan earthquake (Mw 6.7), which occurred almost 5 years after the 2008 Wenchuan earthquake, recorded preseismic deformation corresponding to the Lushan earthquake within the southern Longmenshan thrust belt. A half-space dislocation model is used to simulate the theoretical values of the postseismic displacements caused by the 2008 Wenchuan earthquake, and after transforming the reference frame and filtering the GPS displacement time series, the theoretical and observed GPS values are compared to identify the geodetic anomaly preceding the Lushan earthquake. The abnormal extent of this geodetic anomaly decreases with increasing epicentral distance for each GPS site. This geodetic signal reflects preslip along a locked section of the 2013 seismogenic fault, which caused the accumulation of elastic strain energy until the faulting strength was overcome, thereby generating the Lushan earthquake. Hence, this anomaly might be used as an observable and identifiable precursor to forecast an impending earthquake within a period of less than two and half years before its occurrence. [ABSTRACT FROM AUTHOR]

Glycyrrhetinic acid (GA) shows great efficiency against non-small cell lung cancer (NSCLC), but the detailed mechanism is unclear, which has limited its clinical application. Herein, we investigated the potential targets of GA against NSCLC by activity-based protein profiling (ABPP) technology and the combination of histopathology and proteomics validation. In vitro and in vivo results indicated GA significantly inhibited NSCLC via promotion of peroxiredoxin-6 (Prdx6) and caspase-3 (Casp3)-mediated mitochondrial apoptosis. This original finding will provide theoretical and data support to improve the treatment of NSCLC with the application of GA. [Display omitted] • First-time integrated analysis profiling of non-small cell lung cancer (NSCLC) and Glycyrrhetinic acid (GA) treatment by integrating activity-based protein profiling (ABPP) technology, histopathology and proteomics validation both in vitro and in vivo. • Identification of GA promoted ROS accumulation and inhibited proliferation of NSCLC cells. • Identification of Casp3 and Prdx6 were direct target proteins of GA in the treatment of NSCLC cells. [ABSTRACT FROM AUTHOR]

Objective: To determine the pharmacodynamic mechanism underlying Cordyceps sinensis relief in a murine model of non-small cell lung cancer (NSCLC). Methods: We created a murine model of NSCLC and studied the potential molecular mechanism by which C. sinensis relieved NSCLC using a combination of transcriptomics, proteomics, and experimental validation. Results: C. sinensis markedly suppressed the fluorescence values in mice with NSCLC, improved the pathologic morphology of lung tissue, ameliorated inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and the oxidative stress indicators superoxide dismutase, malondialdehyde, and glutathione peroxidase). Transcriptomics results showed that the therapeutic effect of C. sinensis was primarily involved in the differentiation and activation of T cells. Based on the proteomic results, C. sinensis likely exerted a protective effect by recruiting immune cells and suppressing tumor cell proliferation via the MAPK pathway. Finally, the experimental validation results indicated that C. sinensis significantly decreased the VEGF and Ki67 expression, downregulated RhoA, Raf-1, and c-fos expression, which are related to cell migration and invasion, increased the serum concentration of hematopoietic factors (EPO and GM-CSF), and improved the percentage of immune cells (natural killer cells, dendritic cells, and CD4+ and CD8+ lymphocytes), which enhanced immune function. Conclusions: Based on our preclinical study, C. sinensis was shown to exert a protective effect on NSCLC, primarily by inhibiting the MAPK pathway. [ABSTRACT FROM AUTHOR]

Until the Mw 6.6 Luding earthquake ruptured the Moxi section of the Xianshuihe fault (XSHF) on 5 September 2022, the region had not experienced an Mw >6 earthquake since instrumental records began. We used Global Positioning System (GPS) and Sentinel-1 interferometric synthetic aperture radar (InSAR) observations to image the coseismic deformation and constrain the location and geometry of the seismogenic fault using a Bayesian method We then present a distributed slip model of the 2022 Mw6.6 Luding earthquake, a left-lateral strike-slip earthquake that occurred on the Moxi section of the Xianshuihe fault in the southwest Sichuan basin, China. Two tracks (T26 and T135) of the InSAR data captured a part of the coseismic surface deformation with the line-of-sight displacements range from ∼−0.16 m to ~0.14 m in the ascending track and from ~−0.12 m to ~0.10 m in the descending track. The inverted best-fitting fault model shows a pure sinistral strike-slip motion on a west-dipping fault plane with a strike of 164.3°. We adopt a variational Bayesian approach and account for the uncertainties in the fault geometry to retrieve the distributed slip model. The inverted result shows that the maximum slip of ~1.82 m occurred at a depth of 5.3 km, with the major slip concentrated within depths ranging from 0.9–11 km. The InSAR-determined moment is 1.3 × 1019 Nm, with a shear modulus of 30 GPa, equivalent to Mw 6.7. The published coseismic slip models of the 2022 Luding earthquake show apparent differences despite the use of similar geodetic or seismic observations. These variations underscore the uncertainty associated with routinely performed source inversions and their interpretations for the underlying fault model. [ABSTRACT FROM AUTHOR]

The use of emerging tobacco products, such as waterpipe or hookah and electronic cigarettes (e-cigs), has gained significant popularity and are promoted as safer alternatives to conventional cigarettes. Circadian systems are internal biological oscillations that are considered important regulators of immune functions in mammals. Tobacco induced inflammatory lung diseases frequently exhibit time-of-day/night variation in lung function and symptom severity. We investigated the impact of inhaled e-cig vapor and waterpipe smoke (WPS) on pulmonary circadian molecular clock disruption by determining the changes in expression levels and abundance of core clock component genes (BMAL1, CLOCK) and clock-controlled output genes (Rev-erbα, Per2, Rev-erbβ, Cry2, Rorα) in mouse lungs. We showed that the expression levels of these pulmonary core clock genes and clock-controlled output genes were altered significantly following exposure to WPS (Bmal1, Clock, and Rev-erbα). We further showed a significant yet differential effect on expression levels of core clock and clock-controlled genes (Bmal1, Per2) in the lungs of mice exposed to e-cig vapor containing nicotine. Thus, acute exposure to WPS and e-cig vapor containing nicotine contributes to altered expression of circadian molecular clock genes in mouse lungs, which may have repercussions on lung cellular and biological functions. [ABSTRACT FROM AUTHOR]

Networked robotics are a typical cyber–physical system (CPS). This paper presents the cyber physical interaction model to perform formation control and tracking in the presence of other robots and static obstacles. It discusses how such a model can be effectively utilized to deal with kinodynamic and operation range constraints. The cyber system is also responsible for feasible trajectory generation based upon regional path segments and to ensure that all the robots maneuver through obstacles in a safe manner. The introduction of virtual robot restructures the formation control problem into a tracking control problem between virtual reference robot and follower robots. A novel obstacle avoidance approach is proposed based upon the scaling of whole (partial) formation corresponding to centralized (distributed) framework. The involved CPS has network structure preserving properties that are key to effective distributed decision making. The novel formation control, obstacle avoidance, and trajectory tracking approaches facilitate networked robots to be effectively controlled through the cyber system. We also discuss efficient and optimal implementation of the proposed trajectory generator using computer-aided design for CPSs. Evaluation of the proposed approach is provided that demonstrate the formation control, trajectory tracking, and obstacle avoidance for multirobots using the proposed scheme. [ABSTRACT FROM AUTHOR]

Cyber-Physical Systems (CPS) integrate discrete-time computing and continuous-time physical-world entities, which are often wirelessly interlinked. The use of wireless safety-critical CPS requires safety guarantees despite communication faults. This paper focuses on one important set of such safety rules: Proper-Temporal-Embedding (PTE), where distributed CPS entities must enter/leave risky states according to properly nested temporal pattern and certain duration spacing. Our solution introduces hybrid automata to formally describe and analyze CPS design patterns. We propose a novel leasing based design pattern, along with closed-form configuration constraints, to guarantee PTE safety rules under arbitrary wireless communication faults. We propose a formal procedure to transform the design pattern hybrid automata into specific wireless CPS designs. This procedure can effectively isolate physical world parameters from affecting the PTE safety of the resultant specific designs. We conduct two wireless CPS case studies, one on medicine and the other on control, to show that the resulted system is safe against communication failures. We also compare our approach with a polling based approach. Both approaches support PTE under arbitrary communication failures. The polling approach performs better under severely adverse wireless medium conditions; while ours performs better under benign or moderately adverse wireless medium conditions. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations.Methods: KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic-pharmacodynamic correlations and the mechanism of actions driving drug combination synergy.Results: In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449.Conclusions: Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK+ NSCLC refractory to earlier-generation ALK inhibitors.Trial Registration: Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019). [ABSTRACT FROM AUTHOR]

Hybrid systems model checking is a great success in guaranteeing the safety of computerized control cyber-physical systems (CPS). However, when applying hybrid systems model checking to Medical Device Plug-and-Play (MDPnP) CPS, we encounter two challenges due to the complexity of human body: 1) there are no good offline differential equation-based models for many human body parameters; 2) the complexity of human body can result in many variables, complicating the system model. In an attempt to address the challenges, we propose to alter the traditional approach of offline hybrid systems model checking of time-unbounded (i.e., infinite horizon, a.k.a., long run) future behavior to online hybrid systems model checking of time-bounded (i.e., finite horizon, a.k.a., short run) future behavior. According to this proposal, online model checking runs as a real-time task to prevent faults. To meet the real-time requirements, certain design patterns must be followed, which brings up the codesign issue. We propose two sets of system codesign patterns for hard real time and soft real time, respectively. To evaluate our proposals, a case study on laser tracheotomy MDPnP is carried out. The study shows the necessity of online model checking. Furthermore, test results based on real-world human subject trace show the feasibility and effectiveness of our proposed codesign. [ABSTRACT FROM AUTHOR]

[Display omitted] • The monolayer nanoporous graphene oxide supported ionic liquid membrane was proposed. • The NPGO-[EMIM][TF 2 N] membrane has a CO 2 permeance of ∼104 GPU and no CH 4 passed with 11 Å thickness. • The cations are suspended above the pore center to dynamically modulate the pore size. • The enhanced selectivity is attributed to the synergistic effect of cations and anions. Nanoporous graphene oxide (NPGO) with a single atomic layer thickness and good mechanical strength has been regarded as a promising candidate in gas separation. However, it is challenging to precisely control the pore size to match the target gas. In this work, the pore size was modulated by supporting ionic liquid (IL) on the monolayer NPGO membrane (NPGO-SILM). The separation performance and mechanism for CO 2 /CH 4 in NPGO-[EMIM][BF 4 ], NPGO-[EMIM][PF 6 ] and NPGO-[EMIM][TF 2 N] were investigated by molecular dynamics simulation. It was found that the pore size of NPGO greatly affects the permeability and selectivity, and 5.6 Å is the most suitable pore size. After coating IL on NPGO, the CO 2 /CH 4 selectivity is obviously enhanced. With the IL thickness increasing from 5 to 11 Å, the CO 2 permeance decreased from ∼105 to ∼104 GPU, while the selectivity increased, and almost no CH 4 passed through the membrane with 11 Å thickness. Among the studied three types of ILs, the NPGO-[EMIM][TF 2 N] membrane shows the best CO 2 /CH 4 separation performance due to the strongest adsorption capacity between [TF 2 N] anion and CO 2. The interaction energy, PMF and probability distribution results suggest that the improved selectivity is attributed to the synergistic effect of cations and anions. The anions are responsible for the adsorption of large amounts of CO 2. At the same time, the cations are mainly distributed around the center of the NPGO pore because of the strong interaction between cation and NPGO, which would be favorable for dynamically adjusting pore size to allow the passage of CO 2 and prevent CH 4 from passing through the membrane. [ABSTRACT FROM AUTHOR]

The Pearl River Delta Economic Zone is one of the fastest growing areas of China's social and economic development. However, the contradiction between people and land, the deterioration of ecological environment and the damage of urban ecological security have become more serious problems. In previous studies there was single land utilization type in small-area and the evaluation method was not suitable to large areas, this study proposes a new method. Firstly, the study implements ecological land zoning from assessing the importance of ecosystem services functional in four aspects: biodiversity, water conservation, soil conservation and coastal protected zone. Then, the suitability evaluation index system of agricultural and construction land is established from the geological environment perspective, and introduces variable weight-analytical hierarchy process-comprehensive index model to evaluate the suitability of agricultural land and construction land. Re-zoning the type of land that has a special effect on the socio-economic, the mining land, protected area of geological relics and groundwater resources, respectively. Finally, considering the actual condition use status and suitability distribution of land, the results of comprehensive zoning of land utilization is got. The results of this study can provide some geological basis for the future land utilization zoning. [ABSTRACT FROM AUTHOR]

Flavored tobacco products are increasing in popularity but remain unregulated, with the exception of the ban on flavored conventional cigarettes. Lack of regulation of cigarillos and little cigars allows vendors to have their own version of popular flavors, each with different chemical components. A new classification system was created for flavored cigars in order to easily communicate our results with the scientific community. To understand the physicochemical characteristics of flavored little cigars and cigarillo smoke, size distribution and concentration of particulate matter in smoke were determined. Acellular reactive oxygen species generation was measured as an indirect measurement of the potential to cause oxidative stress in cells. In addition, cigarillo smoke extract treatment on bronchial epithelial (Beas-2b) cells were assessed to determine the flavor-induced cellular toxicity. Flavored cigars/cigarillos showed significant variability in the tested parameters between flavors as well as brands of the same flavor, but most of the cigars showed higher potential of generating oxidative stress, than research grade cigarettes. Flavored cigars produced maximum particle concentrations at 1.0μm and 4.0 μm compared with 3R4F reference research cigarettes. A differential cytotoxic response was observed with cigarillo smoke extract treatments, with "fruits/candy" and "drinks" being the most toxic, but were not more cytotoxic than smoke from cigarettes. These cigarillos with flavors must be well characterized for toxicity in order to prevent adverse effects caused by exposure to flavor chemicals. Our study provides insight into understanding the potential health effects of flavor-infused cigars/cigarillos and the need for the regulation of those flavoring chemicals in these products. Future research is directed to determine the flavoring toxicity of little cigars and cigarillos in vivo studies. [ABSTRACT FROM AUTHOR]

The mechanisms of tectonic transfer and strain partitioning at the eastern termination of the Kunlun fault system, particularly the role of the relatively strong Ruoergai Subblock, remain unclear. In this work, we used the finite element method to determine how the Ruoergai Subblock affects regional deformation. The results show that the Ruoergai Subblock is moving to the east or northeast in a manner that differs from the motion of the Bayan Har Block in the eastward extrusion process and thus accounts for the formation and behavior of the Awancang and Longriba faults. In addition, strain partitioning on the eastern margin of the Tibetan Plateau is progressively transferring from the Awancang fault, Ruoergai Subblock, and Longriba fault to the Longmenshan thrust. In this study, a block-controlled pattern is proposed that accounts for the distribution and behavior of most of the faults on the northern and eastern margins of the Tibetan Plateau. Our study has played a certain reference role in the consideration of railway fracture resistance parameters in the area of the southern section of the Longmenshan fault and the Xianshuihe fault during construction of the Tibet Railway. • Influence of Subblock in the consideration of Tibet railway fracture resistance parameters. • Tectonic partitioning near the eastern margin of the Tibetan Plateau. • Influence of the Ruoergai Subblock's physical properties on tectonics. • Strong block control on fault formation and behavior. [ABSTRACT FROM AUTHOR]

The Sichuan-Tibet Railway in eastern Tibet runs across numerous seismogenic faults with high seismic risks. The Lancangjiang fault (LCJF), one of the essential strike-slip faults within the Qiangtang block, traverses the railway. However, the geometry and late Quaternary activities of the LCJF remain unclear, limiting the assessment of seismic hazards on the Sichuan-Tibet Railway and the understanding of kinematic patterns in eastern Tibet. Based on the interpretation of high-resolution satellite imagery, field observations, and shallow geophysical exploration, we first mapped the detailed geometry of the northern LCJF. It consists of two branches: Yangda-Yaxu fault (YYF) and Baqing-Leiwuqi fault (BLF), which merge eastwards onto the main LCJF. Displaced landforms and multiple numerical dating techniques reveal that the YYF is a mainly sinistral fault with a late Quaternary slip rate of ~2.2 + 0.6/−0.5 mm/yr and a minor vertical component (~0.1 mm/yr). The BLF undergoes an oblique motion with a left-lateral slip rate of ~1.2 + 0.5/−0.3 mm/yr and a northeast-vergent reverse rate of ~1.2 + 0.4/−0.2 mm/yr in the Holocene. Vector analysis of slip rates suggests that the LCJF has a sinistral rate of ~3.5 + 1.1/−0.8 mm/yr with a reverse component of ~1.6 + 0.4/−0.3 mm/yr, displaying an essential role in strain partitioning of eastern Tibet. Together with slip rates of other intra-block faults, the kinematic pattern of eastern Tibet probably applies to the sub-block model. Offset geologic units yield a total displacement of ~10–11 km for the YYF. Using the slip rate of the YYF, the LCJF was initiated at ~5.9–3.9 Ma, probably related to the establishment of the present-day strain pattern and the onset of crustal thickening in eastern Tibet during the late Miocene. In addition, the active YYF and BLF across the Sichuan-Tibet Railway have a seismic potential of Mw ~7.2–7.3 that will produce a ~ 1.8–2.0 m sinistral slip on the YYF, and a ~ 2.0 m horizontal, and ~ 1.1–1.3 m reverse motion on the BLF. They will pose a high seismic hazard potential on the railway. This study provides quantitative data for regional seismic hazard analysis and shows insights into the deformation mechanism of the plateau. • The geometry of the northern LCJF is first mapped. • The northern LCJF has a late Quaternary ~3.5 mm/yr sinistral and ~ 1.6 mm/yr reverse rate. • The seismic potential of the northern LCJF on the Sichuan-Tibet Railway is estimated. • The LCJF takes an important role in strain partitioning in eastern Tibet. • The initiation of the LCJF is related to the late-Miocene tectonic event in eastern Tibet. [ABSTRACT FROM AUTHOR]

Background: Programmed death-1 (PD-1) immune checkpoint blockade has achieved clinical successes in cancer therapy. However, the response rate of anti-PD-1 agents remains low. Additionally, a subpopulation of patients developed hyperprogressive disease upon PD-1 blockade therapy. Combination therapy with targeted agents may improve immunotherapy. Recent studies show that p53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization, and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may augment antitumor immunity elicited by anti-PD-1 therapy. Method: Using APG-115 that is a MDM2 antagonist in clinical development as a pharmacological p53 activator, we investigated the role of p53 in immune modulation and combination therapy with PD-1 blockade. Results: In vitro treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21, and a decrease in immunosuppressive M2 macrophage population through downregulation of c-Myc and c-Maf. Increased proinflammatory M1 macrophage polarization was observed in the spleen from mice treated with APG-115. Additionally, APG-115 has co-stimulatory activity in T cells and increases PD-L1 expression in tumor cells. In vivo, APG-115 plus anti-PD-1 combination therapy resulted in enhanced antitumor activity in Trp53wt, Trp53mut, and Trp53-deficient (Trp53−/−) syngeneic tumor models. Importantly, such enhanced activity was abolished in a syngeneic tumor model established in Trp53 knockout mice. Despite differential changes in tumor-infiltrating leukocytes (TILs), including the increases in infiltrated cytotoxic CD8+ T cells in Trp53wt tumors and M1 macrophages in Trp53mut tumors, a decrease in the proportion of M2 macrophages consistently occurred in both Trp53wt and Trp53mut tumors upon combination treatment. Conclusion: Our results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53mut tumors. [ABSTRACT FROM AUTHOR]