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ABSTRACT The interaction between coexisting plasmids can affect plasmid-carried resistance gene persistence and spread. However, whether the persistence of the blaCTX-M gene in clinical Enterobacteriaceae is related to the interaction of coresident nonresistance-conferring plasmids has not been reported. This study was initiated to elucidate how a nonresistance-conferring IncI1 plasmid affected the blaCTX-M-bearing IncFII plasmid colocated on the same cell. Herein, we constructed three isogenic derivatives of E. coli C600, designated as C600FII, C600I1, and C600FII+I1, which harbored the blaCTX-M-IncFII plasmid and/or the nonresistance-IncI1 one. We discovered that strain C600FII+I1 conferred higher fitness advantages than strain C600FII; also, the stability of the blaCTX-M-IncFII plasmid was noticeably improved in an antibiotic-free environment when it coexisted with the IncI1 plasmid. To further explore why the IncI1 plasmid enhanced the persistence of the blaCTX-M-IncFII plasmid, we assessed the blaCTX-M-IncFII plasmid's copy numbers, conjugation frequencies, and rep gene expressions in strains C600FII and C600FII+I1. The results demonstrated that the rep expressions of the blaCTX-M-IncFII plasmid in strain C600FII+I1 was greatly decreased, along with the plasmid’s copy numbers and mating efficiencies, compared to those in strain C600FII. Moreover, further study revealed that the intracellular ATP levels of strain C600FII+I1 were far lower than those of strain C600FII. Our findings confirmed that coexistence of the nonresistance-IncI1 plasmid can keep the blaCTX-M-IncFII plasmid more stable by increasing the fitness advantages of the host bacteria, which will pose a threat to preventing the long-term presence of the plasmid-carried blaCTX-M gene in clinical Enterobacteriaceae.IMPORTANCESo far, plasmid-carried blaCTX-M is still the most common extended-spectrum beta-lactamase (ESBL) genotype in clinical settings worldwide. Except for the widespread use of third-generation cephalosporins, the interaction between coexisting plasmids can also affect the long-term stable existence of the blaCTX-M gene; however, the study on that is still sparse. In the present study, we assess the interaction of coinhabitant plasmids blaCTX-M-IncFII and nonresistance-IncI1. Our results confirmed that the increased fitness advantages of strain C600FII+I1 were attributable to the cohabitant nonresistance-IncI1 plasmid, which largely reduced the intracellular ATP levels of host bacteria, thus decreasing the rep gene expression of the blaCTX-M-IncFII plasmid, its copy numbers, and mating efficiencies, while the higher fitness advantages of strain C600FII+I1 enhanced the persistence of the blaCTX-M-IncFII plasmid. The results indicate that the nonresistance-IncI1 plasmid contributes to the long-term existence of the blaCTX-M-IncFII plasmid, implying a potentially new strategy for controlling the spread of resistance plasmids in clinical settings by targeting nonresistance plasmids.

Abstract Background The goal of therapy for many patients with advanced stage malignancies, including those with metastatic gastric and esophageal cancers, is to extend overall survival while also maintaining quality of life. After weighing the risks and benefits of treatment with palliative chemotherapy (PC) with non-curative intent, many patients decide to pursue treatment. It is known that a subset of patients who are treated with PC experience significant side effects without clinically significant survival benefits from PC. Methods We use data from 150 patients with stage-IV gastric and esophageal cancers to train machine learning models that predict whether a patient with stage-IV gastric or esophageal cancers would benefit from PC, in terms of increased survival duration, at very early stages of the treatment. Results Our findings show that machine learning can predict with high accuracy whether a patient will benefit from PC at the time of diagnosis. More accurate predictions can be obtained after only two cycles of PC (i.e., about 4 weeks after diagnosis). The results from this study are promising with regard to potential improvements in quality of life for patients near the end of life and a potential overall survival benefit by optimizing systemic therapy earlier in the treatment course of patients.

Introductions: Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated. Objectives: To identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis. Methods: Chondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested. Results: Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium. Conclusions: Our findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment.

As the largest global carbon pool system, terrestrial ecosystems have an important role to maintain the stability of ecosystems. Human activities affect the structural changes in the ground surface and interfere with terrestrial ecosystem evolution, and consequently, carbon stock is changed in the region. Therefore, forecasting future carbon stock changes under different land use scenarios has important research implications for promoting stable evolution and cycling of terrestrial ecosystems. This study is conducted with the land use data from 2000 to 2020, and incorporates the Patch-generating Land Use Simulation model with the Integrated Valuation of Ecosystem Services and Trade-Offs model to analyze the changes in land use in Hefei, and its influence on the carbon stock in Hefei in various scenarios. During the study period, the mutual conversion between different land types in Hefei City made the land structure change within the study area more significant. The rapidly evolving surface structure is the reason for the decrease of carbon storage in terrestrial ecosystems, with a cumulative decrease of 1.2 × 108 t. The spatial distribution in carbon storage in the study area shows a distribution pattern of low in the north and high in the south. The high carbon storage area is obviously banded in the study area. The area with obvious changes in surface structure has more obvious changes in carbon storage. Compared with the natural development scenario, the downward trend of carbon storage in the ecological protection scenario and the comprehensive development scenario has slowed down due to the restrictions on the structural transformation of land types and the implementation of relevant ecological protection policies. Therefore, this study will support the future management and policy making of Hefei City with the background of China's “double carbon” target and the significant position of Hefei City.

The transition metal iron plays a crucial role in living cells. However, high levels of iron are potentially toxic through the production of reactive oxygen species (ROS), serving as a deterrent to the commensal fungus Candida albicans for colonization in the iron-rich gastrointestinal tract. We observe that the mutant lacking an iron-responsive transcription factor Hap43 is hyper-fit for colonization in murine gut. We demonstrate that high iron specifically triggers multiple post-translational modifications and proteasomal degradation of Hap43, a vital process guaranteeing the precision of intestinal ROS detoxification. Reduced levels of Hap43 de-repress the expression of antioxidant genes and therefore alleviate the deleterious ROS derived from iron metabolism. Our data reveal that Hap43 functions as a negative regulator for oxidative stress adaptation of C. albicans to gut colonization and thereby provide a new insight into understanding the interplay between iron homeostasis and fungal commensalism.

Objective: Postural stability is essential for high-level physical activities after anterior cruciate ligament reconstruction (ACLR). This study was conducted to investigate the relationship of muscle strength, joint kinesthesia, and plantar tactile sensation to dynamic and static postural stability among patients with anterior cruciate ligament reconstruction.Methods: Forty-four patients over 6 months post anterior cruciate ligament reconstruction (age: 27.9 ± 6.8 years, height: 181.7 ± 8.7 cm, weight: 80.6 ± 9.4 kg, postoperative duration: 10.3 ± 3.6 months) participated in this study. Their static and dynamic postural stability, muscle strength, hamstring/quadriceps ratio, joint kinesthesia, and plantar tactile sensation were measured. Partial correlations were used to determine the correlation of the above-mentioned variables with time to stabilization (TTS) and root mean square of the center of pressure (COP-RMS) in anterior-posterior (AP) and mediolateral (ML) directions.Results: Both TTSAP and TTSML were related to muscle strength and joint kinesthesia of knee flexion and extension; COP-RMSAP was correlated with plantar tactile sensations at great toe and arch, while COP-RMSML was correlated with joint kinesthesia of knee flexion, and plantar tactile sensation at great toe and heel. Dynamic stability was sequentially correlated with strength and joint kinesthesia, while static stability was sequentially correlated with plantar tactile sensation and joint kinesthesia.Conclusion: Among patients with anterior cruciate ligament reconstruction, strength is related to dynamic postural stability, joint kinesthesia is related to dynamic and static postural stability, and plantar tactile sensation is related to static postural stability. Strength has a higher level of relationship to dynamic stability than joint kinesthesia, and plantar tactile sensation has a higher level of relationship to static stability than joint kinesthesia.

Abstract We hypothesized that postoperative malrotation of humeral shaft fractures can alter the bio-mechanical environment of the shoulder; thus, rotator cuff and cartilage degeneration could be induced. Therefore, we designed an animal experiment to evaluate the impact of malrotation deformities after minimally invasive surgery for humeral fractures on the rotator cuff and cartilage, which has rarely been described in previous studies. Twenty-four New Zealand white rabbits were randomly divided into the sham control group (A), negative control group (B) and malrotated group (C). A sham operation with surgical exposure alone was performed in group A. Humeral shaft osteotomy was performed in Group B and C. In Group B, the fractures were fixed in situ with plate -screw system. While in Group C, iatrogenic rotational deformity was created after the proximal end of the fracture being internally rotated by 20 degrees and then subsequently fixed. The animals with bone healing were sacrificed for pathological and biochemical examination. In group C, the modified Mankin scale for cartilage pathology evaluation and the modified Movin scale for tendon both showed highest score among groups with statistical significance (P

Abstract Aflatoxin B1 (AFB1) and zearalenone (ZEN) are two predominant mycotoxins ubiquitously found in corn, peanuts, and other grains, which pose a great threat to human health. Therefore, safe and effective methods for detoxification of these mycotoxins are urgently needed. To achieve simultaneous degradation of multiple mycotoxins, a fusion enzyme ZPF1 was constructed by linking zearalenone hydrolase and manganese peroxidase with a linker peptide GGGGS. This fusion enzyme was secretory expressed successfully in the newly constructed food-grade recombinant strain Kluyveromyces lactis GG799(pKLAC1-ZPF1), and was investigated with the mycotoxins degradation efficiency in two reaction systems. Results showed that both AFB1 and ZEN can be degraded by ZPF1 in reaction system 1 (70.0 mmol/L malonic buffer with 1.0 mmol/L MnSO4, 0.1 mmol/L H2O2, 5.0 µg/mL AFB1 and ZEN, respectively) with the ratios of 46.46% and 38.76%, respectively. In reaction system 2 (50.0 mmol/L Tris–HCl, with 5.0 µg/mL AFB1 and ZEN, respectively), AFB1 cannot be degraded while ZEN can be degraded with the ratio of 35.38%. To improve the degradation efficiency of these mycotoxins, optimization of the induction and degradation conditions were fulfilled subsequently. The degradation ratios of AFB1 and ZEN by ZPF1 in reaction system 1 reached 64.11% ± 2.93% and 46.21% ± 3.17%, respectively. While in reaction system 2, ZEN was degraded by ZPF1 at a ratio of 41.45% ± 3.34%. The increases of degradation ratios for AFB1 and ZEN in reaction system 1 were 17.65% and 7.45%, respectively, while that for ZEN in reaction system 2 was 6.07%, compared with the unoptimized results.

Though two-dimensional (2D) nanocomposite materials have been attractive for flexible electrochromic (EC) devices, achieving both high performance and durability remains a challenge. Here, the authors report high-performance, environmentally stable 2D MXene/transition metal oxide-based EC devices.

BackgroundHost-microbiota crosstalk has been implicated in multiple host metabolic pathway axes that regulate intestinal barrier function. Although constitutive cytochrome P4501A1 (CYP1A1) expression perturbs the microbiome-derived autoregulatory loop following enteric infection, little is known about the role of host CYP1A1 in modulating gut microbiome-mediated signaling during methicillin-resistant Staphylococcus aureus (MRSA)-induced abdominal sepsis and its effects on intestinal barrier integrity.MethodsAbdominal sepsis was induced by the intraperitoneal injection of MRSA in mice. The effect of CYP1A1 deficiency on gut barrier integrity was investigated using RNA sequencing, microbiome analyses, and targeted metabolomics. The microbiota-produced metabolites were validated in patients with sepsis and persistent MRSA infection.ResultsMice lacking CYP1A1 exhibited an altered gut microbiome, a reduced metabolic shift from lysine to cadaverine in the caecal contents and antimicrobial molecule production (Retnlb, Gbp7, and Gbp3), and they were protected against gut barrier disruption when subjected to MRSA challenge. These beneficial effects were validated in aryl hydrocarbon receptor (AHR) knockout (KO) mice by cohousing with CYP1A1 KO mice and abrogated after supplementation with cadaverine or Enterococcus faecalis, the primary microbiota genus for cadaverine synthesis. Antibiotic-driven gut dysbacteriosis impaired the survival benefit and disrupted the intestinal barrier integrity in CYP1A1 KO mice after MRSA infection. Furthermore, increased cadaverine levels in feces and serum were detected in critically ill patients with gut leakiness during persistent MRSA infection, whereas cadaverine was not detected in healthy controls. Additionally, microbiota-derived cadaverine induced enterocyte junction disruption by activating the histamine H4 receptor/nuclear factor-κB/myosin light-chain kinase signaling pathway.ConclusionThis study revealed the unexpected function of host CYP1A1 in microbiota-mediated cadaverine metabolism, with crucial consequences for dysbacteriosis following MRSA-induced abdominal sepsis, indicating that inhibiting CYP1A1 or blocking cadaverine-histamine H4 receptor signaling could be a potential therapeutic target against abdominal sepsis.Clinical Trial Registration[http://www.chictr.org.cn/index.aspx], identifier [ChiCTR1800018646].

Abstract Gas diffusion layers (GDLs) are the most rigid layers in a 5‐layer or 7‐layer membrane electrode assembly (MEA) of a proton exchange membrane fuel cell. Therefore, in the fuel cell analysis, the mechanical properties of GDLs have a great impact on the stress distribution of the membrane as well as the performance of the whole cell. However, the mechanical properties of GDLs are not sufficiently studied. Nonlinear behavior of GDLs under cyclic compression is discussed rarely in literature. The existing model takes both constraints into consideration, but due to a geometrical oversimplification of the carbon paper microstructure, it shows some deviation, which cannot be overcome by selecting appropriate parameters. In this paper, the geometry of carbon paper microstructure has been reanalyzed. Based on the improved geometry formula, a modified model of carbon paper GDL is presented and verified by experimental data. Furthermore, both the experimental mechanical characteristics are achieved as support data for the improved model.

Conformational biosensors to monitor the activation state of G protein-coupled receptors are a useful addition to the molecular pharmacology assay toolbox to characterize ligand efficacy at the level of receptor proteins instead of downstream signaling. We recently reported the initial characterization of a NanoBRET-based conformational histamine H3 receptor (H3R) biosensor that allowed the detection of both (partial) agonism and inverse agonism on living cells in a microplate reader assay format upon stimulation with H3R ligands. In the current study, we have further characterized this H3R biosensor on intact cells by monitoring the effect of consecutive ligand injections in time and evaluating its compatibility with photopharmacological ligands that contain a light-sensitive azobenzene moiety for photo-switching. In addition, we have validated the H3R biosensor in membrane preparations and found that observed potency values better correlated with binding affinity values that were measured in radioligand competition binding assays on membranes. Hence, the H3R conformational biosensor in membranes might be a ready-to-use, high-throughput alternative for radioligand binding assays that in addition can also detect ligand efficacies with comparable values as the intact cell assay.

The histamine H1 receptor (H1R) is a G protein-coupled receptor (GPCR) and plays a key role in allergic reactions upon activation by histamine which is locally released from mast cells and basophils. Consequently, H1R is a well-established therapeutic target for antihistamines that relieve allergy symptoms. H1R signals via heterotrimeric Gq proteins and is phosphorylated by GPCR kinase (GRK) subtypes 2, 5, and 6, consequently facilitating the subsequent recruitment of β-arrestin1 and/or 2. Stimulation of a GPCR with structurally different agonists can result in preferential engagement of one or more of these intracellular signaling molecules. To evaluate this so-called biased agonism for H1R, bioluminescence resonance energy transfer (BRET)-based biosensors were applied to measure H1R signaling through heterotrimeric Gq proteins, second messengers (inositol 1,4,5-triphosphate and Ca2+), and receptor-protein interactions (GRKs and β-arrestins) in response to histamine, 2-phenylhistamines, and histaprodifens in a similar cellular background. Although differences in efficacy were observed for these agonists between some functional readouts as compared to reference agonist histamine, subsequent data analysis using an operational model of agonism revealed only signaling bias of the agonist Br-phHA-HA in recruiting β-arrestin2 to H1R over Gq biosensor activation.

Background: COVID-19 first appeared in China in December 2019, with a high rate of infectivity and morbidity, which brought tremendous psychological pressure to healthcare workers. Purpose: To understand the psychological health status of healthcare workers during the COVID-19 outbreak and decline, and to provide a theoretical reference for the future establishment of a psychological crisis intervention system. Methods: Healthcare workers were recruited using convenience sampling and snowball sampling methods, and the electronic version of the SCL-90 scale and a sociodemographic questionnaire were administered. In the pretest, a total of 5018 responses were collected; after six weeks, random sampling was performed. The SCL-90 and measures of other epidemic-related problems were administered, with 1570 responses received; then, the final data analysis was performed. Results: After six weeks, the post-test GSI score; SCL-90 total score; and PST, PSDI, O-C, I-S, DEP, ANX, PHOB, PAR, PSY, and HOS scores were significantly lower than the corresponding pretest scores (p < 0.05). The results by occupational category showed that the scores of nursing staff decreased significantly for 12 indexes and that the scores of the doctors and other hospital staff also significantly decreased. There was a significant difference between the pretest (50.78 ± 28.18) and post-test (45.00 ± 28.49) scores for the degree of worry about the epidemic. Healthcare workers believed that the top three aspects of life affected by the epidemic were economic problems (816 people), interpersonal communication problems (731 people), and mental health (728 people). Conclusion: Over the course of the epidemic, the item scores generally declined significantly. Therefore, during an outbreak period, attention should be paid to psychological crisis interventions for healthcare workers; problems caused by psychological pressure, and even other psychological conditions, can be significantly alleviated to reduce the probability of subsequent health problems.

Concurrent transmission (CT)-based wireless sensor networks, where nodes transmit at the same moment upon receiving successfully, begin to be applied to real-world scenarios. CT-based protocols have been proven experimentally that they can achieve good the end-to-end performance, namely high reliability, low latency, and high energy efficiency. For various communication patterns (one-to-many, many-to-one, and many-to-many), most current CT-based networks require a given and fixed host to realize global synchronization and scheduling. However, in real-world cases, there is a great deal of interference in the 2.4 GHz ISM band. Interference can partition the network unexpectedly due to the centralized scheduling in current CT-based networks. Even worse, current CT-based networks cannot complete the initialization phase if the unexpected partition occurs at an very beginning. To address this problem, we propose a dependable CT-based protocol (DeCoT) for wireless sensor network (WSN) to support information exchange under adverse conditions. In DeCoT, continuous transmission with a channel hopping mechanism maintains links under interference and an initiated mechanism decentralizes the network. Through our experiments in FlockLab, under interference, DeCoT achieves an average reliability of 87%, and outperforms the state-of-the-art flooding protocol, namely Robust Flooding that won the 1st place in the EWSN 2017 Dependability Competition. Especially when the source nodes are placed sparsely, DeCoT speeds up the information exchange. Above all, DeCoT can complete the initialization and work properly even when the network partitions unexpectedly. DeCoT has been evaluated as the most reliable protocol in the EWSN 2018 Dependability Competition with respect to resistance against interference. Thus, DeCoT can function dependably under interference.

The histamine H4 receptor (H4R) is a G protein-coupled receptor that is predominantly expressed on immune cells and considered to be an important drug target for various inflammatory disorders. Like most GPCRs, the H4R activates G proteins and recruits β-arrestins upon phosphorylation by GPCR kinases to induce cellular signaling in response to agonist stimulation. However, in the last decade, novel GPCR-interacting proteins have been identified that may regulate GPCR functioning. In this study, a split-ubiquitin membrane yeast two-hybrid assay was used to identify H4R interactors in a Jurkat T cell line cDNA library. Forty-three novel H4R interactors were identified, of which 17 have also been previously observed in MYTH screens to interact with other GPCR subtypes. The interaction of H4R with the tetraspanin TSPAN4 was confirmed in transfected cells using bioluminescence resonance energy transfer, bimolecular fluorescence complementation, and co-immunoprecipitation. Histamine stimulation reduced the interaction between H4R and TSPAN4, but TSPAN4 did not affect H4R-mediated G protein signaling. Nonetheless, the identification of novel GPCR interactors by MYTH is a starting point to further investigate the regulation of GPCR signaling.

Methyleugenol (Mlg), a natural ingredient of many herbs and used as a flavoring substance in dietary products, inhibits inflammation and oxidative stress. The aim of the study is to explore the antioxidative potential of Mlg against tert-butyl hydroperoxide (t-BHP)-triggered oxidative injury and the involvement of antioxidative mechanisms. Our findings indicated that Mlg exposure significantly alleviated t-BHP-stimulated cytotoxicity, suppressed reactive oxygen species (ROS) generation, and increased superoxide dismutase (SOD) and glutathione (GSH) levels, which were related to the induction of the glutamate-cysteine ligase catalytic/modifier (GCLC/GCLM) subunit, heme oxygenase-1 (HO-1), and NAD (P) H: quinone oxidoreductase (NQO1) largely dependent upon upregulating the nuclear factor-erythroid 2-related factor 2 (Nrf2) induction, inhibiting the Keap1 protein expression, and heightening the antioxidant response element (ARE) activity. Additionally, Mlg exposure obviously induced AMP-activated protein kinase (AMPK), glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinase (ERK) phosphorylation, but AMPK and ERK inhibitors treatment exhibited effectively reduced levels of Mlg-enhanced Nrf2 nuclear translocation, respectively. Furthermore, Mlg exposure significantly lessened t-BHP-induced cytotoxicity and ROS production which were evidently abolished by treatment with AMPK and ERK inhibitors and Nrf2 siRNA. Accordingly, Mlg might exhibit a protective role against t-BHP-triggered cytotoxicity via the activation of the AMPK/GSK3β- and ERK-Nrf2 signaling pathways. Keywords: Methyleugenol, Oxidative stress, Reactive oxygen species, Nrf2

Objective To measure the inductive effect of kartogenin on matrix metalloproteinase-2 levels during the differentiation of human bone marrow mesenchymal stem cells (hMSCs) into chondrocytes in vitro . Methods In vitro cultured bone marrow hMSCs were grown to the logarithmic phase and then divided into three groups: control group (0 µM kartogenin), 1 µM kartogenin group and 10 µM kartogenin group. After 72 h of culture, cell proliferation and differentiation were observed microscopically. Matrix metalloproteinase-2 (MMP-2) in the cell supernatant and type II collagen levels in the cells were detected by enzyme linked immunosorbent assay and immunofluorescence staining, respectively. Results Kartogenin induced the proliferation and differentiation of hMSCs. With the increase of kartogenin concentration, the level of type II collagen was increased, while the level of MMP-2 decreased. Conclusion These findings indicate that kartogenin can induce hMSCs to differentiate into chondrocytes, and with the increase of kartogenin concentration, degeneration of the cartilage extracellular matrix may be inhibited.

The NF-E2 p45-related factor 2 (Nrf2), a transcription factor that regulates the cellular adaptive response to oxidative stress, is a target for limiting tissue damage from exposure to environmental toxins, including arsenic. In the current study, we determine whether Pterostilbene (Pts), as a potent activator of Nrf2, has a protective effect on arsenic-induced cytotoxicity and apoptosis in human keratinocytes. Human keratinocytes (HaCaT) or mouse epidermal cells (JB6) were pretreated with Pts for 24 h prior to arsenic treatment. Harvested cells were analyzed by MTT, DCFH-DA, commercial kits, Flow cytometry assay and western blot analysis. Our results demonstrated that Pts effectively regulated the viability in HaCaT and JB6 cells, decreased the reactive oxygen species (ROS) generation and lipid peroxidation (MDA), and improved the NaAsO2-induced depletion of superoxide dismutase (SOD). Moreover, Pts treatment further dramatically inhibited NaAsO2-induced apoptosis, specifically the mitochondrial mediation of apoptosis, which coincided with the effective recovery of NaAsO2-induced mitochondrial membrane potential (ΔΨm) depolarization and cytochrome c release from the mitochondria. Furthermore, arsenic-induced decrease of anti-apoptotic factor Bcl-2 and Bcl-xl, and increase of pro-apoptotic factor Bax and Bad, as well as survival signal related factor caspase 3 activation were reversed by Pts treatment. Further mechanistic studies confirmed that Pts increased antioxidant enzyme expression in a dose-dependent manner, which was related to Nrf2 nuclear translocation. In addition, the effects of Pts on NaAsO2-induced cell viability were largely weakened when Nrf2 was knocked down. Together, our results provide evidence for the use of Pts to activate the Nrf2 pathway to alleviate arsenic-induced dermal damage.

The Exome Aggregation Consortium has collected the protein-encoding DNA sequences of almost 61,000 unrelated humans. Analysis of this dataset for G protein-coupled receptor (GPCR) proteins (available at GPCRdb) revealed a total of 463 naturally occurring genetic missense variations in the histamine receptor family. In this research, we have analyzed the distribution of these missense variations in the four histamine receptor subtypes concerning structural segments and sites important for GPCR function. Four missense variants R1273.52×52H, R13934.57×57H, R4096.29×29H, and E4106.30×30K, were selected for the histamine H1 receptor (H1R) that were hypothesized to affect receptor activity by interfering with the interaction pattern of the highly conserved D(E)RY motif, the so-called ionic lock. The E4106.30×30K missense variant displays higher constitutive activity in G protein signaling as compared to wild-type H1R, whereas the opposite was observed for R1273.52×52H, R13934.57×57H, and R4096.29×29H. The E4106.30×30K missense variant displays a higher affinity for the endogenous agonist histamine than wild-type H1R, whereas antagonist affinity was not affected. These data support the hypothesis that the E4106.30×30K mutation shifts the equilibrium towards active conformations. The study of these selected missense variants gives additional insight into the structural basis of H1R activation and, moreover, highlights that missense variants can result in pharmacologically different behavior as compared to wild-type receptors and should consequently be considered in the drug discovery process.

The aryl hydrocarbon receptor (AhR) is an important immune regulator with a role in inflammatory response. However, the role of AhR in IL-10 production by inflammatory macrophages is currently unknown. In this study, we investigated LPS-induced IL-10 expression in macrophages from AhR-KO mice and AhR-overexpressing RAW264.7 cells. AhR was highly expressed after LPS stimulation through NF-κB pathway. Loss of AhR resulted in reduced IL-10 expression in LPS-induced macrophages. Moreover, the IL-10 expression was elevated in LPS-induced AhR-overexpressing RAW264.7 cells. Maximal IL-10 expression was dependent on an AhR non-genomic pathway closely related to Src and STAT3. Furthermore, AhR-associated Src activity was responsible for tyrosine phosphorylation of STAT3 and IL-10 expression by inflammatory macrophages. Adoptive transfer of AhR-expressing macrophages protected mice against LPS-induced peritonitis associated with high IL-10 production. In conclusion, we identified the AhR-Src-STAT3-IL-10 signaling pathway as a critical pathway in the immune regulation of inflammatory macrophages, It suggests that AhR may be a potential therapeutic target in immune response.

The propagation model is an essential component in the design and deployment of a wireless sensor network (WSN). Although much attention has been given to near-ground propagation models, few studies place the transceiver directly on the ground with the height of antennas at the level of a few centimeters, which is a more realistic deployment scenario for WSNs. We measured the Received Signal Strength Indication (RSSI) of these truly near-ground WSNs at 470 MHz under four different terrains, namely flat concrete road, flat grass and two derived scenarios, and obtained the corresponding path loss models. By comprehensive analysis of the influence of different antenna heights and terrain factors, we showed the limit of existing theoretical models and proposed a propagation model selection strategy to more accurately reflect the true characteristics of the near-ground wireless channels for WSNs. In addition, we implemented these models on Cooja simulator and showed that simplistic theoretical models would induce great inaccuracy of network connectivity estimation.

BackgroundAortic valve (AV) disease presents critical situations requiring surgery in over 2% of the US population and is increasingly the reason for cardiac surgery. Throughout the AV cycle, mechanical forces of multiple types and varying intensities are exerted on valve leaflets. The mechanisms whereby forces regulate leaflet homeostasis are incompletely understood. We used a novel flow bioreactor culture to investigate alteration of AV opening or closure on leaflet genes. Methods and ResultsCulture of rat AV was conducted in a flow bioreactor for 7 days at 37°C under conditions approximating the normal stroke volume. Three force condition groups were compared: Cycling (n=8); always open (Open; n=3); or always closed (Closed; n=5). From each culture, AV leaflets were pooled by force condition and RNA expression evaluated using microarrays. Hierarchical clustering of 16 transcriptome data sets from the 3 groups revealed only 2 patterns of gene expression: Cycling and Closed groups clustered together, whereas Open AV were different (P2‐fold; P2‐fold; P40 Open group genes with progression toward disease. ConclusionsFailure of AV to close initiates an extensive response characterized by expression changes common to progression to calcific aortic valve disease. AV coaptation, whether phasic or chronic, preserved phenotypic gene expression. These results demonstrate, for the first time, that coaptation of valve leaflets is a fundamentally important biomechanical cue driving homeostasis.

Conventional computed tomography (CT) approaches provides limited visualization of the entire endoluminal changes of aortic dissection (AD), which is essential for its treatment. As an important supplement, three-dimensional CT virtual intravascular endoscopy (VIE) can show relevant details. This study aims to determine the value of VIE in displaying the entry tear and intimal flap of AD.Among 127 consecutive symptomatic patients with suspected AD who underwent CT angiography (CTA), 84 subjects were confirmed to have AD and were included in the study. Conventional CT and VIE images were observed and evaluated. From the 92 entry tears revealed via conventional CT, 88 (95.7%) tears appeared on VIE with round (n = 26), slit-shaped (n = 9), or irregular (n = 53) shapes, whereas the intimal flaps were sheetlike (n = 34), tubular (n = 34), wavelike (n = 13), or irregular (n = 7) in shape. The VIE also showed the spatial relationship between the torn flap and adjacent structures. Among 58 entry tears with multiple-line type flap shown on conventional CT, 41 (70.7%) appeared with an irregular shape on VIE, whereas among 30 tears with single-line type flap, 17 (56.7%) appeared as round or slit-shaped on VIE. These results demonstrated a significant difference (P < 0.05). The poor display of tears on VIE was related to the low CT attenuation values in lumen or in neighboring artifacts (P < 0.01).CT VIE presents the complete configurations and details of the intimal tears and flaps of AD better than conventional CT approaches. Accordingly, it should be recommended as a necessary assessment tool for endovascular therapy and as part of strategy planning in pre-surgical patients.

Dynamic accurate heart-rate (HR) estimation using a photoplethysmogram (PPG) during intense physical activities is always challenging due to corruption by motion artifacts (MAs). It is difficult to reconstruct a clean signal and extract HR from contaminated PPG. This paper proposes a robust HR-estimation algorithm framework that uses one-channel PPG and tri-axis acceleration data to reconstruct the PPG and calculate the HR based on features of the PPG and spectral analysis. Firstly, the signal is judged by the presence of MAs. Then, the spectral peaks corresponding to acceleration data are filtered from the periodogram of the PPG when MAs exist. Different signal-processing methods are applied based on the amount of remaining PPG spectral peaks. The main MA-removal algorithm (NFEEMD) includes the repeated single-notch filter and ensemble empirical mode decomposition. Finally, HR calibration is designed to ensure the accuracy of HR tracking. The NFEEMD algorithm was performed on the 23 datasets from the 2015 IEEE Signal Processing Cup Database. The average estimation errors were 1.12 BPM (12 training datasets), 2.63 BPM (10 testing datasets) and 1.87 BPM (all 23 datasets), respectively. The Pearson correlation was 0.992. The experiment results illustrate that the proposed algorithm is not only suitable for HR estimation during continuous activities, like slow running (13 training datasets), but also for intense physical activities with acceleration, like arm exercise (10 testing datasets).

Using dimethylsilylated silica as emulsifier, W/O Pickering emulsions were prepared by homogeneous emulsification. The kinds of oils, rheological modifiers and their effects on the stability and rheological properties of the W/O Pickering emulsions were studied. The results showed that, compared with the nonpolar oil, the W/O Pickering emulsion prepared with polar oil had smaller droplets and better stability, e.g., the emulsion prepared with jojoba oil had narrow particle size distribution, uniform shape and good stability. With the addition of rheological modifier, the particle size of the emulsion decreased to a certain extent, and the stability at room temperature and at low temperature was both slightly increased. For different oils, the rheological modifier which was similar to the oil in molecular structure had better effects in the reduction of particle size and the improvement of stability. All these W/O Pickering emulsions prepared with different oils were non-Newtonian fluids. With the increase of shear rate, the viscosity of the emulsions decreased, and the elastic modulus (G') of all emulsions was higher than viscous modulus (G"). All the emulsions were gel emulsions, and the linear viscoelastic region was 0.001%-0.100%. With the addition of rheological modifier, the viscosity of the emulsion increased and the shear thinning phenomenon was basically unchanged, but the linear viscoelastic region was enlarged, which might be related to the change of emulsion particle size and oil-water interfacial energy. [ABSTRACT FROM AUTHOR]

The popularity of concurrent transmissions (CT) has soared after recent studies have shown their feasibility on the four physical layers specified by BLE 5, hence providing an alternative to the use of IEEE 802.15.4 for the design of reliable and efficient low-power wireless protocols. However, to date, the extent to which physical layer properties affect the performance of CT has not yet been investigated in detail. This article fills this gap and provides an extensive study on the impact of the physical layer on CT-based solutions using IEEE 802.15.4 and BLE 5. We first highlight through simulation how the impact of errors induced by relative carrier frequency offsets on the performance of CT highly depends on the choice of the underlying physical layer. We then confirm these observations experimentally on real hardware and with varying environmental conditions through an analysis of the bit error distribution across received packets, unveiling possible techniques to effectively handle these errors. We further study the performance of CT-based data collection and dissemination protocols in the presence of RF interference on a large-scale testbed, deriving insights on how the employed physical layer affects their dependability. [ABSTRACT FROM AUTHOR]