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Abstract Alzheimer's disease (AD) is the most common age‐related neurodegenerative disorder leading to cognitive decline. Excessive cytosolic calcium (Ca2+) accumulation plays a critical role in the pathogenesis of AD since it activates the NOD‐like receptor family, pyrin domain containing 3 (NLRP3), switches the endoplasmic reticulum (ER) unfolded protein response (UPR) toward proapoptotic signaling and promotes Aβ seeding. Herein, a liposomal nanodrug (felodipine@LND) is developed incorporating a calcium channel antagonist felodipine for Alzheimer's disease treatment through a low‐intensity pulse ultrasound (LIPUS) irradiation‐assisted blood brain barrier (BBB)‐crossing drug delivery. The multifunctional felodipine@LND is effectively delivered to diseased brain through applying a LIPUS irradiation to the skull, which resulted in a series of positive effects against AD. Markedly, the nanodrug treatment switched the ER UPR toward antioxidant signaling, prevented the surface translocation of ER calreticulin (CALR) in microglia, and inhibited the NLRP3 activation and Aβ seeding. In addition, it promoted the degradation of damaged mitochondria via mitophagy, thereby inhibiting the neuronal apoptosis. Therefore, the anxiety‐like behavior and cognitive impairment of 5xFAD mice with AD is significantly ameliorated, which manifested the potential of LIPUS – assisted BBB‐crossing delivery of felodipine@LND to serve as a paradigm for AD therapy based on the well‐recognized clinically available felodipine.

Abstract Background miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined. Methods To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget™ assays were performed to measure the frequency of methylation at the miR-182 promoter. Bone marrow cells were isolated from miR-182 knockout (182KO) and 182 wild type (182WT) mice to construct BCR-ABL (P190) and Notch-induced murine B-ALL and T-ALL models, respectively. Primary ALL samples were performed to investigate synergistic effects of the hypomethylation agents (HMAs) and the BCL2 inhibitor venetoclax (Ven) in vitro. Results miR-182 (miR-182-5P) expression was substantially lower in ALL blasts than in normal controls (NCs) because of DNA hypermethylation at the miR-182 promoter in ALL blasts but not in normal controls (NCs). Knockout of miR-182 (182KO) markedly accelerated ALL development, facilitated the infiltration, and shortened the OS in a BCR-ABL (P190)-induced murine B-ALL model. Furthermore, the 182KO ALL cell population was enriched with more leukemia-initiating cells (CD43+B220+ cells, LICs) and presented higher leukemogenic activity than the 182WT ALL population. Furthermore, depletion of miR-182 reduced the OS in a Notch-induced murine T-ALL model, suggesting that miR-182 knockout accelerates ALL development. Mechanistically, overexpression of miR-182 inhibited proliferation and induced apoptosis by directly targeting PBX3 and BCL2, two well-known oncogenes, that are key targets of miR-182. Most importantly, DAC in combination with Ven had synergistic effects on ALL cells with miR-182 promoter hypermethylation, but not on ALL cells with miR-182 promoter hypomethylation. Conclusions Collectively, we identified miR-182 as a tumor suppressor gene in ALL cells and low expression of miR-182 because of hypermethylation facilitates the malignant phenotype of ALL cells. DAC + Ven cotreatment might has been applied in the clinical try for ALL patients with miR-182 promoter hypermethylation. Furthermore, the methylation frequency at the miR-182 promoter should be a potential biomarker for DAC + Ven treatment in ALL patients.

Abstract Background Ferroptosis is a new form of nonapoptotic and iron-dependent type of cell death. Glutathione peroxidase-4 (GPX4) plays an essential role in anti-ferroptosis by reducing lipid peroxidation. Although acute myeloid leukemia (AML) cells, especially relapsed and refractory (R/R)-AML, present high GPX4 levels and enzyme activities, pharmacological inhibition of GPX4 alone has limited application in AML. Thus, whether inhibition of GPX4 combined with other therapeutic reagents has effective application in AML is largely unknown. Methods Lipid reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) assays were used to assess ferroptosis in AML cells treated with the hypomethylating agent (HMA) decitabine (DAC), ferroptosis-inducer (FIN) RAS-selective lethal 3 (RSL3), or their combination. Combination index (CI) analysis was used to assess the synergistic activity of DAC + RSL3 against AML cells. Finally, we evaluated the synergistic activity of DAC + RSL3 in murine AML and a human R/R-AML-xenografted NSG model in vivo. Results We first assessed GPX4 expression and found that GPX4 levels were higher in AML cells, especially those with MLL rearrangements, than in NCs. Knockdown of GPX4 by shRNA and indirect inhibition of GPX4 enzyme activity by RSL3 robustly induced ferroptosis in AML cells. To reduce the dose of RSL3 and avoid side effects, low doses of DAC (0.5 µM) and RSL3 (0.05 µM) synergistically facilitate ferroptosis by inhibiting the AMP-activated protein kinase (AMPK)-SLC7A11-GPX4 axis. Knockdown of AMPK by shRNA enhanced ferroptosis, and overexpression of SLC7A11 and GPX4 rescued DAC + RSL3-induced anti-leukemogenesis. Mechanistically, DAC increased the expression of MAGEA6 by reducing MAGEA6 promoter hypermethylation. Overexpression of MAGEA6 induced the degradation of AMPK, suggesting that DAC inhibits the AMPK-SLC7A11-GPX4 axis by increasing MAGEA6 expression. In addition, DAC + RSL3 synergistically reduced leukemic burden and extended overall survival compared with either DAC or RSL3 treatment in the MLL-AF9-transformed murine model. Finally, DAC + RSL3 synergistically reduced viability in untreated and R/R-AML cells and extended overall survival in two R/R-AML-xenografted NSG mouse models. Conclusions Our study first identify vulnerability to ferroptosis by regulating MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway. Combined treatment with HMAs and FINs provides a potential therapeutic choice for AML patients, especially for R/R-AML.

Consumption of locally caught fish provides health benefits but can be a route of exposure to methylmercury and other persistent environmental contaminants. Previous studies found that Asian women of childbearing age (WCBA) in the Milwaukee area have high levels of exposure through fish consumption but limited awareness of fish advisories. We conducted a focus group project to understand the influence of culture, attitudes, and beliefs on the fish consumption habits of Chinese, Hmong, and Karen WCBA who reside in the Milwaukee area to develop culturally appropriate educational materials.A total of 19 women aged 18–50 years identifying as Chinese, Hmong, or Karen were recruited. Three focus groups were held, each consisting of 6–7 participants from one ethnicity. Focus group transcripts were thematically analyzed and coded based on the integrated behavioral model.Nutritional benefits and availability were the most common reasons to eat locally caught fish. All participants were aware of risks associated with eating fish, yet few knew ways to mitigate risk and maximize benefits. Participants expressed interest in receiving health messages from trusted sources and recommended that messaging target families rather than just individuals. Participants who were confident in their self-efficacy expressed a greater likelihood of following health message guidelines.Results suggest providing culturally appropriate educational materials in preferred languages to Asian communities via local community organizations may increase self-efficacy and adherence to fish advisories. Future projects will evaluate the effectiveness of self-affirmation messaging among Asian WCBA and assess changes in fish consumption based on message content.

IntroductionThe high incidence of breast cancer (BC) prompted us to explore more factors that might affect its occurrence, development, treatment, and also recurrence. Dysregulation of cholesterol metabolism has been widely observed in BC; however, the detailed role of how cholesterol metabolism affects chemo-sensitivity, and immune response, as well as the clinical outcome of BC is unknown. MethodsWith Mendelian randomization (MR) analysis, the potential causal relationship between genetic variants of cholesterol and BC risk was assessed first. Then we analyzed 73 cholesterol homeostasis-related genes (CHGs) in BC samples and their expression patterns in the TCGA cohort with consensus clustering analysis, aiming to figure out the relationship between cholesterol homeostasis and BC prognosis. Based on the CHG analysis, we established a CAG_score used for predicting therapeutic response and overall survival (OS) of BC patients. Furthermore, a machine learning method was adopted to accurately predict the prognosis of BC patients by comparing multi-omics differences of different risk groups. ResultsWe observed that the alterations in plasma cholesterol appear to be correlative with the venture of BC (MR Egger, OR: 0.54, 95% CI: 0.35-0.84, p

Abstract Background The repair of white matter injury is of significant importance for functional recovery after ischemic stroke, and the up-regulation of triggering receptors expressed on myeloid cells 2 (TREM2) after ischemic stroke is neuroprotective and implicated in remyelination. However, the lack of effective therapies calls for the need to investigate the regenerative process of remyelination and the role of rehabilitation therapy. This study sought to investigate whether and how moderate physical exercise (PE) promotes oligodendrogenesis and remyelination in rats with transient middle cerebral artery occlusion (tMCAO). Methods Male Sprague–Dawley rats (weighing 250–280 g) were subjected to tMCAO. AAV-shRNA was injected into the lateral ventricle to silence the Trem2 gene before the operation. The rats in the physical exercise group started electric running cage training at 48 h after the operation. The Morris water maze and novel object recognition test were used to evaluate cognitive function. Luxol fast blue staining, diffusion tensor imaging, and electron microscopy were used to observe myelin injury and repair. Immunofluorescence staining was applied to observe the proliferation and differentiation of oligodendrocyte precursor cells (OPCs). Expression of key molecules were detected using immunofluorescence staining, quantitative real-time polymerase chain reaction, Western blotting, and Enzyme-linked immunosorbent assay, respectively. Results PE exerted neuroprotective efects by modulating microglial state, promoting remyelination and recovery of neurological function of rats over 35 d after stroke, while silencing Trem2 expression in rats suppressed the aforementioned effects promoted by PE. In addition, by leveraging the activin-A neutralizing antibody, we found a direct beneficial effect of PE on microglia-derived activin-A and its subsequent role on oligodendrocyte differentiation and remyelination mediated by the activin-A/Acvr axis. Conclusions The present study reveals a novel regenerative role of PE in white matter injury after stroke, which is mediated by upregulation of TREM2 and microglia-derived factor for oligodendrocytes regeneration. PE is an effective therapeutic approach for improving white matter integrity and alleviating neurological function deficits after ischemic stroke.

Abstract Objective This study aimed at determining the characteristics of systemic inflammation and brain iron deposition in Parkinson's disease (PD) patients. Methods Thirty two PD patients and 30 gender‐ as well as age‐matched controls were enrolled. Serum interleukin (IL)‐1β, IL‐33, tumor necrosis factor (TNF)‐α, IL‐6, IL‐10, ferritin, iron, and total iron binding capacity (TIBC) levels were assayed. Quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron accumulation in the regions of interest (ROIs). Correlations between concentrations of inflammatory cytokines and biomarkers for peripheral iron metabolism, brain iron deposition were evaluated in the PD group. Results Serum concentrations of IL‐1β and IL‐33 were found to be significantly elevated in the PD group compared to the control group, and in early‐stage PD group compared to advanced‐stage PD group. Total QSM value for bilateral ROIs was significantly elevated in the PD group compared to the control group, and in advanced‐stage PD group compared to early‐stage PD group. There was a significant inverse correlation between serum IL‐1β concentration and total QSM value for bilateral ROIs, between serum ferritin, iron, TIBC concentrations, and total QSM value for bilateral ROIs in PD patients. However, there was no significant correlation between serum IL‐1β concentrations and serum ferritin, iron, TIBC concentrations in PD patients. Interpretation The inflammatory state and chronic brain iron deposition progression in PD patients might be asynchronous. Alterations in systemic inflammation were not correlated with peripheral iron metabolism and might not contribute to the aggravation of brain iron deposition in PD patients.

In recent years, universities worldwide have experienced rapid changes with an immense impact, which have been influenced by technological progress and the social trends of digitalization. Like all other revolutionary changes, digital transformation involves intense adjustment/readjustment. University sustainability must be the active concern of all higher education institutions. Thus, the present research aims to analyse teachers' acceptance of new technologies and the impact on their wellbeing and university sustainability. The main objective was to analyse the acceptance of technology in special the e-learning opportunities and the wellbeing of teacher in an emergent country like Romania. To achieve our goal, we created a questionnaire based on the literature, and with the help of the technology acceptance model, we tested our hypotheses. The results indicate several discontents on the part of teachers concerning adapting to new technologies and even a personal discomfort in adapting to these new technologies. Thus, we can note that wellbeing significantly influences job satisfaction and teachers' involvement in sustainable development.

Northern maize leaf blight is one of the major diseases that endanger the health of maize. The complex background of the field and different light intensity make the detection of diseases more difficult. A multi-scale feature fusion instance detection method, based on convolutional neural network, is proposed to detect maize leaf blight. The proposed technique incorporates three major steps of data set preprocessing part, fine-tuning network and detection module. In the first step, the improved retinex is used to process data sets, which successfully solves the problem of poor detection effects caused by high-intensity light. In the second step, the improved RPN is utilized to adjust the anchor box of diseased leaves. The improved RPN network identifies and deletes negative anchors, which reduces the search space of the classifier and provides better initial information for the detection network. In this paper, a transmission module is designed to connect the fine-tuning network with the detection module. On the one hand, the transmission module fuses the features of the low-level and high-level to improve the detection accuracy of small target diseases. On the other hand, the transmission module converts the feature map associated with the fine-tuning network to the detection module, thus realizing the feature sharing between the detection module and the fine-tuning network. In the third step, the detection module takes the optimized anchor as input, focuses on detecting the diseased leaves. By sharing the features of the transmission module, the time-consuming process of using candidate regions layer by layer to detect is eliminated. Therefore, the efficiency of the whole model has reached the efficiency of the one-stage model. In order to further optimize the detection effect of the model, we replace the loss function with generalized intersection over union (GIoU). After 60000 iterations, the highest mean average precision (mAP) reaches 91.83%. The experimental results indicate that the improved model outperforms several existing methods in terms of greater precision and frames per second (FPS).

Several sets of energetic particle diagnostics, including a set of neutron flux monitoring systems, a solid-state neutral particle analyzer and a fast ion loss probe (FILP), have been used to investigate the energetic ion losses induced by the long-lived saturated internal mode (LLM) in the HL-2A tokamak. Clear experimental evidence for different levels of energetic ion losses induced by LLM, sawtooth and minor disruption has been observed. A numerical calculation for the evolution of neutron emissions was carried out with the FBURN code, and it shows that the neutron emission drop rate linearly increases with the LLM amplitude and no threshold perturbation amplitude exists, illustrating that the loss mechanism for LLM induced energetic ion loss is dominantly convective. In addition, measurement results of the FILP demonstrate that LLM tends to expel energetic ions with relatively low energy ( $E \lt 27\,$ keV) and high pitch angle ( $\theta\gt60^{\circ}$ ), and can suppress the prompt loss of energetic ions with high energy and low pitch angle to a certain degree. Furthermore, the physical process for LLM induced energetic ion loss can be explained by orbit calculations, which show that LLM induced lost energetic ions will transport from center to peripheral region first, and then get lost out of plasma. The experimental observations are successfully reproduced by calculations using the ORBIT code combined with both the NUBEAM code and the MARS-K code. The paper clearly describes the whole physical process of LLM induced energetic ion loss for the first time in the HL-2A tokamak.

Vegetation phenology is a commonly used indicator of ecosystem responses to climate change and plays a vital role in ecosystem carbon and hydrological cycles. Previous studies have mostly focused on the response of vegetation phenology to temperature and precipitation. Soil moisture plays an important role in maintaining vegetation growth. However, our understanding of the influences of soil moisture dynamics on vegetation phenology is sparse. In this study, using a time series of the normalized difference vegetation index (NDVI) from the moderate resolution imaging spectroradiometer (MODIS) dataset (2001–2020), the start of the growing season (SOS), the end of the growing season (EOS), and the length of the growing season (LOS) in the Qilian Mountains (QLMs) were extracted. The spatiotemporal patterns of vegetation phenology (SOS, EOS, and LOS) were explored. The partial coefficient correlations between the SOS, EOS, and seasonal climatic factors (temperature, precipitation, and soil moisture) were analyzed. The results showed that the variation trends of vegetation phenology were not significant (p > 0.05) from 2001 to 2020, the SOS was advanced by 0.510 d/year, the EOS was delayed by 0.066 d/year, and the LOS was prolonged by 0.580 d/year. The EOS was significantly advanced and the LOS significantly shortened with increasing altitude. The seasonal temperature, precipitation, and soil moisture had spatiotemporal heterogeneous effects on the vegetation phenology. Overall, compared with temperature and soil moisture, precipitation had a weaker influence on the vegetation phenology in the QLMs. For different elevation zones, the temperature and soil moisture influenced the vegetation phenology in most areas of the QLMs, and spring temperature was the key driving factor influencing SOS; the autumn soil moisture and autumn temperature made the largest contributions to the variations in EOS at lower (3500 m a.s.l.), respectively. For different vegetation types, the spring temperature was the main factor influencing the SOS for broadleaf forests, needleleaf forests, shrublands, and meadows because of the relative lower soil moisture stress. The autumn soil moisture was the main factor influencing EOS for deserts because of the strong soil moisture stress. Our results demonstrate that the soil moisture strongly influences vegetation phenology, especially at lower elevations and water-limited areas. This study provides a scientific basis for better understanding the response of vegetation phenology to climate change in arid mountainous areas and suggests that the variation in soil moisture should be considered in future studies on the influence of climate warming and environmental effects on the phenology of water-limited areas.

G protein-coupled receptor 68 (GPR68) responds to extracellular protons, thus called the proton-sensing G protein-coupled receptor (GPCR), leading to activation of the phospholipase C-β (PLCβ)/calcium (Ca2+) pathway or the adenylyl cyclase (AC)/cyclic AMP (cAMP) pathway. We recently found that whole body deletion of Gpr68 (Gpr68−/− mice) reduced the number of B lymphocytes with age and during hematopoietic regeneration, such as in response to fluorouracil (5-FU) administration. This prompted us to characterize the hematopoietic stem cell (HSC) phenotype in Gpr68−/− mice. Despite high level of Gpr68 protein expression on HSC in bone marrow (BM), the pool size of HSC was unaltered in Gpr68−/− mice either under steady state or upon stress, including aging and 5-FU treatment. HSC from Gpr68−/− mice exhibited comparable cellular features, such as cell cycle quiescence and cell survival. HSC from Gpr68−/− mice also exhibited comparable competitiveness after serial transplantation. Surprisingly, cytosolic Ca2+ accumulation was increased in HSC from Gpr68−/− mice. In contrast, cAMP levels were reduced in hematopoietic stem and progenitor cells (HSPC) from Gpr68−/− mice. Intriguingly, we found high level of Gpr68 protein expression on non-hematopoietic cells in BM, especially endothelial cells that function as HSC niche. In addition, expression of other proton-sensing GPCR was upregulated in HSPC from Gpr68−/− mice. Our studies suggest that Gpr68−/− mice display insignificant phenotype on HSC biology, possibly due to the function of Gpr68 in non-hematopoietic cells and/or the compensatory effects from other proton-sensing GPCR.

Mutations in transmembrane protein 230 (TMEM230) gene are suggested to be associated with the autosomal dominant Parkinson’s disease (PD) with typical movement disorders and Lewy body pathology. However, the normal functions and the pathological roles of TMEM230 are not clear. In this study, we used TMEM230 isoform II constructs including wild-type (WT) and four reported PD-linked mutation constructs (Y92C, R141L, 184Wext*5, and 184PGext*5). Ectopic expression of WT and PD-linked mutant TMEM230 variants in cultured cells dramatically induced apoptotic cell death compared with that of vector control cells. Mutant TMEM230 caused cell toxicity at an increased severity than WT TMEM230. Moreover, expression of TMEM230 increased mitochondrial reactive oxygen species (ROS) levels, decreased cellular ATP, activated caspase 3/7, and increased poly(ADP-ribose) polymerase-1 (PARP1) cleavage. Treatment with N-acetylcysteine (NAC; an ROS scavenger) or Z-VAD-FMK (a caspase inhibitor) significantly attenuated TMEM230-induced apoptosis in both cultured cells and primary neurons. Our results indicated that TMEM230 mediated a PARP1-linked apoptotic cell death pathway. These findings not only provide the novel insight into the biological roles of TMEM230 in the PARP1-linked pathway but also provide a TMEM230-induced cell death mechanism underlying PD pathogenesis.

The Internet of Things (IoT) now permeates our daily lives, providing important measurement and collection tools to inform our every decision. Millions of sensors and devices are continuously producing data and exchanging important messages via complex networks supporting machine-to-machine communications and monitoring and controlling critical smart-world infrastructures. As a strategy to mitigate the escalation in resource congestion, edge computing has emerged as a new paradigm to solve IoT and localized computing needs. Compared with the well-known cloud computing, edge computing will migrate data computation or storage to the network “edge”, near the end users. Thus, a number of computation nodes distributed across the network can offload the computational stress away from the centralized data center, and can significantly reduce the latency in message exchange. In addition, the distributed structure can balance network traffic and avoid the traffic peaks in IoT networks, reducing the transmission latency between edge/cloudlet servers and end users, as well as reducing response times for real-time IoT applications in comparison with traditional cloud services. Furthermore, by transferring computation and communication overhead from nodes with limited battery supply to nodes with significant power resources, the system can extend the lifetime of the individual nodes. In this paper, we conduct a comprehensive survey, analyzing how edge computing improves the performance of IoT networks. We categorize edge computing into different groups based on architecture, and study their performance by comparing network latency, bandwidth occupation, energy consumption, and overhead. In addition, we consider security issues in edge computing, evaluating the availability, integrity, and the confidentiality of security strategies of each group, and propose a framework for security evaluation of IoT networks with edge computing. Finally, we compare the performance of various IoT applications (smart city, smart grid, smart transportation, and so on) in edge computing and traditional cloud computing architectures.

Sepsis-associated encephalopathy (SAE) is a poorly understood condition that leads to long-term cognitive impairment and increased mortality in survivors. Recent research revealed that IL-17A/IL-17R might serve as a checkpoint in microglia-mediated neuroinflammation. The present study was designed to determine the specific role of IL-17A-mediated microglia activation in the development of SAE. A mouse model of SAE was induced by cecal ligation and puncture (CLP), and behavior performance was evaluated by the inhibitory avoidance test and the open field test. Cytokine expression and microglia activation in brain tissue were determined at 6 h, 12 h, 24 h, 48 h, and day 7 post surgery. Further, septic mice were intracerebral ventricle- (i.c.v.-) injected with recombinant IL-17A, anti-IL-17A ab, anti-IL-17R ab, or isotype controls to evaluate the potential effects of IL-17A/IL-17R blockade in the prevention of SAE. Septic peritonitis induced significant impairment of learning memory and exploratory activity, which was associated with a higher expression of IL-17A, IL-1β, and TNF-α in the brain homogenate. Fluorescence intensity of Iba-1 and IL-17R in the hippocampus was significantly increased following CLP. Treatment with recombinant IL-17A enhanced the neuroinflammation and microglia activation in CLP mice. On the contrary, neutralizing anti-IL-17A or anti-IL-17R antibodies mitigated the CNS inflammation and microglia activation, thus alleviating the cognitive dysfunction. Furthermore, as compared to the sham control, microglia cultured from CLP mice produced significantly higher levels of cytokines and expressed with higher fluorescence intensity of Iba-1 in response to IL-17A or LPS. Pretreatment with anti-IL-17R ab suppressed the Iba-1 expression and cytokine production in microglia stimulated by IL-17A. In conclusion, blockade of the IL-17A/IL-17R pathway inhibited microglia activation and neuroinflammation, thereby partially reversing sepsis-induced cognitive impairment. The present study suggested that the IL-17A/IL-17R signaling pathway had an important, nonredundant role in the development of SAE.

We investigated the effects of the austenitizing temperature on the microstructure, hardness, and tensile properties of case-carburized steel after vacuum carburization at 930 °C and then re-austenitization at 820–900 °C followed by oil quenching and tempering. The results show that fractures occurred early with the increase in the austenitizing temperature, although all the carburized specimens showed a similar case hardness of 800 HV0.2 and case depth of 1.2 mm. The highest fracture stress of 1919 MPa was obtained for the experimental steel when the austenitizing temperature was 840 °C due to its fine microstructure and relatively high percentage of retained austenite transformed into martensite during the tensile tests. We also found that the stress–strain behavior of case-carburized specimens could be described by the area-weighted curves of the carburized case and the core in combination. The strain hardening exponent was about 0.4 and did not vary with the increase in the austenitizing temperature. We concluded that the optimum austenitizing temperature was around 840 °C for the experimental steel.

Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson’s disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn’s disease and leprosy. Previous studies have reported that LRRK2 is expressed in B lymphocytes and macrophages, suggesting a role for LRRK2 in immunological functions. In this study, we characterized the LRRK2 protein expression and phosphorylation using human lymphoblasts. Lipopolysaccharide (LPS), a proinflammatory agent, induced the increase of LRRK2 expression and kinase activities in human lymphoblasts in a time-dependent manner. Moreover, LPS activated the Toll-like receptor (TLR) signaling pathway, increased TRAF6/LRRK2 interaction, and elevated the phosphorylation levels of MAPK (JNK1/2, p38, and ERK1/2) and IkBα. Treatment with LRRK2 inhibitor 68 reduced LPS-induced TRAF6/LRRK2 interaction and MAPK and IkBα phosphorylation, thereby reducing TNF-α secretion. These results indicate that LRRK2 is actively involved in proinflammatory responses in human lymphoblasts, and inhibition of GTP binding by 68 results in an anti-inflammation effect against proinflammatory stimuli. These findings not only provide novel insights into the mechanisms of LRRK2-linked immune and inflammatory responses in B-cell-like lymphoblasts, but also suggest that 68 may also have potential therapeutic value for LRRK2-linked immunological disorders.

Chitosan’s activities are significantly affected by degree of deacetylation (DDA), while fully deacetylated chitosan is difficult to produce in a large scale. Therefore, this paper introduces a compression method for preparing 100% deacetylated chitosan with less environmental pollution. The product is characterized by XRD, FT-IR, UV and HPLC. The 100% fully deacetylated chitosan is produced in low-concentration alkali and high-pressure conditions, which only requires 15% alkali solution and 1:10 chitosan powder to NaOH solution ratio under 0.11–0.12 MPa for 120 min. When the alkali concentration varied from 5% to 15%, the chitosan with ultra-high DDA value (up to 95%) is produced.

Cerebral cortical microinfarct (CMI) is common in patients with dementia and cognitive decline. Emerging studies reported that intestinal dysfunction influenced the outcome of ischemic stroke and that vagus nerve stimulation (VNS) protected against ischemic stroke. However, the effects of intestinal dysfunction and VNS on CMI are not clear. Therefore, we examined the influence of colitis and VNS on CMI and the mechanisms of VNS attenuating CMI in mice with colitis. CMI was induced using a two-photon laser. Colitis was induced using oral dextran sodium sulfate (DSS). The cervical vagus nerve was stimulated using a constant current. In vivo blood-brain barrier (BBB) permeability was evaluated using two-photon imaging. Infarct volume, microglial and astrocyte activation, oxidative stress and proinflammatory cytokine levels were assessed using immunofluorescent and immunohistochemical staining. The BBB permeability, infarct volume, activation of microglia and astrocytes and oxidative stress increased significantly in mice with colitis and CMI compared to those in mice with CMI. However, these processes were reduced in CMI mice when VNS was performed. Brain lesions in mice with colitis and CMI were significantly ameliorated when VNS was performed during the acute phase of colitis. Our study demonstrated that VNS alleviated CMI and this neuroprotection was associated with the suppression of BBB permeability, neuroinflammation and oxidative stress. Also, our results indicated that VNS reduced colitis-induced microstroke aggravation.

In the smart grid, measurement devices may be compromised by adversaries, and their operations could be disrupted by attacks. A number of schemes to efficiently and accurately detect these compromised devices remotely have been proposed. Nonetheless, most of the existing schemes detecting compromised devices depend on the incremental response time in the attestation process, which are sensitive to data transmission delay and lead to high computation and network overhead. To address the issue, in this paper, we propose a low-cost remote memory attestation scheme (LRMA), which can efficiently and accurately detect compromised smart meters considering real-time network delay and achieve low computation and network overhead. In LRMA, the impact of real-time network delay on detecting compromised nodes can be eliminated via investigating the time differences reported from relay nodes. Furthermore, the attestation frequency in LRMA is dynamically adjusted with the compromised probability of each node, and then, the total number of attestations could be reduced while low computation and network overhead can be achieved. Through a combination of extensive theoretical analysis and evaluations, our data demonstrate that our proposed scheme can achieve better detection capacity and lower computation and network overhead in comparison to existing schemes.

The present study investigated and compared the hypoglycemic activity of differently regioselective chitosan sulfates in alloxan-induced diabetic rats. Compared with the normal control rats, significantly higher blood glucose levels were observed in the alloxan-induced diabetic rats. The differently regioselective chitosan sulfates exhibited hypoglycemic activities at different doses and intervals, especially 3-O-sulfochitosan (3-S). The major results are as follows. First, 3,6-di-O-sulfochitosan and 3-O-sulfochitosan exhibited more significant hypoglycemic activities than 2-N-3, 6-di-O-sulfochitosan and 6-O-sulfochitosan. Moreover, 3-S-treated rats showed a more significant reduction of blood glucose levels than those treated by 3,6-di-O-sulfochitosan. These results indicated that –OSO3− at the C3-position of chitosan is a key active site. Second, 3-S significantly reduced the blood glucose levels and regulated the glucose tolerance effect in the experimental rats. Third, treatment with 3-S significantly increased the plasma insulin levels in the experimental diabetic rats. A noticeable hypoglycemic activity of 3-S in the alloxan-induced diabetic rats was shown. Clinical trials are required in the future to confirm the utility of 3-S.

In the current natural environment, due to the complexity of the background and the high similarity of the color between immature green tomatoes and the plant, the occlusion of the key organs (flower and fruit) by the leaves and stems will lead to low recognition rates and poor generalizations of the detection model. Therefore, an improved tomato organ detection method based on convolutional neural network (CNN) has been proposed in this paper. Based on the original Faster R-CNN algorithm, Resnet-50 with residual blocks was used to replace the traditional vgg16 feature extraction network, and a K-means clustering method was used to adjust more appropriate anchor sizes than manual setting, to improve detection accuracy. The test results showed that the mean average precision (mAP) was significantly improved compared with the traditional Faster R-CNN model. The training model can be transplanted to the embedded system, which lays a theoretical foundation for the development of a precise targeting pesticide application system and an automatic picking device.

By using the saddle point theorem, some new existence theorems are obtained for second-order Hamiltonian systems with impulsive effects in the cases when the gradient of the nonlinearity grows sublinearly and grows linearly respectively. Our results generalize some existing results and our conditions on the potential are rather relaxed.

Diverse and varied cyber-attacks challenge the operation of the smart-world system that is supported by Internet-of-Things (IoT) (smart cities, smart grid, smart transportation, etc.) and must be carefully and thoughtfully addressed before widespread adoption of the smart-world system can be fully realized. Although a number of research efforts have been devoted to defending against these threats, a majority of existing schemes focus on the development of a specific defensive strategy to deal with specific, often singular threats. In this paper, we address the issue of coalitional attacks, which can be launched by multiple adversaries cooperatively against the smart-world system such as smart cities. Particularly, we propose a game-theory based model to capture the interaction among multiple adversaries, and quantify the capacity of the defender based on the extended Iterated Public Goods Game (IPGG) model. In the formalized game model, in each round of the attack, a participant can either cooperate by participating in the coalitional attack, or defect by standing aside. In our work, we consider the generic defensive strategy that has a probability to detect the coalitional attack. When the coalitional attack is detected, all participating adversaries are penalized. The expected payoff of each participant is derived through the equalizer strategy that provides participants with competitive benefits. The multiple adversaries with the collusive strategy are also considered. Via a combination of theoretical analysis and experimentation, our results show that no matter which strategies the adversaries choose (random strategy, win-stay-lose-shift strategy, or even the adaptive equalizer strategy), our formalized game model is capable of enabling the defender to greatly reduce the maximum value of the expected average payoff to the adversaries via provisioning sufficient defensive resources, which is reflected by setting a proper penalty factor against the adversaries. In addition, we extend our game model and analyze the extortion strategy, which can enable one participant to obtain more payoff by extorting his/her opponents. The evaluation results show that the defender can combat this strategy by encouraging competition among the adversaries, and significantly suppress the total payoff of the adversaries via setting the proper penalty factor.

By establishing a new proper variational framework and using the critical point theory, we establish some new existence criteria to guarantee that the 2nth-order nonlinear difference equation containing both advance and retardation with p-Laplacian Δn(r(t−n)φp(Δnu(t−1)))+q(t)φp(u(t))=f(t,u(t+n),…,u(t),…,u(t−n)), n∈ℤ(3), t∈ℤ, has infinitely many homoclinic orbits, where φp(s) is p-Laplacian operator; φp(s)=|s|p−2s(1

A class of two-neuron networks with resonant bilinear terms is considered. The stability of the zero equilibrium and existence of Hopf bifurcation is studied. It is shown that the zero equilibrium is locally asymptotically stable when the time delay is small enough, while change of stability of the zero equilibrium will cause a bifurcating periodic solution as the time delay passes through a sequence of critical values. Some explicit formulae for determining the stability and the direction of the Hopf bifurcation periodic solutions bifurcating from Hopf bifurcations are obtained by using the normal form theory and center manifold theory. Finally, numerical simulations supporting the theoretical analysis are carried out.

We establish several new Lyapunov-type inequalities for some quasilinear dynamic system involving the (p1,p2,…,pm)-Laplacian on an arbitrary time scale 𝕋, which generalize and improve some related existing results including the continuous and discrete cases.

Carbazole is a recalcitrant compound with a dioxin-like structure and possesses mutagenic and toxic activities. Bacteria respond to a xenobiotic by recruiting exogenous genes to establish a pathway to degrade the xenobiotic, which is necessary for their adaptation and survival. Usually, this process is mediated by mobile genetic elements such as plasmids, transposons, and insertion sequences.The genes encoding the enzymes responsible for the degradation of carbazole to catechol via anthranilate were cloned, sequenced, and characterized from a carbazole-degrading Sphingomonas sp. strain XLDN2-5. The car gene cluster (carRAaBaBbCAc) and fdr gene were accompanied on both sides by two copies of IS6100 elements, and organized as IS6100::ISSsp1-ORF1-carRAaBaBbCAc-ORF8-IS6100-fdr-IS6100. Carbazole was converted by carbazole 1,9a-dioxygenase (CARDO, CarAaAcFdr), meta-cleavage enzyme (CarBaBb), and hydrolase (CarC) to anthranilate and 2-hydroxypenta-2,4-dienoate. The fdr gene encoded a novel ferredoxin reductase whose absence resulted in lower transformation activity of carbazole by CarAa and CarAc. The ant gene cluster (antRAcAdAbAa) which was involved in the conversion of anthranilate to catechol was also sandwiched between two IS6100 elements as IS6100-antRAcAdAbAa-IS6100. Anthranilate 1,2-dioxygenase (ANTDO) was composed of a reductase (AntAa), a ferredoxin (AntAb), and a two-subunit terminal oxygenase (AntAcAd). Reverse transcription-PCR results suggested that carAaBaBbCAc gene cluster, fdr, and antRAcAdAbAa gene cluster were induced when strain XLDN2-5 was exposed to carbazole. Expression of both CARDO and ANTDO in Escherichia coli required the presence of the natural reductases for full enzymatic activity.We predict that IS6100 might play an important role in the establishment of carbazole-degrading pathway, which endows the host to adapt to novel compounds in the environment. The organization of the car and ant genes in strain XLDN2-5 was unique, which showed strong evolutionary trail of gene recruitment mediated by IS6100 and presented a remarkable example of rearrangements and pathway establishments.

The methods of lower and upper solutions and monotone iterative technique are employed to the study of integral boundary value problems for a class of first-order impulsive functional differential equations. Sufficient conditions are obtained for the existence of extreme solutions.