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IMPDH inhibitor MPA reduces the interaction of Arl13b and Smo. Arl13b regulates activity of Smo. Arl13b regulates Hh signaling activity. Knockdown of Arl13b inhibits the proliferation, migration and invasion of gastric cancer cells. Overexpression of Arl13b promotes the proliferation, migration and invasion of gastric cancer cells. Knockdown of Arl13b inhibits the growth of SGC7901 cells in vivo. Anti-Smo and Anti-Arl13b antibodies effectively and specifically recognize the indicated proteins. Arl13b expression at RNA level is elevated in gastric cancer tissues.

TGFβ signaling inhibits cell proliferation to block cancer initiation, yet it also enhances metastasis to promote malignancy during breast cancer development. The mechanisms underlying these differential effects are still unclear. Here, we report that HER2/EGFR signaling switches TGFβ function in breast cancer cells from antiproliferation to cancer promotion. Inhibition of HER2/EGFR activity attenuated TGFβ–induced epithelial–mesenchymal transition and migration but enhanced the antiproliferative activity of TGFβ. Activation of HER2/EGFR induced phosphorylation of Smad3 at Ser208 of the linker region through AKT, which promoted the nuclear accumulation of Smad3 and subsequent expression of the genes related to EMT and cell migration. In contrast, HER2/EGFR signaling had no effects on the nuclear localization of Smad2. Knockdown of Smad3, but not Smad2, blocked TGFβ–induced breast cancer cell migration. We observed a positive correlation between the nuclear localization of Smad3 and HER2 activation in advanced human breast cancers. Our results demonstrate a key role for HER2/EGFR in differential regulation of Smad3 activity to shift TGFβ function from antitumorigenic to protumorigenic during breast cancer development.Significance: TGFβ signaling can shift from inhibiting to promoting breast cancer development via HER2/EGFR AKT-mediated phosphorylation of Smad3 at S208, enhancing its nuclear accumulation and upregulation of EMT-related genes.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6073/F1.large.jpg. Cancer Res; 78(21); 6073–85. ©2018 AACR.

Multiple myeloma is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here, we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in multiple myeloma cell lines and primary bone marrow cells from patients. CD166+ multiple myeloma cells homed more efficiently than CD166− cells to the bone marrow of engrafted immunodeficient NSG mice. CD166 silencing in multiple myeloma cells enabled longer survival, a smaller tumor burden, and less osteolytic lesions, as compared with mice bearing control cells. CD166 deficiency in multiple myeloma cell lines or CD138+ bone marrow cells from multiple myeloma patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Furthermore, CD166 deficiency in multiple myeloma cells also reduced the formation of osteolytic disease in vivo after intratibial engraftment. Mechanistic investigation revealed that CD166 expression in multiple myeloma cells inhibited osteoblastogenesis of bone marrow–derived osteoblast progenitors by suppressing Runx2 gene expression. Conversely, CD166 expression in multiple myeloma cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in multiple myeloma cell homing to the bone marrow and multiple myeloma progression, rationalizing its further study as a candidate therapeutic target for multiple myeloma treatment. Cancer Res; 76(23); 6901–10. ©2016 AACR.

Financial time series are nonlinear, volatile and chaotic. Inspired by quantum computing, this paper proposed a new model, called primary ensemble empirical mode decomposition combined with quantum neural network (PEEMD-QNN) in predicting the stock index. PEEMD-QNN takes the advantages of the PEEMD which retains the main component of modal component and QNN. To demonstrate that our PEEMD-QNN model is robust, we used the new model to predict six major stock index time series in China at a specific time. Detailed experiments are implemented for both of the proposed prediction models, in which empirical mode decomposition combined with QNN (EMD-QNN), QNN and BP neural network are compared. The results demonstrate that the proposed PEEMD-QNN model has higher accuracy than BP neural network, QNN model and EMD-QNN model in stock market prediction.

To investigate the antitumor effects of the selective hypoxia-inducible factor-1 (HIF-1) inhibitors echinomycin and PX-478 on uterine fibroids.Experimental study using in vitro primary culture systems and an in vivo mouse xenograft model.Academic university center.Women with uterine fibroids who underwent hysterectomy or myomectomy.Administration of the selective HIF-1 inhibitors echinomycin and PX-478 to the media of the primary cultured uterine fibroid cells and to nonobese diabetic/severe combined immunodeficient mice bearing fibroid xenografts consisting of the primary cultured fibroid cells and type Ⅰ collagen gels beneath the kidney capsule.Cell proliferation was measured by Cell Counting Kit-8 assay. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and by measuring caspase 3 and 7 activities. The xenografts were evaluated by gross appearance, surface area, and histology. The Ki-67 index was measured to evaluate proliferation of the xenografts.Both echinomycin and PX-478 inhibited cell proliferation and induced apoptosis in fibroid cells cultured under hypoxia and normoxia. Enlargement of the fibroid xenografts was significantly attenuated. The Ki-67 index significantly decreased after the administration of the HIF-1 inhibitors in the xenograft model. Eight of 27 xenografts treated with the HIF-1 inhibitors contained calcification and hyalinizing components from 3 days after the grafting to 2 weeks, suggesting that the HIF-inhibitors induce degeneration of the fibroid xenografts.The selective HIF-1 inhibitors echinomycin and PX-478 show antitumor effects against uterine fibroids both in vitro and in vivo. These findings support the potential use of HIF-1 inhibitors for the treatment of uterine fibroids.

To build small and efficient neural networks for hyperspectral image (HSI) classification, this letter presents a depthwise separable residual neural network (ResNet). This approach, motivated by the popular MobileNet architecture, decomposes the traditional spatial-spectral convolution operation into a spatial-independent pointwise spectral convolution and a spectral-independent depthwise spatial convolution. It allows the separation of spectral and spatial information in HSI and also greatly reduces the network size to prevent the overfitting issue. To better preserve the class boundaries and edges, the proposed ResNet is integrated into a maximum a posteriori (MAP) framework to allow the use of the conditional random field (CRF) model. The experiment results on benchmark HSI scene demonstrate that the proposed ResNet compares favorably with several popular deep learning HSI classifiers and that the ResNet-CRF approach achieves higher accuracy and better boundaries among neighboring classes.

Sentinel-1 is a synthetic aperture radar platform that provides free and open-source images of the Earth. A product type of Sentinel-1 is ground range detected (GRD), which records intensity while discarding phase information from the radar backscatter. Especially in cross-polarized GRD images, there are noticeable intensity changes throughout the image that are caused by amplifying the noise floor of the signal, which varies due to the nonuniform radiation pattern of the satellite's antenna. While Sentinel-1 has instrument processing facility (IPF) software to estimate the noise floor, even in the newer versions (3.1 or above) of the IPF software there are still instances where the estimates provided do not fit the actual noise floor in the image, which is particularly noticeable in transitions between adjacent subswaths. In this work, we propose a method that reduces the impact of the varying noise-floor throughout the image. The method models the intensity of the noise floor to be a power function of the radiation pattern power. The method divides the swath into several sections depending on the location of the local minimum and maximum of the radiation pattern power with respect to the range. The parameter estimation is portrayed as a geometric programming problem that is transformed into a linear programming problem by logarithmic transformation. Affine offsets are computed for each subswath by a weighted least squares approach. Vast improvement is found on extra-wide (EW) and interferometric wide (IW) Sentinel-1 modes over cross-polarized images. Code implementation is available at https://github.com/PeterQLee/sentinel1_denoise_rs.

Hedgehog (Hh) signalling plays essential roles in regulating embryonic development and contributes to tumour initiation, growth and progression in multiple cancers. The detailed mechanism by which Hh signalling participates in tumour growth warrants thorough study, although several downstream target genes have been identified. Herein, a set of novel targets of Hh signalling was identified in multiple types of tumour cells via RNA-Seq analysis. Among these targets, the expression regulation and oncogenic function of the extracellular matrix component biglycan (BGN) were investigated. Further investigation verified that Hh signalling activates the expression of BGN via the transcription factor Gli2, which directly binds to the promoter region of BGN. Functional assays revealed that BGN facilitates tumour cell growth and proliferation in colorectal cancer (CRC) cells, and xenograft assays confirmed that BGN also promotes tumour growth . Moreover, analysis of clinical CRC samples showed that both the protein and mRNA levels of BGN are increased in CRC tissues compared to those in adjacent tissues, and higher expression of BGN is correlated with poorer prognosis of CRC patients, further confirming the function of BGN in CRC. Taken together, aberrantly activated Hh signalling increases the expression of BGN, possibly regulates the extracellular matrix, and thereby promotes tumour growth in CRC.

Timely information on lake ice cover conditions is critical in support of commercial shipping, winter-road transportation, and winter leisure activities such as snowmobiling and ice fishing. Monito...

OBJECTIVES The purpose of this study was to evaluate the relationship between blood glucose level and the prevalence and frequency of stress urinary incontinence (SUI) in women. METHODS We conducted a cross-sectional study of female participants in the National Health and Nutrition Examination Survey database between 2007 and 2016. Dose-response analysis curves and univariate and multivariate logistic regressions were used to determine the relationship between blood glucose level and the prevalence and frequency of SUI. RESULTS A total of 10,771 participants were included in this study, of which 6,466 (60.0%) reported no SUI, 4,305 (31.1%) reported monthly SUI, and 953 (8.8%) reported weekly SUI. We found that the blood glucose levels were higher in the weekly SUI group than in the monthly SUI and no SUI groups. Based on blood glucose levels, participants were divided into 3 groups: ≤86.0 mg/dL group, >86.0 to 98.0 mg/dL group, and >98.0 mg/dL group. Dose-response curves showed a nonlinear positive correlation between blood glucose levels and the prevalence and extent of SUI, and participants in the glucose >98.0 mg/dL group had a 15.2% higher risk (adjusted odds risk, 1.152; 95% confidence interval, 1.027-1.293; P = 0.016) of SUI prevalence and 12.5% higher risk (adjusted odds risk 1.125; 95% confidence interval, 1.009-1.255; P = 0.034) of SUI frequency than participants in the glucose ≤86.0 mg/dL group. CONCLUSIONS We found that the prevalence and frequency of SUI in women were positively correlated with blood glucose levels, and these findings warrant further study and application to clinical practice to control SUI in women.

Objectives This study aims to infer phylogenetic relationship of OXA-232-producing Klebsiella pneumoniae (OXA232Kp) strains collected from a Chinese hospital, and to determine the composition and genetic background of antimicrobial resistance genes (ARGs) among these strains. Methods A total of three non-duplicated OXA232Kp strains were collected from a Chinese hospital. Whole genome sequencing (WGS) was used to determined their genome sequences, and then a genomic comparison of ARG-carrying genetic elements from these three strains with related sequences were performed. Phylogenetic analysis was conducted by constructing maximum-likelihood phylogenetic tree. Results Compared with other Chinese sequence type 15 (ST15)-OXA232Kp strains, three ST15-OXA232Kp strains in this study could be divided into a single subgroup in phylogenetic relationship. The composition and genetic background of ARGs were identical in these three strains. A total of three ARG-carrying genetic elements or multidrug resistance (MDR) regions were determined, including a truncated Tn2013-like IS-based transposition unit, a unit transposition Tn6867b and a 40.9-kb MDR region. Conclusions This study reported a clonal dissemination of ST15-OXA232Kp strains carrying multiple ARGs in a Chinese hospital. A comprehensive evolutionary and genomic analysis gained a deeper understanding of OXA232Kp. Further surveillance and study should be advocated to prevent the dissemination of OXA232Kp strains in China.

Despite unprecedented successes of antibody-based cancer immunotherapy, the serious side effects and rapid clearance following systemic administration remain big challenges to realize its full potential. At the same time, combination immunotherapy using multiple antibodies has shown particularly promising in cancer treatment. It is noticed that the working mechanisms of natural holdase and foldase chaperone are desirable to overcome the limitations of therapeutic antibodies. Holdase chaperone stabilizes unfolded client and prevents it from activation and degradation, while foldase chaperone assists unfolded client to its native state to function. Here a holdase/foldase mimetic nanochaperone (H/F-nChap) to co-delivery two types of monoclonal antibodies (mAbs), αCD16 and αPDL1, and resiquimod (R848) is developed, which significantly improves cancer immunotherapy. The H/F-nChap presents holdase activity in blood and normal tissues that hides and protects mAbs from unnecessary targeted activation and degradation, thereby prolonging blood circulation and reducing immunotoxicity in vivo. Furthermore, H/F-nChap switches to foldase activity in the tumor microenvironment that exposes mAbs and releases R848 to enhance the engagement between NK cells and tumor cells and promote immune activation, respectively. The H/F-nChap represents a strategy for safe and spatiotemporal delivery of multiple mAbs, providing a promising platform for improved cancer immunotherapy.

This qualitative study explores novice nurse academics’ experiences and perceptions of academic identity formation through the theoretical lens of space. We analyse the data from four participants ...

The COVID-19 pandemic is having a huge impact on global tourism, including wildlife tourism. Based on the Theory of Planned Behavior (TPB), risk perceptions of wildlife tourism are explored and a s...

Cr/Al/Ti/Au stacks with two thicknesses of Al layers were employed as reflective n-type electrodes for 274 nm AlGaN-based flip-chip deep ultraviolet light-emitting diodes (DUV LEDs). Large bulges arose in the annealed n-type electrode with 120-nm-thick Al layer, resulting in cracks within the upper rugged SiO2 passivation layer after burn-in test. Sn atoms from solder paste migrated along the cracks and served as leakage current channels, which accelerated device degradation. In contrast, the annealed n-type electrode with 60-nm-thick Al layer retained uniform morphology. And the DUV LEDs with such n-type electrode exhibited good reliability and normalized optical power of 86.8% after burn-in test of 1000 h. This study provides insight into electrode defects related degradation behavior and helps to improve the reliability of AlGaN-based flip-chip DUV LEDs with reflective electrode.

This study aims to further clarify whether the addition of metformin to insulin treatment improve cardiovascular and cerebrovascular risk factors in individuals with T1DM.Electronic databases were searched for randomized controlled trials in which the efficacy and safety of metformin were compared with those of a placebo for risk factors of cardiovascular and cerebrovascular disease among individuals with T1DM, and a meta-analysis was conducted.Thirteen cardiovascular studies were identified. In the metformin group, mean carotid intimal media thickness was significantly reduced by 0.03 mm, ascending aortic pulse wave velocity by 6.3 m/s, descending aortic wall shear stress by 1.77 dyn/cmMetformin can ameliorate cardiovascular and cerebrovascular risk factors through non-hypoglycemic multiple pathways in individuals with T1DM.

Hereditary spherocytosis (HS) is a common hematological genetic disorder that results in anemia, jaundice and splenomegaly. It is caused by mutations in the ANK1, SPTA, SPTB, SLC4A1 and EPB42 genes, which encode red blood cell membrane and skeletal proteins. Patients show high heterogeneity in phenotype and genotype and the genotype-phenotype correlation still requires clarification. Here, a novel splicing mutation (ANK1: c.4391-2 AC) was identified by whole-exome sequencing (WES) and Sanger sequencing in a Chinese boy who exhibited a moderately severe HS phenotype. However, his father exhibited a mild phenotype, despite carrying the same HS-causing mutation. The function of the mutant ANK1 protein was analyzed by both bioinformatics and experimental analysis. The mutant protein (p.N1463Kfs*4) showed a different 3D-structure and altered subcellular localization, when compared with the wild-type ANK1 protein. These changes disrupted the normal cell membrane structure and resulted in spheroidized red blood cells. Amplification of cDNA from the son and his father revealed a difference in expression of the abnormal transcript produced by the splicing mutation. We proposed that the lower expression of the mutant allele may have contributed to the relatively mild symptoms of the father. Our study verified ANK1 c. c.4391-2 AC as a novel pathogenic mutation that causes HS. We have also provided new insights into the interpretation of phenotypic variability within families, which could greatly improve the clinical diagnosis and genetic counseling of HS.

We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies.This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437.Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6).Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib.BeiGene.

Continuous glucose monitoring systems have been widely used but discrepancies among various brands of devices are rarely discussed. This study aimed to explore differences in glycemic metrics between FreeStyle Libre (FSL) and iPro2 among adults with type 1 diabetes mellitus (T1DM).Participants with T1DM and glycosylated hemoglobin of 7%-10% were included and wore FSL and iPro2 for 2 weeks simultaneously. Datasets collected on the insertion and detachment day, and those with insufficient quantity (90%) were excluded. Agreements of measurement accuracy and glycemic metrics were evaluated.A total of 40 498 paired data were included. Compared with the values from FSL, significantly higher median value was observed in iPro2 (147.6 [106.2, 192.6] vs. 144.0 [100.8, 192.6] mg/dl, p 0.001) and the largest discordance was observed in hypoglycemic range (median absolute relative difference with iPro2 as reference value: 25.8% [10.8%, 42.1%]). Furthermore, significant differences in glycemic metrics between iPro2 and FSL were also observed in time in range (TIR) 70-180 mg/dl (TIR, 62.8 ± 12.4% vs. 58.8 ± 12.3%, p = 0.004), time spent below 70 mg/dl (4.4 [1.8, 10.9]% vs. 7.2 [5.4, 13.3]%, p 0.001), time spent below 54 mg/dl (0.9 [0.3, 4.0]% vs. 2.6 [1.3, 5.6]%, p = 0.011), and coefficient of variation (CV, 38.7 ± 8.5% vs. 40.9 ± 9.3%, p = 0.017).During 14 days of use, FSL and iPro2 provided different estimations on TIR, CV, and hypoglycemia-related parameters, which needs to be considered when making clinical decisions and clinical trial designs.背景: 连续血糖监测系统已被广泛使用，但不同品牌的设备之间的差异很少被讨论。本研究旨在探讨成人1型糖尿病(T1DM)患者中Freestyle Libre(FSL)和iPro2在血糖指标上的差异。 方法: 选择T1DM和糖化血红蛋白(HbA1c)为7%~10%的受试者，同时使用FSL和iPRO 2两周。排除了在植入和取出当天收集的数据集，以及质量不够高(90%)的数据集。对测量准确度和血糖指标的一致性进行评估。 结果: 共纳入40498对数据。与FSL相比，iPro2的中位数显著升高(147.6[106.2,192.6]vs 144.0[100.8,192.6]mg/dL，P0.001)，其中不一致性最高的是低血糖范围(以iPro2为参考值的绝对差值中位数:25.8% [10.8%,42.1%])。此外，iPro2和FSL在70-180 mg/dL达标时间(TIR)内的血糖指标也有显著差异(TIR，62.8±12.4vs.58.8±12.3%，P=0.004)，在70 mg/dL以下的时间(4.4 [1.8, 10.9]% vs.7.2[5.4，13.3]%，P0.001])，在54 mg/dL以下的时间(0.9[0.3，4.0]% vs.2.6[1.3，5.6]%, p=0.011)，变异系数(CV, 38.7±8.5% vs.40.9±9.3%，P=0.017)。 结论: 在使用的14天中，FSL和iPro2对TIR、CV和低血糖相关参数提供了不同的估计，在临床决策和临床试验设计时需要考虑这些因素。.

This paper investigates the deep neural networks for rapid and accurate detection of building rooftops in aerial orthoimages. The networks were trained using the manually labeled rooftop vector dat...

Hedgehog (Hh) signaling plays a critical role in embryogenesis and tissue homeostasis, and its deregulation has been associated with tumor growth. The tumor suppressor SuFu inhibits Hh signaling by preventing the nuclear translocation of Gli and suppressing cell proliferation. Regulation of SuFu activity and stability is key to controlling Hh signaling. Here, we unveil SuFu Negating Protein 1 (SNEP1) as a novel Hh target, that enhances the ubiquitination and proteasomal degradation of SuFu and thus promotes Hh signaling. We further show that the E3 ubiquitin ligase LNX1 plays a critical role in the SNEP1-mediated degradation of SuFu. Accordingly, SNEP1 promotes colorectal cancer (CRC) cell proliferation and tumor growth. High levels of SNEP1 are detected in CRC tissues and are well correlated with poor prognosis in CRC patients. Moreover, SNEP1 overexpression reduces sensitivity to anti-Hh inhibitor in CRC cells. Altogether, our findings demonstrate that SNEP1 acts as a novel feedback regulator of Hh signaling by destabilizing SuFu and promoting tumor growth and anti-Hh resistance.

Mitochondrial dysfunction plays a key role in the pathogenesis and progression of Alzheimer's Disease (AD). Our previous studies showed that over expression of AD-associated mutant β-amyloid precursor protein (APP) led to abnormalities of mitochondrial biogenesis and mitophagy, leading to mitochondrial dysfunction. However, the mechanism remains unclear. In this study, we investigated the effect of orexin-A on mitochondrial biogenesis, mitophagy and mitochondrial structure in overexpression of AD-associated mutant APP cells. We used 20E2 cells as the AD cell model. 20E2 cells were treated with orexin-A (50, 100 nmol/L). The effect of different concentrations of orexin-A on cell activity was detected by MTT. As compared with the non-treated 20E2 cells, orexin-A-treated 20E2 cells showed increased expression of APP, decreased cell viability and decreased adenosine triphosphate (ATP) level, decreased levels of regulatory proteins of mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC-1α], nuclear respiratory factor 1/2 [NRF1/2], mitochondrial transcription factor A [TFAM]), increased levels of regulatory proteins of mitophagy (Parkin, PTEN-induced putative kinase 1 [PINK1], microtubule-associated protein light chain 3 II/I [LC3-II/LC3-I]) and decreased p62 level, with damaged mitochondrial structure. Orexin-A may reduce mitochondrial biogenesis, enhance mitophagy and damage mitochondrial structure in AD.

Multi-scale image decomposition (MID) is a fundamental task in computer vision and image processing that involves the transformation of an image into a hierarchical representation comprising of different levels of visual granularity from coarse structures to fine details. A well-engineered MID disentangles the image signal into meaningful components which can be used in a variety of applications such as image denoising, image compression, and object classification. Traditional MID approaches such as wavelet transforms tackle the problem through carefully designed basis functions under rigid decomposition structure assumptions. However, as the information distribution varies from one type of image content to another, rigid decomposition assumptions lead to inefficiently representation, i.e., some scales can contain little to no information. To address this issue, we present Deep Residual Transform (DRT), a data-driven MID strategy where the input signal is transformed into a hierarchy of non-linear representations at different scales, with each representation being independently learned as the representational residual of previous scales at a user-controlled detail level. As such, the proposed DRT progressively disentangles scale information from the original signal by sequentially learning residual representations. The decomposition flexibility of this approach allows for highly tailored representations cater to specific types of image content, and results in greater representational efficiency and compactness. In this study, we realize the proposed transform by leveraging a hierarchy of sequentially trained autoencoders. To explore the efficacy of the proposed DRT, we leverage two datasets comprising of very different types of image content: 1) CelebFaces and 2) Cityscapes. Experimental results show that the proposed DRT achieved highly efficient information decomposition on both datasets amid their very different visual granularity characteristics.

Hyperspectral images classification relies on the accurate and efficient extraction of discriminative features, detail preservation, and efficient learning with limited training samples. This article, therefore, presents an advanced neural network architecture combined with convolutional conditional random fields (ConvCRF) and region growing (RGW) approaches to address these key issues. First, a depthwise separable fully convolutional residual network (DFRes) is proposed for efficient feature learning, where a fully convolutional operation ensures a larger field of view, and residual learning and depthwise separable convolution can mitigate the problem of vanishing gradient and overfitting. Second, because the collection of ground-truth labels is usually difficult, the proposed architecture integrates the RGW method to effectively overcome the problem of limited training samples. Third, ConvCRF is used to preserve the image details for fine-grained predictions. Finally, the abovementioned key components are coherently integrated into the new semisupervised framework, i.e., DFRes with conditional random fields and RGW. Experimental results on three hyperspectral datasets demonstrate that the proposed approach outperforms other state-of-the-art methods.

Although accurate training and initialization information is difficult to acquire, unsupervised hyperspectral subpixel mapping (SPM) without relying on this predefined information is an insufficiently addressed research issue. This letter presents a novel Bayesian approach for unsupervised SPM of hyperspectral imagery (HSI) based on the Markov random field (MRF) and a band-weighted discrete spectral mixture model (BDSMM), with the following key characteristics. First, this is an unsupervised approach that allows adjustment of abundance and endmember information adaptively for less relying on algorithm initialization. Second, this approach consists of the BDSMM for accommodating the noise heterogeneity and the hidden label field of subpixels in HSI. The BDSMM also integrates SPM into the spectral mixture analysis and allows enhanced SPM by fully exploring the endmember-abundance patterns in HSI. Third, the MRF and BDSMM are integrated into a Bayesian framework to use both the spatial and spectral information efficiently, and an expectation-maximization (EM) approach is designed to solve the model by iteratively estimating the endmembers and the label field. Experiments on both simulated and real HSI demonstrate that the proposed algorithm can yield better performance than traditional methods.

High-resolution lake ice/water observations retrieved from satellite imagery through efficient, automated methods can provide critical information to lake ice forecasting systems. Synthetic aperture radar (SAR) data is well-suited to this purpose due to its high spatial resolution (approximately 50 m). With recent increases in the volume of SAR data available, the development of automated retrieval methods for these data is a priority for operational centres. However, automated retrieval of ice/water data from SAR imagery is difficult, due to ambiguity in ice and open water signatures, both in terms of image tone and in terms of parameterized texture features extracted from these images. Convolutional neural networks (CNNs) can learn features from imagery in an automated manner, and have been found effective in previous studies on sea ice concentration estimation from SAR. In this study the use of CNNs to retrieve ice/water observations from dual-polarized SAR imagery of two of the Laurentian Great Lakes, Lake Erie and Lake Ontario, is investigated. For data assimilation, it is crucial that the retrieved observations are of high quality. To this end, quality control measures based on the uncertainty of the CNN output to eliminate incorrect retrievals are discussed and demonstrated. The quality control measures are found to be effective in both dual-polarized and single-polarized retrievals. The ability of the CNN to downscale the coarse resolution training labels is demonstrated qualitatively.

Background Tumor angiogenesis is essential for solid tumor progression, invasion and metastasis. The aim of this study was to identify potential signaling pathways involved in tumor angiogenesis. Methods Genetically engineered mouse models were used to investigate the effects of endothelial ARL13B(ADP-ribosylation factor-like GTPase 13B) over-expression and deficiency on retinal and cerebral vasculature. An intracranially transplanted glioma model and a subcutaneously implanted melanoma model were employed to examine the effects of ARL13B on tumor growth and angiogenesis. Immunohistochemistry was used to measure ARL13B in glioma tissues, and scRNA-seq was used to analyze glioma and endothelial ARL13B expression. GST-fusion protein-protein interaction and co-immunoprecipitation assays were used to determine the ARL13B-VEGFR2 interaction. Immunobloting, qPCR, dual-luciferase reporter assay and functional experiments were performed to evaluate the effects of ARL13B on VEGFR2 activation. Results Endothelial ARL13B regulated vascular development of both the retina and brain in mice. Also, ARL13B in endothelial cells regulated the growth of intracranially transplanted glioma cells and subcutaneously implanted melanoma cells by controlling tumor angiogenesis. Interestingly, this effect was attributed to ARL13B interaction with VEGFR2, through which ARL13B regulated the membrane and ciliary localization of VEGFR2 and consequently activated its downstream signaling in endothelial cells. Consistent with its oncogenic role, ARL13B was highly expressed in human gliomas, which was well correlated with the poor prognosis of glioma patients. Remarkably, ARL13B, transcriptionally regulated by ZEB1, enhanced the expression of VEGFA by activating Hedgehog signaling in glioma cells. Conclusions ARL13B promotes angiogenesis and tumor growth by activating VEGFA-VEGFR2 signaling. Thus, targeting ARL13B might serve as a potential approach for developing an anti-glioma or anti-melanoma therapy.

For several decades, Western universities have been subject to wide-ranging structural, financial and ideological changes. These changes have problematised afresh the meaning of academic identity a...

New to the academy’s ‘publish or perish’ game, doctoral students hold varied expectations of supervisors in relation to their publishing endeavours. These expectations can be unrealistic or contrad...

Unmixing is a key but difficult issue in hyperspectral image (HSI) processing, and many unmixing methods have been proposed. However, an effective introduction of the spatial context in unmixing remains a challenge but is a necessary condition for many real scene applications. In this letter, a new nonnegative matrix factorization (NMF) method that combines nonlocal spatial information with spatial group sparsity (NLNMF) is proposed. Each superpixel generated by the simple linear iterative clustering (SLIC) segmentation method was used as a group. The search region of the nonlocal means method was adaptively set using a superpixel label from each spectrum to find the similar spectra to reestimate the reference spectrum. Additionally, the sparsity of spectra in the same superpixel was considered to be the same. Experiment results for synthetic and real HSI showed that the proposed method not only can more accurately estimate the endmember and abundance compared with other unmixing methods but also has good performance regarding antinoise.

Di-2-ethylhexyl phthalate (DEHP) has been widely used as a plasticizer in industry and can affect memory; however, the underlying mechanism remains unclear. In the present study, mouse HT22 cells, an immortalized hippocampal neuronal cell line, was utilized as an in vitro model. We showed that DEHP dramatically inhibited cell viability and increased lactate dehydrogenase (LDH) release from the cells in a dose-dependent manner, suggesting that DEHP could cause cytotoxicity of mouse HT22 cells. The protein levels of cleaved Caspase-8, cleaved Caspase-3, and Bax markedly increased in the DEHP-treated cells, whereas there was a significant decrease in the Bcl-2 protein level, implying that DEHP could induce apoptosis of mouse HT22 cells. DEHP exposure significantly increased the content of malondialdehyde, whereas it markedly decreased the level of glutathione and the activities of glutathione peroxidase and superoxide dismutase, suggesting that DEHP induced oxidative stress of the cells. Compared with the DEHP-treated group, the inhibition of cell viability and the release of LDH were rescued in the N-acetyl-l-cysteine plus DEHP group. Furthermore, inhibition of oxidative stress could rescue the induction of apoptosis by DEHP. Collectively, our results indicated that DEHP could induce apoptosis of mouse HT22 cells via oxidative stress.

Food safety and quality are issues of great concern to food producers and consumers. Key challenges towards achieving these include availability of rapid, user-friendly, economic and reliable techniques to detect problems such as antibiotic residues. Therefore, the present study was conducted to evaluate performance of plastic film test plate (PFTP) as influenced by antibiotic type, test bacterium, inoculum volume and concentration. Comparison was made to the microtiter test plate (MTP) and the National Standard method (SN/T 3979-2014). For this, antibiotic susceptibility testing was conducted on four bacterial types (Micrococcus luteus, Streptococcus thermophillus suspensions, Staphylococcus aureus and Coliform bacteria) against three antibiotics (penicillin G, sulfadiazine and tetracycline). Results showed high susceptibility of Micrococcus luteus to penicillin G with minimum inhibitory concentration of 3 µg L−1 and 1 µg L−1 via PFTP and MTP respectively. Optimum performance was realized at bacterial concentration of 104 CFU ml−1 with detection limit of 1 µg L−1, sensitivity and predictive positive value (PPV) of 81–83% and 97–100% respectively. Detection time was recorded as 6 and 9 h for MTP and PFTP respectively compared to the 18–24 h of the National Standard method (SN/T 3979–2014). The microbiological plastic film test plate under optimized bacterial culture conditions demonstrated tremendous potential for rapid and reliable detection of antibiotics in milk.

Although efficient hyperspectral image (HSI) denoising relies on complete and accurate description and modeling the spatial–spectral signal in HSI, the current approaches do not fully account for key characteristics of HSI, i.e., the mixed spectra effect, the spatial nonstationarity effect, and noise variance heterogeneity effect. To address this issue, this article presents a linear spectral mixture model with nonlocal means constraint (LSMM-NLMC), with the following advantages. First, LSMM-NLMC can effectively learn the signal in mixed pixels in HSI by estimating clean endmembers and abundances for image restoration. Second, LSMM-NLMC can efficiently address nonstationary spatial correlation effect by imposing NLMC on the latent scene signal. Last, LSMM-NLMC provides accurate noise characterization by accounting for noise variance heterogeneity effect using a band-dependent noise model and a band-weighted Mahalanobis distance for similarity measurement. A novel optimization method based on the expectation–maximization (EM) algorithm and the purified means approach is used to efficiently solve the resulting maximum a posterior (MAP) problem. The experiments on both simulated and real HSI data sets demonstrate that the visual quality and denoising accuracy are significantly improved by the proposed LSMM-NLMC compared with previous methods.

Gold nanostars (AuNS) are promising carriers for targeted delivery of therapeutic oligonucleotides, but their potential in fabricating an on-demand drug release system in a facile and robust way remains to be explored. In this paper, we used a model aptamer (HApt), acting not only as a target ligand but also as a natural thermal-responsive material, to decorate AuNS. The prepared gold nanoconstruct, HApt@AuNS, displayed stoichiometric loading capacity of the anthracycline drug doxorubicin (Dox). The on-demand drug release was realized by illuminating nanoconstructs with near-infrared (NIR) light. Furthermore, a higher degree of Dox release from the nanoconstructs was achieved in an acidic environment, compared to neutral conditions. The

Research has shown that cognitive and physical functioning of older adults can be reflected in indicators such as walking speed. While changes in cognition, mobility, or health cause changes in gait speed, often gradual variations in walking speed go undetected until severe problems arise. Discrete clinical assessments during clinical consultations often fail to detect changes in day-to-day walking speeds and do not reflect walking speeds in everyday environments, where most of the mobility issues happen. In this paper, we compare four walking speed measurement technologies to a GAITRite mat (gold standard): (1) an ultra wideband radar (covering the band from 3.3 GHz to 10 GHz), (2) a narrow band 24-GHz radar (with a bandwidth of 250 MHz), (3) a perception Neuron Motion Tracking suit, and (4) a thermal camera. Data were collected in parallel using all sensors at the same time for 10 healthy adults for normal and slow walking paces. A comparison of the sensors indicates better performance at lower gait speeds, with offsets (when compared to GAITRite) between 0.1 and 20% for the ultra wideband radar, 1.9 and 17% for the narrowband radar, 0.1 and 38% for the thermal camera, and 1.7 and 38% for the suit. This paper supports the potential of unobtrusive radar-based sensors and thermal camera technologies for ambient autonomous gait speed monitoring for contextual, privacy-preserving monitoring of participants in the community.

Antibiotic residues in animal-derived food products such as milk pose a potential health risk to consumers. A portable antimicrobial screening test plate was fabricated particularly for on-farm testing of milk. A cold-water soluble compound gelling agent composed of guar gum (GG) and konjac glucomannan (KG) was prepared and its properties were optimized for enhancing performance of the test plate. A ratio of 4:6 (GG:KG) showed improved gel strength, cohesiveness, transmittance, and water diffusion of the compound gel. Microbial colony number and size were also increased. The test plate displayed a minimum inhibition concentration of 4 µg/L penicillin G and clearer zone of inhibition. Detection time was also significantly reduced to approximately 9–15 h compared to the conventional agar plate method. The plastic film test plate with optimized compound gel demonstrated tremendous potential for detection of antibiotics in milk.

To guarantee that ships can navigate safely, the International Maritime Organization mandates that all ships navigating internationally must install the automatic identification system (AIS). AIS works in the very high-frequency (VHF) maritime mobile band, and to ensure the signal receiving performance of AIS equipment, it is necessary that the receiver sensitivity can be quickly evaluated and detected. Hence, we propose an evaluation model of AIS receiver sensitivity. The model first measures the packet error rate (PER) of AIS data transmission at a specific power. The distribution of the AIS receiver sensitivity characteristic curve under any transmitted power can be directly obtained, and then whether or not the sensitivity of the AIS receiver satisfies the performance requirements can be quickly evaluated. Regression analysis and the results of actual measurement demonstrate that this model has a goodness of fit (R-squared) value of 0.99 between the power–PER curve of the analog input signal and the measured data, which signifies test efficiency and accuracy beyond conventional test methods.

Over a half of the diabetic individuals develop macrovascular complications that cause high mortality. Oxidative stress (OS) promotes endothelial dysfunction (ED) which is a critical early step toward diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system and combats diabetes-induced OS. Previously, we found that impaired NRF2 antioxidant signaling contributed to diabetes-induced endothelial OS and dysfunction in mice. The present study has investigated the effect of microRNA-200a (miR-200a) on NRF2 signaling and diabetic ED. In aortic endothelial cells (ECs) isolated from C57BL/6 wild-type (WT) mice, high glucose (HG) reduced miR-200a levels and increased the expression of kelch-like ECH-associated protein 1 (Keap1) – a target of miR-200a and a negative regulator of NRF2. This led to the inactivation of NRF2 signaling and exacerbation of OS and inflammation. miR-200a mimic (miR-200a-M) or inhibitor modulated KEAP1/NRF2 antioxidant signaling and manipulated OS and inflammation under HG conditions. These effects were completely abolished by knockdown of Keap1, indicating that Keap1 mRNA is a major target of miR-200a. Moreover, the protective effect of miR-200a-M was completely abrogated in aortic ECs isolated from C57BL/6 Nrf2 knockout (KO) mice, demonstrating that NRF2 is required for miR-200a’s actions. In vivo, miR-200a-M inhibited aortic Keap1 expression, activated NRF2 signaling, and attenuated hyperglycemia-induced OS, inflammation and ED in the WT, but not Nrf2 KO, mice. Therefore, the present study has uncovered miR-200a/KEAP1/NRF2 signaling that controls aortic endothelial antioxidant capacity, which protects against diabetic ED.