Optical Imaging Deformation Inspection and Quality Level Determination of Multifocal Glasses.

Multifocal glasses are a new type of lens that can fit both nearsighted and farsighted vision on the same lens. This property allows the glass to have various curvatures in distinct regions within the glass during the grinding process. However, when the curvature varies irregularly, the glass is prone to optical deformation during imaging. Most of the previous studies on imaging deformation focus on the deformation correction of optical lenses. Consequently, this research uses an automatic deformation defect detection system for multifocal glasses to replace professional assessors. To quantify the grade of deformation of curved multifocal glasses, we first digitally imaged a pattern of concentric circles through a test glass to generate an imaged image of the glass. Second, we preprocess the image to enhance the clarity of the concentric circles' appearance. A centroid-radius model is used to represent the form variation properties of every circle in the processed image. Third, the deviation of the centroid radius for detecting deformation defects is found by a slight deviation control scheme, and we gain a difference image indicating the detected deformed regions after comparing it with the norm pattern. Fourth, based on the deformation measure and occurrence location of multifocal glasses, we build fuzzy membership functions and inference regulations to quantify the deformation's severity. Finally, a mixed model incorporating a network-based fuzzy inference and a genetic algorithm is applied to determine a quality grade for the deformation severity of detected defects. Testing outcomes show that the proposed methods attain a 94% accuracy rate of the quality levels for deformation severity, an 81% recall rate of deformation defects, and an 11% false positive rate for multifocal glass detection. This research contributes solutions to the problems of imaging deformation inspection and provides computer-aided systems for determining quality levels that meet the demands of inspection and quality control.

A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c acute myeloid leukemia.

Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.

PML nuclear bodies, membrane-less domains acting as ROS sensors?

PML Nuclear bodies (PML NBs) are spherical domains associated with a broad range of activities upon stress responses such as apoptosis, senescence DNA repair, epigenetic control, as well as control of oncogenesis. These bodies are considered as privileged sites for post-translational modifications, where sumoylation plays a key role. Here we summarize recent in vitro and in vivo findings on the link between PML NBs and ROS, in particular PML contributions to oxidative stress response. We discuss how it may regulate switch from cell protection against stress to cell arrest/cell death.

Imidazoquinoxaline derivative EAPB0503: A promising drug targeting mutant nucleophosmin 1 in acute myeloid leukemia.

BACKGROUND: Nucleophosmin 1 (NPM1) is a nucleocytoplasmic shuttling protein mainly localized in the nucleolus. NPM1 is frequently mutated in acute myeloid leukemia (AML). NPM1c oligomerizes with wild-type nucleophosmin 1 (wt-NPM1), and this leads to its continuous cytoplasmic delocalization and contributes to leukemogenesis. Recent studies have shown that Cytoplasmic NPM1 (NPM1c) degradation leads to growth arrest and apoptosis of NPM1c AML cells and corrects wt-NPM1 normal nucleolar localization. METHODS: AML cells expressing wt-NPM1 or NPM1c or transfected with wt-NPM1 or NPM1c as well as wt-NPM1 and NPM1c AML xenograft mice were used. Cell growth was assessed with trypan blue or a CellTiter 96 proliferation kit. The cell cycle was studied with a propidium iodide (PI) assay. Caspase-mediated intrinsic apoptosis was assessed with annexin V/PI, the mitochondrial membrane potential, and poly(adenosine diphosphate ribose) polymerase cleavage. The expression of NPM1, p53, phosphorylated p53, and p21 was analyzed via immunoblotting. Localization was performed with confocal microscopy. The leukemia burden was evaluated by flow cytometry with an anti-human CD45 antibody. RESULTS: The imidazoquinoxaline 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503) induced selective proteasome-mediated degradation of NPM1c, restored wt-NPM1 nucleolar localization in NPM1c AML cells, and thus yielded selective growth arrest and apoptosis. Introducing NPM1c to cells normally harboring wt-NPM1 sensitized them to EAPB0503 and led to their growth arrest. Moreover, EAPB0503 selectively reduced the leukemia burden in NPM1c AML xenograft mice. CONCLUSIONS: These findings further reinforce the idea of targeting the NPM1c oncoprotein to eradicate leukemic cells and warrant a broader preclinical evaluation and then a clinical evaluation of this promising drug. Cancer 2017;123:1662-1673. © 2017 American Cancer Society.

Antiangiogenic and antihepatocellular carcinoma activities of the Juniperus chinensis extract.

BACKGROUND: To identify a novel therapeutic agent for hepatocellular carcinoma (HCC), for which no promising therapeutic agent exists, we screened a panel of plants and found that Juniperus chinensis exhibited potential antiangiogenic and anti-HCC activities. We further investigated the antiangiogenic and anti-HCC effects of the active ingredient of J. chinensis extract, CBT-143-S-F6F7, both in vitro and in vivo. METHODS: A tube formation assay conducted using human umbilical vein endothelial cells (HUVECs) was first performed to identify the active ingredient of CBT-143-S-F6F7. A series of angiogenesis studies, including HUVEC migration, Matrigel plug, and chorioallantoic membrane (CAM) assays, were then performed to confirm the effects of CBT-143-S-F6F7 on angiogenesis. The effects of CBT-143-S-F6F7 on tumor growth were investigated using a subcutaneous and orthotopic mouse model of HCC. In vitro studies were performed to investigate the effects of CBT-143-S-F6F7 on the cell cycle and apoptosis in HCC cells. Moreover, protein arrays for angiogenesis and apoptosis were used to discover biomarkers that may be influenced by CBT-143-S-F6F7. Finally, nuclear magnetic resonance analysis was conducted to identify the compounds of CBT-143-S-F6F7. RESULTS: CBT-143-S-F6F7 showed significantly antiangiogenic activity in various assays, including HUVEC tube formation and migration, CAM, and Matrigel plug assays. In in vivo studies, gavage with CBT-143-S-F6F7 significantly repressed subcutaneous Huh7 tumor growth in severe combined immunodeficient (SCID) mice, and prolonged the survival of orthotopic Huh7 tumor-bearing SCID mice (a 40 % increase in median survival duration compared with the vehicle-treated mice). Immunohistochemical staining of subcutaneous Huh7 tumors in CBT-143-S-F6F7-treated mice showed a significantly decrease in the cell cycle regulatory protein cyclin D1, cellular proliferation marker Ki-67, and endothelial marker CD31. CBT-143-S-F6F7 caused arrest of the G2/M phase and induced Huh7 cell apoptosis, possibly contributing to the inhibition of HCC tumors. Protein array analysis revealed that several angiogenic and antiapoptotic factors were suppressed in CBT-143-S-F6F7-treated Huh7 cells. Finally, five compounds from CBT-143-S-F6F7 were identified. CONCLUSIONS: According to these results, we report for the first time the antiangiogenic and anti-HCC activities of CBT-143-S-F6F7, the active fractional extract of J. chinensis. We believe that CBT-143-S-F6F7 warrants further evaluation as a new anti-HCC drug.

Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities.

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion oncoprotein. Over the years, it has emerged as a model system to understand how this simple (and sometimes sole) genetic alteration can transform hematopoietic progenitors through the acquisition of dominant-negative properties toward both transcriptional control by nuclear receptors and PML-mediated senescence. The fortuitous identification of two drugs, arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA), that respectively bind PML and RARA to initiate PML/RARA degradation, has allowed an unprecedented dissection of the cellular and molecular mechanisms involved in patients' cure by the ATO/ATRA combination. This analysis has unraveled the dual and complementary roles of RARA and PML in both APL initiation and cure by the ATRA/ATO combination. We discuss how some of the features unraveled by APL studies may be more broadly applicable to some other forms of leukemia. In particular, the functional synergy between drugs that promote differentiation and those that initiate apoptosis/senescence to impede self-renewal could pave the way to novel curative combinations.

Comparative study on electro-microfiltration (EMF) of water containing different carbon nanotubes (CNTs).

Disposal and penetration of carbon nanotubes (CNTs) into the environment have raised increasing concerns over the years. In this study, a laboratory scale electro-microfiltration (EMF) was used to treat water containing single wall carbon nanotubes (SWCNTs) and multi-wall carbon nanotubes (MWCNTs). The goal was to examine and compare the performance during EMF of SWCNT and MWCNT. The results showed that the initial flux was increased as the applied electrical voltage increased. At an applied pressure of 49 kPa, the final flux was comparable to pure water flux when the applied electrical field strength was greater than the critical electrical field strength (Ecritical). In addition, dissolved organic carbon (DOC) removal efficiency increased as the electrical voltage increased. Due to high convective transport of organic matter toward the membrane at 98 kPa, a decrease in DOC removal efficiency with increasing electrical field strength was observed. Overall, the fluxes and DOC removal efficiencies for EMF of SWCNT and MWCNT were not significantly different with a 95% confidence.

Assessing the sustainability of smart healthcare applications using a multi-perspective fuzzy comprehensive evaluation approach.

A smart healthcare application can be judged as sustainable if it was already widely used before and will also be prevalent in the future. In contrast, if a smart healthcare application developed during the COVID-19 pandemic is not used after it, then it is not sustainable. Assessing the sustainability of smart healthcare applications is a critical task for their users and suppliers. However, it is also a challenging task due to the availability of data, users' subjective beliefs, and different perspectives. In response to this problem, this study proposes a multi-perspective fuzzy comprehensive evaluation approach to evaluate the sustainability of a smart healthcare application from qualitative, multi-criteria decision-making and time-series perspectives. The proposed methodology has been used to evaluate the sustainability of eight smart healthcare applications. The experimental results showed that the sustainability of a smart healthcare application evaluated from different perspectives may be different. Nevertheless, another technique can be used to confirm the evaluation result generated using one technique. In other words, these views compensate for each other.

Chlorella sorokiniana-Induced Activation and Maturation of Human Monocyte-Derived Dendritic Cells through NF-κB and PI3K/MAPK Pathways.

Chlorella sorokiniana (CS) is a unicellular green alga. The extracts of Chlorella have been used as treatments for relieving hypertension and modulating immune response. The detailed mechanisms are not clear yet. In this study, we sought to study the molecular mechanisms for the polysaccharide fraction of CS-induced immune response. We pulsed dendritic cells (DCs) with CS and found that CS could maturate DCs. CS-maturated DC could activate naïve T cells and stimulate T-cell proliferation and IFN-γ secretion. Furthermore, CS activated PI3K and MAPKs signaling pathways in DCs by interacting with TLR4 receptor. These CS-activated signaling pathways could further activate NF-κB and induce IL-12 production in DCs. This study provides molecular mechanisms for CS-induced DCs activation and immune response.

A fuzzy analytic hierarchy process-enhanced fuzzy geometric mean-fuzzy technique for order preference by similarity to ideal solution approach for suitable hotel recommendation amid the COVID-19 pandemic.

Cities around the world have reopened from the lockdown caused by the COVID-19 pandemic, and more and more people are planning regional travel. Therefore, it is a practical problem to recommend suitable hotels to travelers amid the COVID-19 pandemic. However, it is also a challenging task since the critical factors that affect hotel selection amid the COVID-19 pandemic may be different from those usually considered. From this perspective, the fuzzy analytic hierarchy process-enhanced fuzzy geometric mean-fuzzy technique for order preference by similarity to ideal solution approach is proposed in this study for hotel recommendation. The proposed methodology not only considers the critical factors affecting hotel selection amid the COVID-19 pandemic, but also establishes a systematic mechanism, that is, enhanced fuzzy geometric mean, to simultaneously improve the accuracy and efficiency of the recommendation process. The fuzzy analytic hierarchy process-enhanced fuzzy geometric mean-fuzzy technique for order preference by similarity to ideal solution approach has been successfully applied to recommend suitable hotels to 10 travelers for regional trips amid the COVID-19 pandemic.

Effects of compression garment on muscular efficacy, proprioception, and recovery after exercise-induced muscle fatigue onset for people who exercise regularly.

Fatigue is a major cause of exercise-induced muscle damage (EIMD). Compression garments (CGs) can aid post-exercise recovery, therefore, this study explored the effects of CGs on muscular efficacy, proprioception, and recovery after exercise-induced muscle fatigue in people who exercise regularly. Twelve healthy participants who exercised regularly were enrolled in this study. Each participant completed an exercise-induced muscle fatigue test while wearing a randomly assigned lower-body CG or sports pants (SP); after at least 7 days, the participant repeated the test while wearing the other garment. The dependent variables were muscle efficacy, proprioception (displacements of center of pressure/COP, and absolute error), and fatigue recovery (muscle oxygen saturation/SmO2, deoxygenation and reoxygenation rate, and subjective muscle soreness). A two-way repeated measure analysis of variance was conducted to determine the effect of garment type. The results indicated that relative to SP use, CG use can promote muscle efficacy, proprioception in ML displacement of COP, and fatigue recovery. Higher deoxygenation and reoxygenation rates were observed with CG use than with SP use. For CG use, SmO2 quickly returned to baseline value after 10 min of rest and was maintained at a high level until after 1 h of rest, whereas for SP use, SmO2 increased with time after fatigue onset. ML displacement of COP quickly returned to baseline value after 10 min of rest and subsequently decreased until after 1 hour of rest. Relative to SP use, CG use was associated with a significantly lower ML displacement after 20 min of rest. In conclusion, proprioception and SmO2 recovery was achieved after 10 min of rest; however, at least 24 h may be required for recovery pertaining to muscle efficacy and soreness regardless of CG or SP use.

Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.

Overweight worsens apoptosis, neuroinflammation and blood-brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation.

BACKGROUND: Apoptosis, neuroinflammation and blood-brain barrier (BBB) damage affect the susceptibility of the developing brain to hypoxic-ischemic (HI) insults. c-Jun N-terminal kinase (JNK) is an important mediator of insulin resistance in obesity. We hypothesized that neonatal overweight aggravates HI brain damage through JNK hyperactivation-mediated upregulation of neuronal apoptosis, neuroinflammation and BBB leakage in rat pups. METHODS: Overweight (OF) pups were established by reducing the litter size to 6, and control (NF) pups by keeping the litter size at 12 from postnatal (P) day 1 before HI on P7. Immunohistochemistry and immunoblotting were used to determine the TUNEL-(+) cells and BBB damage, cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP), and phospho-JNK and phospho-BimEL levels. Immunofluorescence was performed to determine the cellular distribution of phospho-JNK. RESULTS: Compared with NF pups, OF pups had a significantly heavier body-weight and greater fat deposition on P7. Compared with the NF-HI group, the OF-HI group showed significant increases of TUNEL-(+) cells, cleaved levels of caspase-3 and PARP, and ED1-(+) activated microglia and BBB damage in the cortex 24 hours post-HI. Immunofluorescence of the OF-HI pups showed that activated-caspase 3 expression was found mainly in NeuN-(+) neurons and RECA1-(+) vascular endothelial cells 24 hours post-HI. The OF-HI group also had prolonged escape latency in the Morris water maze test and greater brain-volume loss compared with the NF-HI group when assessed at adulthood. Phospho-JNK and phospho-BimEL levels were higher in OF-HI pups than in NF-HI pups immediately post-HI. JNK activation in OF-HI pups was mainly expressed in neurons, microglia and vascular endothelial cells. Inhibiting JNK activity by AS601245 caused more attenuation of cleaved caspase-3 and PARP, a greater reduction of microglial activation and BBB damage post-HI, and significantly reduced brain damage in OF-HI than in NF-HI pups. CONCLUSIONS: Neonatal overweight increased HI-induced neuronal apoptosis, microglial activation and BBB damage, and aggravated HI brain damage in rat pups through JNK hyperactivation.

Electronic paper display preferred viewing distance and character size for different age groups.

This study explores the preferred viewing distance and character size for an electronic paper display for three age groups. Proofreading speed and accuracy ratio were measured during Chinese proofreading tests using the preferred character size and minimum acceptable character size. Data analysis showed that the mean preferred viewing distance for young, middle-aged and older groups was 503, 455 and 444 mm, respectively. The mean preferred character size determined by young, middle-aged and older groups was 42.0, 50.0 and 55.2 min arc, respectively. The proofreading test results indicated that the older group proofread significantly more slowly (1.25 word/sec) than the young (1.76 word/sec) and middle-aged groups (1.74 word/sec). Further, the participants proofread more correctly with their preferred character size (73.3%) than with their minimum acceptable character size (65.4%). This study provides valuable information for the design of Chinese text presentations for various age groups. STATEMENT OF RELEVANCE: This study confirmed the preferred viewing distance and character size for E-paper display were influenced by age. The preferred Chinese character size for young, middle-aged and older people was 42, 50 and 55 min arc, respectively. Therefore, the age factor should be considered for E-paper displays design and video display terminal (VDT) guidelines.

Analyzing the Impact of Vaccine Availability on Alternative Supplier Selection Amid the COVID-19 Pandemic: A cFGM-FTOPSIS-FWI Approach.

The supply chain disruption caused by the coronavirus disease 2019 (COVID-19) pandemic has forced many manufacturers to look for alternative suppliers. How to choose a suitable alternative supplier in the COVID-19 pandemic has become an important task. To fulfill this task, this research proposes a calibrated fuzzy geometric mean (cFGM)-fuzzy technique for order preference by similarity to ideal solution (FTOPSIS)-fuzzy weighted intersection (FWI) approach. In the proposed methodology, first, the cFGM method is proposed to accurately derive the priorities of criteria. Subsequently, each expert applies the FTOPSIS method to compare the overall performances of alternative suppliers in the COVID-19 pandemic. The sensitivity of an expert to any change in the overall performance of the alternative supplier is also considered. Finally, the FWI operator is used to aggregate the comparison results by all experts, for which an expert's authority level is set to a value proportional to the consistency of his/her pairwise comparison results. The cFGM-FTOPSIS-FWI approach has been applied to select suitable alternative suppliers for a Taiwanese foundry in the COVID-19 pandemic.

PML/RARA destabilization by hyperthermia: a new model for oncogenic fusion protein degradation?

In this issue, Maimaitiyiming and colleagues demonstrate thermic stress-induced PML/RARA oncogenic fusion protein destabilization driven by corepressor aggregation. Hyperthermia synergizes with PML/RARA degradation by ATO and may circumvent ATO-resistance in historical APL patients. This novel approach could be extended to other corepressor-associated oncogenic fusion proteins.

A novel leukemic route of mutant NPM1 through nuclear import of the overexpressed long noncoding RNA LONA.

The most frequent genetic alteration in acute myeloid leukemia (AML) is the mutation of nucleophosmin 1 (NPM1). Yet, its downstream oncogenic routes are not fully understood. Here, we report the identification of one long noncoding RNA (lncRNA) overexpressed in NPM1-mutated AML patients (named LONA) whose intracellular localization inversely reflects that of NPM1. While NPM1 is nuclear and LONA cytoplasmic in wild-type NPM1 AML cells, LONA becomes nuclear as mutant NPM1 moves toward the cytoplasm. Gain or loss of function combined with a genome-wide RNA-seq search identified a set of LONA mRNA targets encoding proteins involved in myeloid cell differentiation (including THSB1, MAFB, and ASB2) and interaction with its microenvironment. Consistently, LONA overexpression in mutant NPM1 established cell lines and primary AML cells exerts an anti-myeloid differentiation effect, whilst it exerts an opposite pro-myeloid differentiation effect in a wild type NPM1 setting. In vivo, LONA overexpression acts as an oncogenic lncRNA reducing the survival of mice transplanted with AML cells and rendering AML tumors more resistant to AraC chemotherapy.These data indicate that mutation-dependent nuclear export of NPM1 leads to nuclear retention and consequent oncogenic functions of the overexpressed lncRNA LONA, thus uncovering a novel NPM1 mutation-dependent pathway in AML pathogenesis.

Usp11 controls cortical neurogenesis and neuronal migration through Sox11 stabilization.

The role of protein stabilization in cortical development remains poorly understood. A recessive mutation in the USP11 gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse Usp11 is expressed highly in embryonic cerebral cortex, and Usp11 deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors. Mechanistically, these functions are mediated by a previously unidentified Usp11 substrate, Sox11. Usp11 ablation compromises Sox11 protein accumulation in the developing cortex, despite the induction of Sox11 mRNA. The disease-associated Usp11 mutant fails to stabilize Sox11 and is unable to support cortical neurogenesis and neuronal migration. Our findings define a critical function of Usp11 in cortical development and highlight the importance of orchestrating protein stabilization mechanisms into transcription regulatory programs for a robust induction of cell fate determinants during early brain development.

Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML).

BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients.