Annexin A2 Stabilizes Oncogenic JAG1 Intracellular Domain by Inhibiting Proteasomal Degradation in Glioblastoma Cells.

Glioblastoma (GBM) is the most lethal brain cancer, causing inevitable deaths of patients owing to frequent relapses of cancer stem cells (CSCs). The significance of the NOTCH signaling pathway in CSCs has been well recognized; however, there is no NOTCH-selective treatment applicable to patients with GBM. We recently reported that Jagged1 (JAG1), a NOTCH ligand, drives a NOTCH receptor-independent signaling pathway via JAG1 intracellular domain (JICD1) as a crucial signal that renders CSC properties. Therefore, mechanisms regulating the JICD1 signaling pathway should be elucidated to further develop a selective therapeutic regimen. Here, we identified annexin A2 (ANXA2) as an essential modulator to stabilize intrinsically disordered JICD1. The binding of ANXA2 to JICD1 prevents the proteasomal degradation of JICD1 by heat shock protein-70/90 and carboxy-terminus of Hsc70 interacting protein E3 ligase. Furthermore, JICD1-driven propagation and tumor aggressiveness were inhibited by ANXA2 knockdown. Taken together, our findings show that ANXA2 maintains the function of the NOTCH receptor-independent JICD1 signaling pathway by stabilizing JICD1, and the targeted suppression of JICD1-driven CSC properties can be achieved by blocking its interaction with ANXA2.

Heterogeneity is a key factor describing the initial outbreak of COVID-19.

Assessing the transmission potential of emerging infectious diseases, such as COVID-19, is crucial for implementing prompt and effective intervention policies. The basic reproduction number is widely used to measure the severity of the early stages of disease outbreaks. The basic reproduction number of standard ordinary differential equation models is computed for homogeneous contact patterns; however, realistic contact patterns are far from homogeneous, specifically during the early stages of disease transmission. Heterogeneity of contact patterns can lead to superspreading events that show a significantly high level of heterogeneity in generating secondary infections. This is primarily due to the large variance in the contact patterns of complex human behaviours. Hence, in this work, we investigate the impacts of heterogeneity in contact patterns on the basic reproduction number by developing two distinct model frameworks: 1) an SEIR-Erlang ordinary differential equation model and 2) an SEIR stochastic agent-based model. Furthermore, we estimated the transmission probability of both models in the context of COVID-19 in South Korea. Our results highlighted the importance of heterogeneity in contact patterns and indicated that there should be more information than one quantity (the basic reproduction number as the mean quantity), such as a degree-specific basic reproduction number in the distributional sense when the contact pattern is highly heterogeneous.

FOXO3a Mediates Homologous Recombination Repair (HRR) via Transcriptional Activation of MRE11, BRCA1, BRIP1, and RAD50.

To test whether homologous recombination repair (HRR) depends on FOXO3a, a cellular aging model of human dermal fibroblast (HDF) and tet-on flag-h-FOXO3a transgenic mice were studied. HDF cells transfected with over-expression of wt-h-FOXO3a increased the protein levels of MRE11, BRCA1, BRIP1, and RAD50, while knock-down with siFOXO3a decreased them. The protein levels of MRE11, BRCA1, BRIP1, RAD50, and RAD51 decreased during cellular aging. Chromatin immunoprecipitation (ChIP) assay was performed on FOXO3a binding accessibility to FOXO consensus sites in human MRE11, BRCA1, BRIP1, and RAD50 promoters; the results showed FOXO3a binding decreased during cellular aging. When the tet-on flag-h-FOXO3a mice were administered doxycycline orally, the protein and mRNA levels of flag-h-FOXO3a, MRE11, BRCA1, BRIP1, and RAD50 increased in a doxycycline-dose-dependent manner. In vitro HRR assays were performed by transfection with an HR vector and I-SceI vector. The mRNA levels of the recombined GFP increased after doxycycline treatment in MEF but not in wt-MEF, and increased in young HDF comparing to old HDF, indicating that FOXO3a activates HRR. Overall, these results demonstrate that MRE11, BRCA1, BRIP1, and RAD50 are transcriptional target genes for FOXO3a, and HRR activity is increased via transcriptional activation of MRE11, BRCA1, BRIP1, and RAD50 by FOXO3a.

Explaining Neural Networks Using Attentive Knowledge Distillation.

Explaining the prediction of deep neural networks makes the networks more understandable and trusted, leading to their use in various mission critical tasks. Recent progress in the learning capability of networks has primarily been due to the enormous number of model parameters, so that it is usually hard to interpret their operations, as opposed to classical white-box models. For this purpose, generating saliency maps is a popular approach to identify the important input features used for the model prediction. Existing explanation methods typically only use the output of the last convolution layer of the model to generate a saliency map, lacking the information included in intermediate layers. Thus, the corresponding explanations are coarse and result in limited accuracy. Although the accuracy can be improved by iteratively developing a saliency map, this is too time-consuming and is thus impractical. To address these problems, we proposed a novel approach to explain the model prediction by developing an attentive surrogate network using the knowledge distillation. The surrogate network aims to generate a fine-grained saliency map corresponding to the model prediction using meaningful regional information presented over all network layers. Experiments demonstrated that the saliency maps are the result of spatially attentive features learned from the distillation. Thus, they are useful for fine-grained classification tasks. Moreover, the proposed method runs at the rate of 24.3 frames per second, which is much faster than the existing methods by orders of magnitude.

Comparison of Facial Proportions Between Eastern and Western Attractive Young Women.

The characteristics of what is considered a beautiful face differ between Eastern and Western countries.The authors of this study analyzed beauty pageant contestants using a three-dimensional (3D) photogrammetric analysis tool. All of the 3D photographs were taken between October and November 2016 in Seoul, Korea. The participants were 43 Miss Korea contestants (Group I) and 22 Miss Paraguay contestants (Group II).In absolute length, those in Group I had longer upper and middle faces. In the proportions of volume and length, Group I had larger upper and middle faces than Group II. Widths of the lower face and entire face were also wider in Group I. The lower facial index was larger in Group I. Group I had longer noses and wider intercanthal distance, not only in absolute length but also in proportion to the face. Group II showed thicker lips, longer chins, and wider noses relative to the face. Group II had wide eyes, in the absolute measurement and in proportion to the face. Group I participants appeared to have an increased height of eyes and had wider angles in their faces as well as wider nasofrontal, labiomental, and nasomental angles.The authors objectively established reference data for faces that are considered attractive in the East and the West. The data are expected to contribute to the clinical practice of plastic surgeons.

Correction of Congenital Telecanthus by Extended Medial Epicanthoplasty With Skin Redraping Method.

BACKGROUND: Recently, skin-redraping medial epicanthoplasty has emerged as an extremely effective way to minimize the resultant scar. We found that the novel skin-redraping medial epicanthoplasty technique, which has been applied to aesthetic surgery, could also be suitable for the correction of congenital epicanthus and telecanthus. METHODS: We retrospectively identified patients who had an epicanthoplasty from December 2007 to August 2017. Among 47 patients, we identified 19 cases with congenital pathologies (nonaesthetic cases). Overall, 7 patients with at least 2 anthropometric measurements were selected. RESULTS: There was a mean presurgical intercanthal distance of 35.85 mm (range, 24-52 mm) and a mean intercanthal distance of 26.85 mm (range, 17-36 mm) with a mean difference of 9 mm following postsurgical revision. To better categorize this difference, statistical analysis was conducted using a paired t test, which showed a significant result with P = 0.008. CONCLUSIONS: Our results revealed that the skin-redraping medial epicanthoplasty technique could be a better option even in the reconstruction of congenital telecanthus as well as aesthetic plastic surgery. It could correct mild to severe telecanthus and minimize scar formation.

Positive Effect of Incubated Adipose-Derived Mesenchymal Stem Cells on Microfat Graft Survival.

Autologous fat grafting is commonly used for soft tissue augmentation, but its unpredictably high resorption rate remains a major limitation. Although adipose-derived mesenchymal stem cells (ASCs) are an attractive candidate for enhancing graft retention, their poor posttransplantation viability limits their application. The authors aimed to evaluate the effect of incubated ASCs on microfat graft survival in an immunocompromised mouse model. Lipoaspirates for microfat injection were collected from the wasted lower abdominal adipose tissues of 5 patients who had undergone breast reconstructive surgery with an abdominal flap. Adipose-derived mesenchymal stem cells were also isolated and proliferated from these fat tissues. Sixty athymic mice were randomly allocated to a control group (microfat grafting alone; n = 30) or ASCs group (microfat grafting plus simultaneous human ASCs injection; n = 30). The volume and weight of survived fat were measured at 8 and 16 weeks, and histopathological and immunologic staining was performed at 16 weeks. The survived fat volume of the ASCs group was significantly greater than that of the control group at 8 and 16 weeks, whereas the weight of survived fat tissues did not significantly differ. Histologic evaluation of the harvested fat indicated significantly higher levels of adipocytes, and fewer cysts and fibrosis in the tissues in the ASCs group than in the control group. The ASCs group also exhibited a significantly higher number of capillary vessels than the control group on CD31 and alpha-smooth muscle actin staining. In conclusion, transplanted fat survival is markedly higher when simultaneous microfat graft and ASCs injection were performed, as compared with that in the classical microfat graft alone method in mice; this improvement was primarily attributed to the increased ability to produce blood vessels.

Comparison of Facial Proportions Between Beauty Pageant Contestants and Ordinary Young Women of Korean Ethnicity: A Three-Dimensional Photogrammetric Analysis.

BACKGROUND: Although the harmony of facial proportions is traditionally perceived as an important element of facial attractiveness, there have been few objective studies that have investigated this esthetic balance using three-dimensional photogrammetric analysis. OBJECTIVES: To better understand why some women appear more beautiful, we investigated differences in facial proportions between beauty pageant contestants and ordinary young women of Korean ethnicity using three-dimensional (3D) photogrammetric analyses. METHODS: A total of 43 prize-winning beauty pageant contestants (group I) and 48 ordinary young women (group II) of Korean ethnicity were photographed using 3D photography. Numerous soft tissue landmarks were identified, and 3D photogrammetric analyses were performed to evaluate 13 absolute lengths, 5 angles, 3 volumetric proportions, and 12 length proportions between soft tissue landmarks. RESULTS: Group I had a greater absolute length of the middle face, nose height, and eye height and width; a smaller absolute length of the lower face, intercanthal width, and nasal width; a larger nasolabial angle; a greater proportion of the upper and middle facial volume, nasal height, and eye height and width; and a lower proportion of the lower facial volume, lower face height, intercanthal width, nasal width, and mouth width. All these differences were statistically significant. CONCLUSIONS: These results indicate that there are significant differences between the faces of beauty pageant contestants and ordinary young women, and help elucidate which factors contribute to facial beauty. The group I mean values could be used as reference values for attractive facial profiles. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Wnt3A Induces GSK-3ß Phosphorylation and ß-Catenin Accumulation Through RhoA/ROCK.

In canonical pathway, Wnt3A has been known to stabilize ß-catenin through the dissociation between ß-catenin and glycogen synthase kinase-3ß (GSK-3ß) that suppresses the phosphorylation and degradation of ß-catenin. In non-canonical signaling pathway, Wnt was known to activate Rho GTPases and to induce cell migration. The cross-talk between canonical and non-canonical pathways by Wnt signaling; however, has not been fully elucidated. Here, we revealed that Wnt3A induces not only the phosphorylation of GSK-3ß and accumulation of ß-catenin but also RhoA activation in RAW264.7 and HEK293 cells. Notably, sh-RhoA and Tat-C3 abolished both the phosphorylation of GSK-3ß and accumulation of ß-catenin. Y27632, an inhibitor of Rho-associated coiled coil kinase (ROCK) and si-ROCK inhibited both GSK-3ß phosphorylation and ß-catenin accumulation. Furthermore, active domain of ROCK directly phosphorylated the purified recombinant GSK-3ß in vitro. In addition, Wnt3A-induced cell proliferation and migration, which were inhibited by Tat-C3 and Y27632. Taken together, we propose the cross-talk between canonical and non-canonical signaling pathways of Wnt3A, which induces GSK-3ß phosphorylation and ß-catenin accumulation through RhoA and ROCK activation. J. Cell. Physiol. 232: 1104-1113, 2017. © 2016 Wiley Periodicals, Inc.

A cell-autonomous positive-signaling circuit associated with the PDGF-NO-ID4-regulatory axis in glioblastoma cells.

Most cancer-related signaling pathways sustain their active or inactive status via genetic mutations or various regulatory mechanisms. Previously, we demonstrated that platelet-derived growth factor (PDGF) activates Notch signaling through nitric oxide (NO)-signaling-driven activation of inhibitor of differentiation 4 (ID4) in glioblastoma (GBM) stem cells (GSCs) and endothelial cells in the vascular niche of GBM, leading to maintenance of GSC traits and GBM progression. Here, we determined that the PDGF-NO-ID4-signaling axis is constantly activated through a positive regulatory circuit. ID4 expression significantly increased PDGF subunit B expression in both in vitro cultures and in vivo tumor xenografts and regulated NO synthase 2 (NOS2) expression and NO production by activating PDGF signaling, as well as that of its receptor (PDGFR). Additionally, ectopic expression of PDGFRα, NOS2, or ID4 activated the PDGF-NO-ID4-signaling circuit and enhanced the self-renewal of GBM cell lines. These results suggested that the positive regulatory circuit associated with PDGF-NO-ID4 signaling plays a pivotal role in regulating the self-renewal and tumor-initiating capacity of GSCs and might provide a promising therapeutic target for GBM.

Analysis of a vector-bias effect in the spread of malaria between two different incidence areas.

In 2005, Lacroix et al. demonstrated that infected humans are more attractive to mosquitoes, a phenomenon known as the vector-bias effect. The aim of this study was to determine how a vector-bias effect affects the changes in the dynamics of malaria transmission, and the changes in control strategies and cost-effectiveness for optimal control considering the regional characteristics or force of infections for different transmission rates. We used a vector-bias mathematical model and considered two different incidence areas: a high transmission area and a low transmission area. Our results showed that the dynamics in the two areas differed; as bias exists and the strategy for optimal control could be changed in the different areas. Thus, this work may give that considering the vector-bias effect in different areas facilitates prediction of the future dynamics and make decisions for establishing controls. We also mention the evolution of malaria parasites in this study.

An Energy-Aware Runtime Management of Multi-Core Sensory Swarms.

In sensory swarms, minimizing energy consumption under performance constraint is one of the key objectives. One possible approach to this problem is to monitor application workload that is subject to change at runtime, and to adjust system configuration adaptively to satisfy the performance goal. As today's sensory swarms are usually implemented using multi-core processors with adjustable clock frequency, we propose to monitor the CPU workload periodically and adjust the task-to-core allocation or clock frequency in an energy-efficient way in response to the workload variations. In doing so, we present an online heuristic that determines the most energy-efficient adjustment that satisfies the performance requirement. The proposed method is based on a simple yet effective energy model that is built upon performance prediction using IPC (instructions per cycle) measured online and power equation derived empirically. The use of IPC accounts for memory intensities of a given workload, enabling the accurate prediction of execution time. Hence, the model allows us to rapidly and accurately estimate the effect of the two control knobs, clock frequency adjustment and core allocation. The experiments show that the proposed technique delivers considerable energy saving of up to 45%compared to the state-of-the-art multi-core energy management technique.

LIM domain only 2 induces glioma invasion via cytosolic p27(KIP1).

High-grade gliomas are considered the most malignant of brain tumors and have a poor prognosis. In a previous study, we showed that LIM domain only 2 (LMO2) regulates glioma stem cell properties and tumor angiogenesis and gave rise to highly invasive glioma xenografts. Glioma invasion in the surrounding parenchymal tissues is a major hurdle with respect to eliminating glioma by surgery. Invasive glioma cells are considered one of the main culprits for the recurrence of tumors after therapies. In the current study, we focused on determining the molecular mechanism(s) by which LMO2 regulates glioma cell migration and invasion. Forced expression of LMO2 in human U87MG glioma cells led to glioma invasion, as determined by in vivo xenograft assays and enhanced in vitro migration and invasion. LMO2 was associated with increased levels of cytosolic p27(Kip1) protein. LMO2 possibly induced the stabilization and augmented interactions between p27(Kip1) and RhoA. We knocked down the expression of p27(Kip1), which led to a decrease in LMO2-driven glioma cell migration and invasion. Taken together, our findings indicate that LMO2 promotes glioma cell migration and invasion by increasing the levels of cytosolic p27(Kip1).

Irradiation induces glioblastoma cell senescence and senescence-associated secretory phenotype.

Glioblastoma multiforme (GBM) is one of the most aggressive and fatal primary brain tumors in humans. The standard therapy for the treatment of GBM is surgical resection, followed by radiotherapy and/or chemotherapy. However, the frequency of tumor recurrence in GBM patients is very high, and the survival rate remains poor. Delineating the mechanisms of GBM recurrence is essential for therapeutic advances. Here, we demonstrate that irradiation rendered 17-20 % of GBM cells dead, but resulted in 60-80 % of GBM cells growth-arrested with increases in senescence markers, such as senescence-associated beta-galactosidase-positive cells, H3K9me3-positive cells, and p53-p21(CIP1)-positive cells. Moreover, irradiation induced expression of senescence-associated secretory phenotype (SASP) mRNAs and NFκB transcriptional activity in GBM cells. Strikingly, compared to injection of non-irradiated GBM cells into immune-deficient mice, the co-injection of irradiated and non-irradiated GBM cells resulted in faster growth of tumors with the histological features of human GBM. Taken together, our findings suggest that the increases in senescent cells and SASP in GBM cells after irradiation is likely one of main reasons for tumor recurrence in post-radiotherapy GBM patients.

Predicting dredging-associated effects to coral reefs in Apra Harbor, Guam - Part 1: Sediment exposure modeling.

Model studies were conducted to investigate the potential coral reef sediment exposure from dredging associated with proposed development of a deepwater wharf in Apra Harbor, Guam. The Particle Tracking Model (PTM) was applied to quantify the exposure of coral reefs to material suspended by the dredging operations at two alternative sites. Key PTM features include the flexible capability of continuous multiple releases of sediment parcels, control of parcel/substrate interaction, and the ability to efficiently track vast numbers of parcels. This flexibility has facilitated simulating the combined effects of sediment released from clamshell dredging and chiseling within Apra Harbor. Because the rate of material released into the water column by some of the processes is not well understood or known a priori, the modeling approach was to bracket parameters within reasonable ranges to produce a suite of potential results from multiple model runs. Sensitivity analysis to model parameters is used to select the appropriate parameter values for bracketing. Data analysis results include mapping the time series and the maximum values of sedimentation, suspended sediment concentration, and deposition rate. Data were used to quantify various exposure processes that affect coral species in Apra Harbor. The goal of this research is to develop a robust methodology for quantifying and bracketing exposure mechanisms to coral (or other receptors) from dredging operations. These exposure values were utilized in an ecological assessment to predict effects (coral reef impacts) from various dredging scenarios.

Epidermal growth factor receptor variant III renders glioma cancer cells less differentiated by JAGGED1.

Glioblastoma is a highly aggressive primary brain tumor in which the majority of cancer cells are undifferentiated. One of the most common oncogenic drivers for this malignancy is the epidermal growth factor receptor variant III (EGFRvIII), which lacks a portion of the extracellular ligand-binding domain due to deletion of exons 2-7 of the EGFR gene. EGFRvIII plays a critical role in tumor progression, promoting acquisition of stem cell-like features including an undifferentiated state and therapy resistance. However, the molecular mechanisms by which EGFRvIII contributes to cancer cell aggressiveness remain poorly understood. Here, we show that EGFR expression correlates with JAGGED1 expression in glioblastoma patients. Overexpression of EGFRvIII in glioma cell lines augmented JAGGED1 expression at the transcriptional level through the mitogen-activated protein kinase signaling pathway. Consequently, EGFRvIII overexpression drove partial dedifferentiation of glioma cells, as determined by tumorsphere-forming ability and expression of stem cell markers, through JAGGED1 induction. EGFRvIII-mediated radioresistance, but not chemoresistance, was also modulated by JAGGED1. Taken together, our results provide new insight into the mechanism underlying EGFRvIII-driven glioblastoma aggressiveness.

IRF7 promotes glioma cell invasion by inhibiting AGO2 expression.

Interferon regulatory factor 7 (IRF7) is the master transcription factor that plays a pivotal role in the transcriptional activation of type I interferon genes in the inflammatory response. Our previous study revealed that IRF7 is an important regulator of tumor progression via the expression of inflammatory cytokines in glioma. Here, we report that IRF7 promotes glioma invasion and confers resistance to both chemotherapy and radiotherapy by inhibiting expression of argonaute 2 (AGO2), a regulator of microRNA biogenesis. We found that IRF7 and AGO2 expression levels were negatively correlated in patients with glioblastoma multiforme. Ectopic IRF7 expression led to a reduction in AGO2 expression, while depletion of IRF7 resulted in increased AGO2 expression in the LN-229 glioma cell line. In an in vitro invasion assay, IRF7 overexpression enhanced glioma cell invasion. Furthermore, reconstitution of AGO2 expression in IRF7-overexpressing cells led to decreased cell invasion, whereas the reduced invasion due to IRF7 depletion was rescued by AGO2 depletion. In addition, IRF7 induced chemoresistance and radioresistance of glioma cells by diminishing AGO2 expression. Finally, AGO2 depletion alone was sufficient to accelerate glioma cell invasion in vitro and in vivo, indicating that AGO2 regulates cancer cell invasion. Taken together, our results indicate that IRF7 promotes glioma cell invasion and both chemoresistance and radioresistance through AGO2 inhibition.

Rab3a promotes brain tumor initiation and progression.

The Rab protein family is composed of small GTP-binding proteins involved in intracellular vesicle trafficking. In particular, Rab3a which is one of four Rab3 proteins (a, b, c, and d isoforms) is associated with synaptic vesicle trafficking in normal brain. However, despite the elevated level of Rab3a in tumors, its role remains unclear. Here we report a tumorigenic role of Rab3a in brain tumors. Elevated level of Rab3a expression in human was confirmed in both glioma cell lines and glioblastoma multiforme patient specimens. Ectopic Rab3a expression in glioma cell lines and primary astrocytes promoted cell proliferation by increasing cyclin D1 expression, induced resistance to anti-cancer drug and irradiation, and accelerated foci formation in soft agar and tumor formation in nude mice. The overexpression of Rab3a augmented the tumorsphere-forming ability of glioma cells and p53(-/-) astrocytes and increased expression levels of various stem cell markers. Taken together, our results indicate that Rab3a is a novel oncogene involved in glioma initiation and progression.

LEAPSE: Learning Environment Affordances for 3D Human Pose and Shape Estimation.

We live in a 3D world where people interact with each other in the environment. Learning 3D posed humans therefore requires us to perceive and interpret these interactions. This paper proposes LEAPSE, a novel method that learns salient instance affordances for estimating a posed body from a single RGB image in a non-parametric manner. Existing methods mostly ignore the environment and estimate the human body independently from the surroundings. We capture the influences of non-contact and contact instances on a posed body as an adequate representation of the "environment affordances". The proposed method learns the global relationships between 3D joints, body mesh vertices, and salient instances as environment affordances on the human body. LEAPSE achieved state-of-the-art results on the 3DPW dataset with many affordance instances, and also demonstrated excellent performance on Human3.6M dataset. We further demonstrate the benefit of our method by showing that the performance of existing weak models can be significantly improved when combined with our environment affordance module.

Diagnosing oral and maxillofacial diseases using deep learning.

The classification and localization of odontogenic lesions from panoramic radiographs is a challenging task due to the positional biases and class imbalances of the lesions. To address these challenges, a novel neural network, DOLNet, is proposed that uses mutually influencing hierarchical attention across different image scales to jointly learn the global representation of the entire jaw and the local discrepancy between normal tissue and lesions. The proposed approach uses local attention to learn representations within a patch. From the patch-level representations, we generate inter-patch, i.e., global, attention maps to represent the positional prior of lesions in the whole image. Global attention enables the reciprocal calibration of path-level representations by considering non-local information from other patches, thereby improving the generation of whole-image-level representation. To address class imbalances, we propose an effective data augmentation technique that involves merging lesion crops with normal images, thereby synthesizing new abnormal cases for effective model training. Our approach outperforms recent studies, enhancing the classification performance by up to 42.4% and 44.2% in recall and F1 scores, respectively, and ensuring robust lesion localization with respect to lesion size variations and positional biases. Our approach further outperforms human expert clinicians in classification by 10.7 % and 10.8 % in recall and F1 score, respectively.