PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors.

Necroptosis, a form of regulated necrotic cell death, is governed by RIP1/RIP3-mediated activation of MLKL. However, the signaling process leading to necroptotic death remains to be elucidated. In this study, we found that PUMA, a proapoptotic BH3-only Bcl-2 family member, is transcriptionally activated in an RIP3/MLKL-dependent manner following induction of necroptosis. The induction of PUMA, which is mediated by autocrine TNF-α and enhanced NF-κB activity, contributes to necroptotic death in RIP3-expressing cells with caspases inhibited. On induction, PUMA promotes the cytosolic release of mitochondrial DNA and activation of the DNA sensors DAI/Zbp1 and STING, leading to enhanced RIP3 and MLKL phosphorylation in a positive feedback loop. Furthermore, deletion of PUMA partially rescues necroptosis-mediated developmental defects in FADD-deficient embryos. Collectively, our results reveal a signal amplification mechanism mediated by PUMA and cytosolic DNA sensors that is involved in TNF-driven necroptotic death in vitro and in vivo

Sampled in Pairs and Driven by Text: A New Graph Embedding Framework

In graphs with rich texts, incorporating textual information with structural information would benefit constructing expressive graph embeddings. Among various graph embedding models, random walk (RW)-based is one of the most popular and successful groups. However, it is challenged by two issues when applied on graphs with rich texts: (i) sampling efficiency: deriving from the training objective of RW-based models (e.g., DeepWalk and node2vec), we show that RW-based models are likely to generate large amounts of redundant training samples due to three main drawbacks. (ii) text utilization: these models have difficulty in dealing with zero-shot scenarios where graph embedding models have to infer graph structures directly from texts. To solve these problems, we propose a novel framework, namely Text-driven Graph Embedding with Pairs Sampling (TGE-PS). TGE-PS uses Pairs Sampling (PS) to improve the sampling strategy of RW, being able to reduce ~99% training samples while preserving competitive performance. TGE-PS uses Text-driven Graph Embedding (TGE), an inductive graph embedding approach, to generate node embeddings from texts. Since each node contains rich texts, TGE is able to generate high-quality embeddings and provide reasonable predictions on existence of links to unseen nodes. We evaluate TGE-PS on several real-world datasets, and experiment results demonstrate that TGE-PS produces state-of-the-art results on both traditional and zero-shot link prediction tasks.Comment: Accepted by WWW 2019 (The World Wide Web Conference. ACM, 2019

A brain tumor computer-aided diagnosis method with automatic lesion segmentation and ensemble decision strategy

ObjectivesGliomas and brain metastases (Mets) are the most common brain malignancies. The treatment strategy and clinical prognosis of patients are different, requiring accurate diagnosis of tumor types. However, the traditional radiomics diagnostic pipeline requires manual annotation and lacks integrated methods for segmentation and classification. To improve the diagnosis process, a gliomas and Mets computer-aided diagnosis method with automatic lesion segmentation and ensemble decision strategy on multi-center datasets was proposed.MethodsOverall, 1,022 high-grade gliomas and 775 Mets patients’ preoperative MR images were adopted in the study, including contrast-enhanced T1-weighted (T1-CE) and T2-fluid attenuated inversion recovery (T2-flair) sequences from three hospitals. Two segmentation models trained on the gliomas and Mets datasets, respectively, were used to automatically segment tumors. Multiple radiomics features were extracted after automatic segmentation. Several machine learning classifiers were used to measure the impact of feature selection methods. A weight soft voting (RSV) model and ensemble decision strategy based on prior knowledge (EDPK) were introduced in the radiomics pipeline. Accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC) were used to evaluate the classification performance.ResultsThe proposed pipeline improved the diagnosis of gliomas and Mets with ACC reaching 0.8950 and AUC reaching 0.9585 after automatic lesion segmentation, which was higher than those of the traditional radiomics pipeline (ACC:0.8850, AUC:0.9450).ConclusionThe proposed model accurately classified gliomas and Mets patients using MRI radiomics. The novel pipeline showed great potential in diagnosing gliomas and Mets with high generalizability and interpretability

Equivalence of Discrete Fracture Network and Porous Media Models by Hydraulic Tomography

Hydraulic tomography (HT) has emerged as a potentially viable method for mapping fractures in geologic media as demonstrated by recent studies. However, most of the studies adopted equivalent porous media (EPM) models to generate and invert hydraulic interference test data for HT. While these models assign significant different hydraulic properties to fractures and matrix, they may not fully capture the discrete nature of the fractures in the rocks. As a result, HT performance may have been overrated. To explore this issue, this study employed a discrete fracture network (DFN) model to simulate hydraulic interference tests. HT with the EPM model was then applied to estimate the distributions of hydraulic conductivity (K) and specific storage (S-s) of the DFN. Afterward, the estimated fields were used to predict the observed heads from DFN models, not used in the HT analysis (i.e., validation). Additionally, this study defined the spatial representative elementary volume (REV) of the fracture connectivity probability for the entire DFN dominant. The study showed that if this spatial REV exists, the DFN is deemed equivalent to EPM and vice versa. The hydraulic properties estimated by HT with an EPM model can then predict head fields satisfactorily over the entire DFN domain with limited monitoring wells. For a sparse DFN without this spatial REV, a dense observation network is needed. Nevertheless, HT is able to capture the dominant fractures.National Science and Technology Major Project of China [2017ZX05008-003-021]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDB10030601]; Youth Innovation Promotion Association of the Chinese Academy of Sciences [2016063]; US Civilain Research and Development Foundation (CRDF) under the award: Hydraulic tomography in shallow alluvial sediments: Nile River Valley, Egypt [DAA2-15-61224-1]; Global Expert award through Tianjin Normal University from the Thousand Talents Plan of Tianjin City6 month embargo; published online: 23 April 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Apocynum Tablet Protects against Cardiac Hypertrophy via Inhibiting AKT and ERK1/2 Phosphorylation after Pressure Overload

Background. Cardiac hypertrophy occurs in many cardiovascular diseases. Apocynum tablet (AT), a traditional Chinese medicine, has been widely used in China to treat patients with hypertension. However, the underlying molecular mechanisms of AT on the hypertension-induced cardiac hypertrophy remain elusive. The current study evaluated the effect and mechanisms of AT on cardiac hypertrophy. Methods. We created a mouse model of cardiac hypertrophy by inducing pressure overload with surgery of transverse aortic constriction (TAC) and then explored the effect of AT on the development of cardiac hypertrophy using 46 mice in 4 study groups (combinations of AT and TAC). In addition, we evaluated the signaling pathway of phosphorylation of ERK1/2, AKT, and protein expression of GATA4 in the cardioprotective effects of AT using Western blot. Results. AT inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, Ser473 site of AKT, and protein expression of GATA4 and significantly inhibited cardiac hypertrophy and cardiac fibrosis at 2 weeks after TAC surgery (P<0.05). Conclusions. We experimentally demonstrated that AT inhibits cardiac hypertrophy via suppressing phosphorylation of ERK1/2 and AKT

Chicken Embryos as a Potential New Model for Early Onset Type I Diabetes

Diabetic retinopathy (DR) is the leading cause of blindness among the American working population. The purpose of this study is to establish a new diabetic animal model using a cone-dominant avian species to address the distorted color vision and altered cone pathway responses in prediabetic and early diabetic patients. Chicken embryos were injected with either streptozotocin (STZ), high concentration of glucose (high-glucose), or vehicle at embryonic day 11. Cataracts occurred in varying degrees in both STZ- and high glucose-induced diabetic chick embryos at E18. Streptozotocin-diabetic chicken embryos had decreased levels of blood insulin, glucose transporter 4 (Glut4), and phosphorylated protein kinase B (pAKT). In STZ-injected E20 embryos, the ERG amplitudes of both a- and b-waves were significantly decreased, the implicit time of the a-wave was delayed, while that of the b-wave was significantly increased. Photoreceptors cultured from STZ-injected E18 embryos had a significant decrease in L-type voltage-gated calcium channel (L-VGCC) currents, which was reflected in the decreased level of L-VGCCα1D subunit in the STZ-diabetic retinas. Through these independent lines of evidence, STZ-injection was able to induce pathological conditions in the chicken embryonic retina, and it is promising to use chickens as a potential new animal model for type I diabetes

Chicken Embryos as a Potential New Model for Early Onset Type I Diabetes

Diabetic retinopathy (DR) is the leading cause of blindness among the American working population. The purpose of this study is to establish a new diabetic animal model using a cone-dominant avian species to address the distorted color vision and altered cone pathway responses in prediabetic and early diabetic patients. Chicken embryos were injected with either streptozotocin (STZ), high concentration of glucose (high-glucose), or vehicle at embryonic day 11. Cataracts occurred in varying degrees in both STZ- and high glucose-induced diabetic chick embryos at E18. Streptozotocin-diabetic chicken embryos had decreased levels of blood insulin, glucose transporter 4 (Glut4), and phosphorylated protein kinase B (pAKT). In STZ-injected E20 embryos, the ERG amplitudes of both a- and b-waves were significantly decreased, the implicit time of the a-wave was delayed, while that of the b-wave was significantly increased. Photoreceptors cultured from STZ-injected E18 embryos had a significant decrease in L-type voltage-gated calcium channel (L-VGCC) currents, which was reflected in the decreased level of L-VGCCα1D subunit in the STZ-diabetic retinas. Through these independent lines of evidence, STZ-injection was able to induce pathological conditions in the chicken embryonic retina, and it is promising to use chickens as a potential new animal model for type I diabetes

Exome Sequencing Identifies Compound Heterozygous Mutations in CYP4V2 in a Pedigree with Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a heterogeneous group of progressive retinal degenerations characterized by pigmentation and atrophy in the mid-periphery of the retina. Twenty two subjects from a four-generation Chinese family with RP and thin cornea, congenital cataract and high myopia is reported in this study. All family members underwent complete ophthalmologic examinations. Patients of the family presented with bone spicule-shaped pigment deposits in retina, retinal vascular attenuation, retinal and choroidal dystrophy, as well as punctate opacity of the lens, reduced cornea thickness and high myopia. Peripheral venous blood was obtained from all patients and their family members for genetic analysis. After mutation analysis in a few known RP candidate genes, exome sequencing was used to analyze the exomes of 3 patients III2, III4, III6 and the unaffected mother II2. A total of 34,693 variations shared by 3 patients were subjected to several filtering steps against existing variation databases. Identified variations were verified in the rest family members by PCR and Sanger sequencing. Compound heterozygous c.802-8_810del17insGC and c.1091-2A>G mutations of the CYP4V2 gene, known as genetic defects for Bietti crystalline corneoretinal dystrophy, were identified as causative mutations for RP of this family

Micro-displacement reconstruction using a laser self-mixing grating interferometer with multiple-diffraction

In this paper, we demonstrated an improved laser self-mixing grating interferometer (SMGI) with auto-collimation design which can avoid the disturbance from the light feedback of the zero-order diffraction beam. In order to obtain higher optical subdivision, SMGI with multiple-diffraction is implemented. Both theoretical analysis and experimental work show that the proposed system for displacement measurement can achieve high sensitivity and low measurement uncertainty. Using the proposed system, different forms of micro-displacement signals applied on the target (grating) have been reconstructed with accuracy of a few nanometers. The work presented in this paper provides a good way to achieve robust and high precision measurement with compact system configuration