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Supplementary Figure Legends 1-4 from Suppression of Epidermal Growth Factor Receptor Signaling by Protein Kinase C-α Activation Requires CD82, Caveolin-1, and Ganglioside

Supplementary Figure 3 from Suppression of Epidermal Growth Factor Receptor Signaling by Protein Kinase C-α Activation Requires CD82, Caveolin-1, and Ganglioside

Supplementary Figure 4 from Suppression of Epidermal Growth Factor Receptor Signaling by Protein Kinase C-α Activation Requires CD82, Caveolin-1, and Ganglioside

Supplementary Figure 1 from Suppression of Epidermal Growth Factor Receptor Signaling by Protein Kinase C-α Activation Requires CD82, Caveolin-1, and Ganglioside

Supplementary Figure 2 from Suppression of Epidermal Growth Factor Receptor Signaling by Protein Kinase C-α Activation Requires CD82, Caveolin-1, and Ganglioside

In this study, the proposed design of a motion chair with four degrees of freedom (DoF) provides the pilot with the tactile sensations required by the human body to increase the immersion of flight simulation training. The chair includes a seat pan, a back pad, and a seat height. For the development of the proposed mechanism structure, the modular design is used to achieve the required displacement and acceleration. In addition, inverse kinematics is also constructed to meet the actuation needs. The control system can achieve real-time closed-loop control using an industrial computer, a motion control card, servo motors and drivers. This enables the structure to reach destinations with the shortest motion time and completes the required T-curve motion trajectory. The displacement, velocity, and acceleration of the designed structure are analyzed using SimWise4D software to verify the performance specifications of the structure. The experimental results indicate that the four-DoF control meets requirements of displacement, velocity, and acceleration.

Aiming at the problems that the traditional classroom teaching method cannot update the database in real time, resulting in incomplete data transmission and low efficiency of tutoring, a remote online 3D teaching platform for industrial design major in colleges and universities is designed. According to the framework of online distance stereoscopic teaching platform, the infrastructure layer, database layer and application service layer are designed. The information is stored in the SQLite lightweight database of memory to provide students with the required course information of industrial design. From the exhibition three-dimensional teaching mode, competition three-dimensional teaching mode, training three-dimensional teaching mode and project driven three-dimensional teaching mode four methods, design online distance three-dimensional teaching platform mode. The experimental results show that all the black box test contents of the system are passed, and the highest counseling efficiency is 99%, which has a good counseling effect.

There are many kinds of teaching resources involved in online teaching courses for art majors. In order to further realize the sharing of all kinds of teaching resources, this paper proposes the design of resource security sharing system. However, due to the poor performance of the algorithms used in the traditional system, the concurrency performance and classification performance of the system can not meet the expectations. Therefore, a new online teaching course resource sharing system for art majors is designed. In hardware design, tracking hardware and RS323 bus circuit are designed. In the software design, TF-IDF weight clustering course resources are set, the load is distributed in a balanced manner, and the teaching database access tasks are allocated, and the P2P network is used to share system information. Experimental results: The concurrent performance of the system designed this time meets the expected set standards. Compared with the traditional design of teaching course resource security sharing system, the classification performance of the design system is better, which meets the requirements of online teaching course resource security sharing for art majors.

Mutations in the proline-rich transmembrane protein 2 (PRRT2) are associated with paroxysmal kinesigenic dyskinesia (PKD) and several other paroxysmal neurological diseases, but the PRRT2 function and pathogenic mechanisms remain largely obscure. Here we show that PRRT2 is a presynaptic protein that interacts with components of the SNARE complex and downregulates its formation. Loss-of-function mutant mice showed PKD-like phenotypes triggered by generalized seizures, hyperthermia, or optogenetic stimulation of the cerebellum. Mutant mice with specific PRRT2 deletion in cerebellar granule cells (GCs) recapitulate the behavioral phenotypes seen in Prrt2-null mice. Furthermore, recording made in cerebellar slices showed that optogenetic stimulation of GCs results in transient elevation followed by suppression of Purkinje cell firing. The anticonvulsant drug carbamazepine used in PKD treatment also relieved PKD-like behaviors in mutant mice. Together, our findings identify PRRT2 as a novel regulator of the SNARE complex and provide a circuit mechanism underlying the PRRT2-related behaviors.

The CRISPR/Cas9 system is an efficient gene-editing method, but the majority of gene-edited animals showed mosaicism, with editing occurring only in a portion of cells. Here we show that single gene or multiple genes can be completely knocked out in mouse and monkey embryos by zygotic injection of Cas9 mRNA and multiple adjacent single-guide RNAs (spaced 10-200 bp apart) that target only a single key exon of each gene. Phenotypic analysis of F0 mice following targeted deletion of eight genes on the Y chromosome individually demonstrated the robustness of this approach in generating knockout mice. Importantly, this approach delivers complete gene knockout at high efficiencies (100% on Arntl and 91% on Prrt2) in monkey embryos. Finally, we could generate a complete Prrt2 knockout monkey in a single step, demonstrating the usefulness of this approach in rapidly establishing gene-edited monkey models.

Malignant glioma is the most common and aggressive form of brain tumor with poor prognosis of survival. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent but is insufficient of inducing apoptosis in some types of gliomas. In this study, we showed that the small-molecule Mcl-1 inhibitor UMI-77 sensitized glioma cells to TRAIL treatment, as evidenced by cell viability assay, Annexin V staining and JC-1 staining. Combination of UMI-77 and TRAIL in glioma cells led to the activation of caspase-8 and Bid, cleavage of caspase-3 and poly-ADP ribose polymerase (PARP), accumulation of tBid in the mitochondria and release of cytochrome c into the cytosol. UMI-77 alone or in combination with TRAIL untethered pro-apoptotic Bcl-2 proteins Bim and Bak from the sequestration of Mcl-1 and promoted the conformational activation of Bak. Small hairpin RNA (shRNA) of Bid attenuated the cleavage of caspase-8, Bid, caspase-3 and PARP, and reduced the cytotoxicity of UMI-77 plus TRAIL as compared with control shRNA cells, indicating this synergy entails the crosstalk between extrinsic and intrinsic apoptotic signaling. Taken together, UMI-77 enhances TRAIL-induced apoptosis by unsequestering Bim and Bak, which provides a novel therapeutic strategy for the treatment of gliomas.

XPO1 (exportin1) mediates nuclear export of proteins and RNAs and is frequently overexpressed in cancers. In this study, we show that the orally bioavailable XPO1 inhibitor KPT-330 reduced Mcl-1 protein level, by which it synergized with Bcl-xL inhibitor A-1331852 to induce apoptosis in cancer cells. KPT-330/A-1331852 combination disrupted bindings of Mcl-1 and Bcl-xL to Bax, Bak, and/or Bim, elicited mitochondrial outer membrane permeabilization, and triggered apoptosis. KPT-330 generally mitigated mRNA expression and protein synthesis rather than mRNA nuclear export or protein stability of Mcl-1. KPT-330 inhibited mTORC1/4E-BP1 and Mnk1/eIF4E axes, which disrupted the eIF4F translation initiation complex but was dispensable for Mcl-1 reduction and KPT-330/A-1331852 combination-induced apoptosis. Mature rRNAs are integral components of the ribosome that determines protein synthesis ability. KPT-330 impeded nucleolar rRNA processing and reduced total levels of multiple mature rRNAs. Reconstitution of XPO1 by expressing degradation-resistant C528S mutant retained rRNA amount, Mcl-1 expression, and Bcl-xL inhibitor resistance upon KPT-330 treatment. KPT-330/A-1331852 combination suppressed growth and enhanced apoptosis of non-small cell lung cancer xenografts. Therefore, we clarify the reason of apoptosis resistance of cancer cells to XPO1 inhibition and develop a potential strategy for treating solid tumors.

A 0.33 mol.% Sb-doped Mg2Si0.5Sn0.5 solid solution was synthesized by combining a liquid–solid reaction and hot-pressing process. The effect of annealing (1068 K, 250 h) on microstructure and thermoelectric properties of the solid solution was studied by x-ray diffraction (XRD), scanning electron microscopy, electron probe microanalysis, transmission electron microscopy, and thermoelectric measurements. The successful synthesis of the solid solution with an antifluorite structure was confirmed by XRD. The as-prepared sample contained Si, Sn, and MgO inclusions tens of nanometers in size. After annealing, Si and Sn inclusions disappeared, while the MgO nanoparticles remained almost unchanged; the charge carrier concentration and electrical conductivity decreased and the lattice thermal conductivity increased. As a result, the thermoelectric figure of merit ZT ∼ 0.34 at 394 K for the as-prepared sample deteriorated to ∼0.24 at 388 K after the annealing. The results suggest the presence of a high density of point defects, such as Mg interstitials in the as-prepared sample. The density of these Mg interstitials was reduced by the annealing, thereby affecting the charge carrier concentration and electrical conductivity. The increase in the lattice thermal conductivity upon annealing is attributed to the disappearance of point defects, grain boundaries (grain growth) and Si and Sn inclusions, which all act as phonon scattering centers. Thus, point defects and nanoinclusions might be important for optimizing the thermoelectric properties of a material. This work provides new insights into the effect of annealing on the microstructure and its relationship with the thermoelectric properties of Sb-doped Mg2Si0.5Sn0.5 solid solutions. It also provides hints for developing Mg2Si0.5Sn0.5-based materials with superior thermoelectric properties.

A multi-scale modeling method based on big data was proposed to establish neural network models for complex plant. Wavelet transform was used to decompose input and output parameters into different scales. The relationship between these parameters were researched in every scale. Then models in each scale were established and added together to form a multi-scale model. A model of coal mill current in power plant was established using the multi-scale modeling method based on big data. The result shows that, the method is effective.

Aiming at the problem of the Alpine, high altitude and other complex environment in the northwest area, and lack of concrete mix and durability data in this harsh environment. Based on the real engineering project, the effect of W/C and the content of cementitious materials on concrete performances were studied, the strength, impermeability and frost resistance of concrete which was mixed respectively two kinds of water reducer and maintained in standard condition and outdoor condition were Studied comparatively. The pore structure of cement paste which was added respectively two kinds of water reducer were also analyzed. The results show that: The self-made polycarboxylate superplasticizer has the effect of low temperature and early strength, and it also can ameliorate the internal pore structure of the sample and improve the impermeability and frost resistance, and improve the durability of concrete.

Background The ACTS-GC study had shown postoperative adjuvant therapy with S-1 improved survival of patients with locally advanced gastric cancer. Addition of oxaliplatin to S-1 is considered to be acceptable as one of the treatment options for gastric cancer patients after radical gastrectomy with D2 lymph node excision. Methods We have commenced a randomized phase III trial in December 2016 to evaluate S-1 plus oxaliplatin compared with S-1 alone in the adjuvant setting for locally advanced gastric cancer. A total of 564 patients will be accrued from 13 Chinese institutions in two years. The primary endpoint is 3-year relapse-free survival. The secondary endpoints are 5-year overall survival, proportion of patients who complete the postoperative chemotherapy and incidence of adverse events. Ethic and dissemination The trial has been approved by the institutional review board of each participating institution and it was activated on December, 2016. The enrollment will be finished in December, 2018. Patient's follow-up will be ended until December, 2023. Trial registration ClinicalTrials.gov, identifier: NCT02867839. Registered on August 4, 2016.

The nuclear import receptor karyopherin β1 (KPNB1) is involved in the nuclear import of most proteins and in the regulation of multiple mitotic events. Upregulation of KPNB1 has been observed in cancers including glioblastoma. Depletion of KPNB1 induces mitotic arrest and apoptosis in cancer cells, but the underlying mechanism is not clearly elucidated. Here, we found that downregulation and functional inhibition of KPNB1 in glioblastoma cells induced growth arrest and apoptosis without apparent mitotic arrest. KPNB1 inhibition upregulated Puma and Noxa and freed Mcl-1-sequestered Bax and Bak, leading to mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Moreover, combination of Bcl-xL inhibitors and KPNB1 inhibition enhanced apoptosis in glioblastoma cells. KPNB1 inhibition promoted cytosolic retention of its cargo and impaired cellular proteostasis, resulting in elevated polyubiquitination, formation of aggresome-like-induced structure (ALIS), and unfolded protein response (UPR). Ubiquitination elevation and UPR activation in KPNB1-deficient cells were reversed by KPNB1 overexpression or inhibitors of protein synthesis but aggravated by inhibitors of autophagy-lysosome or proteasome, indicating that rebalance of cytosolic/nuclear protein distribution and alleviation of protein overload favor proteostasis and cell survival. Chronic activation of eIF2α/ATF4 cascade of UPR was responsible for the upregulation of Puma and Noxa, apoptosis and ABT-263 sensitivity. Taken together, our findings demonstrate that KPNB1 is required for proteostasis maintenance and its inhibition induces apoptosis in glioblastoma cells through UPR-mediated deregulation of Bcl-2 family members.

Today’s Internet-based service systems tend to run in open environments and try to satisfy varying requirements. In the context, the changes of requirements and environments can emerge at any point of their life cycle, and their runtime variability is supposed to be evolvable to deal with the changes. In other words, the number, type or attribute of variability elements (variation points and their associated variants) in the systems is regarded to be changeable, especially at runtime. How to realise evolvable runtime variability in software systems is a challenge in the community of software engineering. Software architecture is supposed to support updating software without interrupting service if runtime variability is to be changed. Besides, the relevant mechanisms have to be provided to achieve dynamic update. Thus, we propose a dynamically reconfigurable reference architecture to construct the systems with evolvable software variability. The resultant system established using our approach consists of variability units and their containers. Variability units embody the variability elements that can be changed through local relay, i.e., starting a new version of variability unit to take place of older ones. Containers are mainly used to carry out the dynamic updating for variability units and realise the functionality invocation among different variability units. They can also be added, removed or replaced without shutting down the entire system. We analyse the requirements and scenarios of evolvable runtime variability in the case of Personal Data Resource Network, and further show the effectiveness and applicability of our approach by constructing the system using our class library and solving the issues proposed in the case.

To observe the effect of pungent dispersion bitter purgation method (PDBPM) on the esophageal mucosal intercellular space of reflux esophagitis (RE) model rats.Totally 100 Wistar rats were randomly divided into the control group, the model group, the Western medicine group (WM), the Chinese medicine group (CM), 25 rats in each group. Rats in the control group only received switch operation. Rats in the rest three groups received modified partial cardia muscle incision combined pylorus ligation of external parts to prepare the RE rat model. Starting from the 3rd day after operation, WM mixture (Motilium 3. 2 mg/kg + Omeprazole Capsule 4.3 mg/kg + Hydrotalcite Tablet 161.4 mg/kg) was administered by gastrogavage to rats in the WM group. Rats in the CM group was administered by gastrogavage with Modified Banxia Xiexin Decoction (5.7 g/kg), 2.5 mL each time, twice daily for 14 consecutive days. Equal volume of normal saline was administered by gastrogavage to rats in the control group and the model group. On day 7 and 14, the lower esophagus pH value, general specimen of mucosa and histopathologic changes were observed. Intercellular spaces of esophageal epithelium were measured for a control study.Compared with the same group at day 7, the lower esophagus pH value increased at day 14 (P0.01); the naked eye integral of esophageal mucosa and intercellular spaces of esophageal epithelium also decreased at day 14 in the CM group and the WM group (P0.05). Compared with the control group at the same time point, the lower esophagus pH value decreased in the model group (P0.01). The naked eye integral of esophageal mucosa, and intercellular spaces of esophageal epithelium increased in the model group with increased intercellular spaces (P0.01). Compared with the model group at the same time point, the lower esophagus pH value increased and the naked eye integral of esophageal mucosa decreased in the CM group and the WM group at day 7 and 14 (P0.01). Intercellular spaces of esophageal epithelium of RE model rats at day 14 was lower in the CM group and the WM group than in the model group (P0.01). Compared with the WM group, the lower esophagus pH value decreased at day 7 in the CM group (P0.05); the naked eye integral of esophageal mucosa and intercellular spaces of esophageal epithelium decreased at day 14 in the CM group (P0.05).PDBPM had favorable treatment effect on RE model rats. The therapeutic effect was more obvious along with the therapeutic course went by. Its mechanism might be achieved through good repair effect on damaged mucosa, increasing the pressure of esophageal sphincter, and inhibiting gastric acid.

The effect of annealing (1068 K, 250 h) on microstructure and thermoelectric properties of a compound, a 0.33 mol% Sb-doped Mg2Si0.5Sn0.5 solid solution, was studied with TEM, thermoelectric measurements, XRD, SEM, and EPMA (electron probe microanalysis). The solid solution was synthesized by combining a liquid-solid reaction and hot-pressing process. The as-prepared sample contained Si, Sn and MgO inclusions tens of nm in size. After annealing, Si and Sn inclusions disappeared, while the MgO nanoparticles remained almost unchanged; the charge carrier concentration and electrical conductivity decreased and the lattice thermal conductivity increased. As a result, the thermoelectric figure of merit ZT ~ 0.34 at 394 K for the as-prepared sample deteriorated to ~ 0.24 at 388 K after the annealing. The results suggest the presence of a high density of point defects, such as Mg interstitials in the as-prepared sample. The density of these Mg interstitials was reduced by the annealing, thereby affecting the charge carrier concentration and electrical conductivity. The increase in the lattice thermal conductivity upon annealing is attributed to the disappearance of point defects, grain boundaries (grain growth) and Si and Sn inclusions, which all act as phonon scattering centers. Thus point defects and nanoinclusions might be important for optimizing the thermoelectric properties of a material. This work provides new insights into the effect of annealing on the microstructure and its relationship with the thermoelectric properties of Sb-doped Mg2Si0.5Sn0.5 solid solutions. It also provides hints for developing Mg2Si0.5Sn0.5-based materials with superior thermoelectric properties. B23-O-15 doi:10.1093/jmicro/dfv174