On behalf of Space Gravitational Wave Detection Working Group in Chinese Academy of Sciences (CAS), ongoing development of gravitational wave detection in space in China has been presented in this ...talk. The preliminary mission design, primary science drivers, program for technological developments and the road-map will be described.
The differential code bias (DCB) of global navigation satellite systems (GNSSs) affects precise ionospheric modeling and applications. In this paper, daily DCBs of the BeiDou Navigation Satellite ...System (BDS) are estimated and investigated from 2-year multi-GNSS network observations (2013–2014) based on global ionospheric maps (GIMs) from the Center for Orbit Determination in Europe (CODE), which are compared with Global Positioning System (GPS) results. The DCB of BDS satellites is a little less stable than GPS solutions, especially for geostationary Earth orbit (GEO) satellites. The BDS GEO observations decrease the precision of inclined geosynchronous satellite orbit (IGSO) and medium Earth orbit (MEO) DCB estimations. The RMS of BDS satellites DCB decreases to about 0.2 ns when we remove BDS GEO observations. Zero-mean condition effects are not the dominant factor for the higher RMS of BDS satellites DCB. Although there are no obvious secular variations in the DCB time series, sub-nanosecond variations are visible for both BDS and GPS satellites DCBs during 2013–2014. For satellites in the same orbital plane, their DCB variations have similar characteristics. In addition, variations in receivers DCB in the same region are found with a similar pattern between BDS and GPS. These variations in both GPS and BDS DCBs are mainly related to the estimated error from ionospheric variability, while the BDS DCB intrinsic variation is in sub-nanoseconds.
Objective: Clinical applications of Glucagon-like peptide-1 receptor agonists (GLP1-RA) were greatly limited due to its short half-life. The current study aims at the formulation and characterization ...of sustained-release (SR)-GLP1-RAs to prolong the release profile with lag phase-free formulation technology.
Methods: The long-acting drugs of those GLP1-RAs were prepared by an ultrasonic spray drying process with biodegradable PLGA polymer. Once the PLGA polymer and each API were dissolved in acetic acid, those were applied to the ultrasonic spray dryer to produce the microspheres which encapsulate the API in PLGA polymer. The pharmacokinetic profiles of long-acting SR-Exenatide, SR-Liraglutide, and SR-Semaglutide were determined by using Sprague-Dawley rats after a single injection subcutaneously. APIs were used as controls.
Results: The optimized SR-Exenatide has demonstrated favorable physicochemical properties, such as mean particle size (20 ± 3 μm), percent of entrapment efficiency (90 ± 5 %), and the final drug loading (5 ± 0.5 %), with uniformly sized microspheres. Furthermore, the pharmacokinetic parameters appeared that its release profile extends up to 4 weeks without lag phase which showed 11.4 days of Tmax and 68% of relative bioavailability (BA) when 2mg/kg dose applied. Not only SR-Exenatide but also SR-Liraglutide and SR-Semaglutide showed the extended-release profile up to 1 week and 4 weeks in the rats, respectively.
Conclusion: Those results showed the potentials of lag phase-free, long-acting, high productivity, and mass production. Taken together with the lag phase-free formulation and long-acting ultrasonic spray drying technologies, it will provide the rationales for the clinical development of SR-GLP1-RAs for once-weekly or -monthly formulations. As we have a GMP facility to produce long-acting drugs, we will actively and clinically investigate those SR-GLP1-RAs for antidiabetic therapy.
Disclosure
J. G. Jung: None.
We investigated the relationship between the serum macrophage chemokine ligand 16 (CXCL16) levels and the vulnerable carotid plaque in patients with ischemic stroke.
We successively selected 118 ...cases of patients with an initial diagnosis of acute ischemic stroke (time of onset < 72 h), recorded risk factors, including gender, age, family history, smoking, body mass index, blood glucose levels, blood lipid levels, average systolic pressure and diastolic blood pressure (DBP) and homocysteine levels. ELISA was used to detect the levels of serum CXCL16. GE-3000 color Doppler ultrasound diagnostic instrument was applied for the detection of the cervical artery (including a bilateral common carotid artery, internal carotid artery and external carotid artery) intima-media thickness (IMT), plaque number, size, nature (stable and vulnerable) and luminal stenosis rate. Delica EMS-9EBx2P type transcranial Doppler ultrasound (TCD) was used to detect micro-arterial micro-embolic signals (MES). Stroke, according to etiologic type, was divided into large artery atherosclerosis (LAA), small artery occlusion (SAA) and others.
Serum CXCL16 levels were not significantly correlated with sex, age, family history, smoking, BMI, blood glucose levels, blood lipid levels, mean systolic blood pressure, diastolic blood pressure, and homocysteine levels. Serum CXCL16 levels increased with an increase of IMT, plaque area and lumen stenosis rate. Serum CXCL16 levels of vulnerable plaques were significantly higher than those of stable plaques; differences were statistically significant (p<0.05). It has nothing to do with the number of atherosclerotic plaques. The levels of serum CXCL16 in MES positive group were significantly higher than that in MES negative group; differences were statistically significant (p<0.05). The serum CXCL16 levels of LAA patients were significantly higher than that of SAA and other types of patients; differences were statistically significant (p<0.05).
The levels of serum CXCL16 are not related to high-risk factors for acute stroke and closely related to characteristics of atherosclerotic plaque, micro-embolic signals and stroke subtypes.
The CRISPR-Cas9 system has raised hopes for developing personalized gene therapies for complex diseases. Its application for genetic and epigenetic therapies in humans raises concerns over ...immunogenicity of the bacterially derived Cas9 protein. Here we detect antibodies to Streptococcus pyogenes Cas9 (SpCas9) in at least 5% of 143 healthy individuals. We also report pre-existing human CD8+T cell immunity in the majority of healthy individuals screened. We identify two immunodominant SpCas9 T cell epitopes for HLA-A*02:01 using an enhanced prediction algorithm that incorporates T cell receptor contact residue hydrophobicity and HLA binding and evaluated them by T cell assays using healthy donor PBMCs. In a proof-of-principle study, we demonstrate that Cas9 protein can be modified to eliminate immunodominant epitopes through targeted mutation while preserving its function and specificity. Our study highlights the problem of pre-existing immunity against CRISPR-associated nucleases and offers a potential solution to mitigate the T cell immune response.
Tumor-stroma interactions significantly influence cancer cell metastasis and disease progression. These interactions are partly comprised of the cross-talk between tumor and stromal fibroblasts, but ...the key molecular mechanisms within the cross-talk that govern cancer invasion are still unclear. Here, we adapted our previously developed microfluidic device as a 3D
organotypic model to mechanistically study tumor-stroma interactions by mimicking the spatial organization of the tumor microenvironment on a chip. We cocultured breast cancer and patient-derived fibroblast cells in 3D tumor and stroma regions, respectively, and combined functional assessments, including cancer cell migration, with transcriptome profiling to unveil the molecular influence of tumor-stroma cross-talk on invasion. This led to the observation that cancer-associated fibroblasts (CAF) enhanced invasion in 3D by inducing expression of a novel gene of interest, glycoprotein nonmetastatic B (
), in breast cancer cells, resulting in increased migration speed. Importantly, knockdown of GPNMB blunted the influence of CAF on enhanced cancer invasion. Overall, these results demonstrate the ability of our model to recapitulate patient-specific tumor microenvironments to investigate the cellular and molecular consequences of tumor-stroma interactions. SIGNIFICANCE: An organotypic model of tumor-stroma interactions on a microfluidic chip reveals that CAFs promote invasion by enhancing expression of GPNMB in breast cancer cells.
Although cancer has classically been regarded as a genetic disease of uncontrolled cell growth, the importance of the tumor microenvironment (TME) 1, 2 is continuously emphasized by the accumulating ...evidence that cancer growth is not simply dependent on the cancer cells themselves 3, 4 but also dependent on angiogenesis 5-8, inflammation 9, 10, and the supporting roles of cancer-associated fibroblasts (CAFs) 11-13. After the discovery that CAFs are able to remodel the tumor matrix within the TME and provide the nutrients and chemicals to promote cancer cell growth 14, many studies have aimed to uncover the cross talk between cancer cells and CAFs. Moreover, a new paradigm in cancer metabolism shows how cancer cells act like "metabolic parasites" to take up the high-energy metabolites, such as lactate, ketone bodies, free fatty acids, and glutamine from supporting cells, including CAFs and cancer-associated adipocytes (CAAs) 15, 16. This chapter provides an overview of the metabolic coupling between CAFs and cancer cells to further define the therapeutic options to disrupt the CAF-cancer cell interactions.
•An improved multivariate Transfer Entropy is proposed to identify causality.•CF-LSTM is proposed, which is more sensitive to anomalous states.•EPOT is proposed to automatically determine anomaly ...detection thresholds.•A new spacecraft on-orbit anomaly detection method is proposed.
For data-driven anomaly detection, it is difficult to model a prediction model with high accuracy and sensitivity to anomalous states. In order to solve the above problems, this paper proposes an improved multivariate Transfer Entropy method to judge the physical causality between high-dimensional time series. According to the causality, combined with the LSTM (Long Short-Term Memory) model, the CF-LSTM (causality features-LSTM) model is proposed. The CF-LSTM model uses the causality features of the parameter to make predictions. Compared with other models, the CF-LSTM model improves the prediction accuracy and it is sensitive to anomalies. Based on this, an anomaly detection algorithm is proposed. Case analysis based on the actual data shows that the detection precision, recall, and F1-score (a measure of classification problem) of this method are improved compared with other anomaly detection models, which illustrates the effectiveness of this method.
A general analytical method is developed for the natural features and vibro-acoustic response analysis of an arbitrarily restrained rectangular plate backed by an irregular cavity. The modeling of ...the structure and the sound space are developed by employing the variational theory based on the sub-structure method. The irregular enclosure is disassembled into sub-cavities and the coupling formulae are deduced. The continuity conditions of both sound pressure and particle velocity at the coupling interface are exactly satisfied. The variational expressions of elastic boundary conditions of the panel are presented and thus the classical boundary conditions can be easily obtained by assigning appropriate elastic coupling coefficients. The vibration and sound pressure solutions are obtained by performing the Rayleigh–Ritz procedure. The accuracy and efficiency of the present method are validated by checking the present results against the finite element method (FEM) results for systems separately with right-angled trapezoidal and concave curved trapezoidal sub-cavity. It is shown that the present method is suitable for a system with an irregular cavity and an elastically restrained plate by exhibiting satisfactory accuracy, fast convergence speed while requiring small computation effort.
The mission of the DNASU Plasmid Repository is to accelerate research by providing high-quality, annotated plasmid samples and online plasmid resources to the research community through the curated ...DNASU database, website and repository (http://dnasu.asu.edu or http://dnasu.org). The collection includes plasmids from grant-funded, high-throughput cloning projects performed in our laboratory, plasmids from external researchers, and large collections from consortia such as the ORFeome Collaboration and the NIGMS-funded Protein Structure Initiative: Biology (PSI:Biology). Through DNASU, researchers can search for and access detailed information about each plasmid such as the full length gene insert sequence, vector information, associated publications, and links to external resources that provide additional protein annotations and experimental protocols. Plasmids can be requested directly through the DNASU website. DNASU and the PSI:Biology-Materials Repositories were previously described in the 2010 NAR Database Issue (Cormier, C.Y., Mohr, S.E., Zuo, D., Hu, Y., Rolfs, A., Kramer, J., Taycher, E., Kelley, F., Fiacco, M., Turnbull, G. et al. (2010) Protein Structure Initiative Material Repository: an open shared public resource of structural genomics plasmids for the biological community. Nucleic Acids Res., 38, D743-D749.). In this update we will describe the plasmid collection and highlight the new features in the website redesign, including new browse/search options, plasmid annotations and a dynamic vector mapping feature that was developed in collaboration with LabGenius. Overall, these plasmid resources continue to enable research with the goal of elucidating the role of proteins in both normal biological processes and disease.
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