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BACKGROUND Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P

Two new furoquinoline alkaloids, named 1'-oxo-isoplatydesmine (1) and demethoxyacrophylline (2), as well as 11 known alkaloids (3-13) were isolated from the root bark of Dictamnus dasycarpus Turcz. The structures of 1 and 2 were established by detailed spectroscopic elucidation, such as 1 D & 2 D NMR and HRMS, etc. The unexpected autoracemization of 1 was discussed based on the stereochemistry of reported dihydrofuroquinolines. Compounds 3–5 exhibited moderate inhibitory activities against Bacillus subtilis, Candida albicans, and Pseudomonas aeruginosa with MICs 32–64 μg/ml, revealing the active principles of D. dasycarpus for treating skin diseases in its traditional usage.

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Objective To explore the genetic spectrum of cerebral palsy (CP) in a Chinese paediatric cohort. Study design This was a retrospective observational study of patients with CP from the Children’s Hospital of Fudan University between June 2015 and December 2019. Their clinical data and exome sequencing data were collected and analysed. Results A total of 217 patients with CP were enrolled, and genetic variants were identified in 78 subjects (35.9%): 65 patients with single-nucleotide variants (SNVs), 12 patients with copy number variants (CNVs) and one patient with both an SNV and a CNV. The genetic diagnosis rates were significantly higher in patients without clinical risk factors than in patients with clinical risk factors (χ 2 =21.705, P = .000) and were significantly higher in patients with a family history than in those without a family history (χ 2 =4.493, P=0.034). Variants in genes related to neurologic disorders were the most commonly detected variants, affecting 41 patients (62.1%, 41/66). Among the patients with SNVs detected, the top 12 genes were found to cover 62.1% (41/66) of cases, and 39.4% (26/66) of patients with SNVs had medically actionable genetic findings. Conclusions The overall genetic diagnostic rate in this study was 35.9%, and patients without any clinical risk factors or with a family history were more likely to have genetic risk factors. The top 12 genes detected in this study as well as genes related to neurologic disorders or other medically actionable disorders should be noted in the analysis of genetic testing results in patients with CP.

Acetaminophen (N‐acetyl‐para‐aminophenol [APAP]) overdose is the most common cause of drug‐induced liver injury in the Western world and has limited therapeutic options. As an important dietary component intake, fructose is mainly metabolized in liver, but its impact on APAP‐induced liver injury is not well established. We aimed to examine whether fructose supplementation could protect against APAP‐induced hepatotoxicity and to determine potential fructose‐sensitive intracellular mediators. We found that both high‐fructose diet feeding before APAP injection and fructose gavage after APAP injection reduced APAP‐induced liver injury with a concomitant induction of the hepatic carbohydrate‐response element‐binding protein α (ChREBPα)–fibroblast growth factor 21 (FGF21) pathway. In contrast, Chrebpα liver‐specific‐knockout (Chrebpα‐LKO) mice failed to respond to fructose following APAP overdose, suggesting that ChREBPα is the essential intracellular mediator of fructose‐induced hepatoprotective action. Primary mouse hepatocytes with deletion of Fgf21 also failed to show fructose protection against APAP hepatotoxicity. Furthermore, overexpression of FGF21 in the liver was sufficient to reverse liver toxicity in APAP‐injected Chrebpα‐LKO mice. Conclusion: Fructose protects against APAP‐induced hepatotoxicity likely through its ability to activate the hepatocyte ChREBPα–FGF21 axis.

Ethnopharmacological relevance Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors, seriously compromising patients’ quality of life. Previous studies showed that Zengshengping (ZSP), a popular traditional Chinese medicine, has certain inhibiting effects on both oral precancerous lesions and OSCC. However, few reports underlined ZSP side effects such as liver toxicity, which limit its long-term application. Aim of the study was to evaluate the chemopreventive effect of a modified ZSPs formula on oral cancer in a hamster model. Its effect on hamster liver was also assessed. Materials and Methods The original medicine (ZSP-1) and other two formulas slightly different and called ZSP-2 and ZSP-3 were prepared ahead of time. DMBA (0.5%) was topically applied for 6 weeks to induce a premalignant lesion on hamsters’ cheek pouch, then ZSP-1/2/3 were intragastrically administered for 8 weeks. Hamster treated with DMBA + each of the ZSPs represented the ZSP-1/2/3 groups, while those without ZSP-1/2/3 treatment represented the DMBA group. To assess the effect of ZSPs in the liver, intragastric administration of ZSP-1/2/3 was carried out to other groups of hamsters for 12 weeks and the blood was collected every two weeks to detect the hepatic function. Some of the hamsters were sacrificed at the end of 12 weeks, while the remaining animals were sacrificed after other 4 weeks to estimate the effect of ZSP-1/2/3 withdrawal on the liver. Results showed that tumor development in the ZSP-1/2/3 groups was less than that in DMBA group. BrdU, CD31 and COX-2 expression in the hyperplastic tissues was significantly lower in the ZSP-1/2/3 groups than that in the DMBA group. In addition, VEGF and COX-2 expression in ZSP-1/2/3 groups was lower while caspase-9 and p53 expression was higher than those in the DMBA group. Finally, PTEN expression in ZSP-1/2/3 groups was higher than that in the DMBA group. As regard the effect in the liver, ALP in the ZSP-1/2/3 groups was higher than that in the control group treated with an intragastric administration of ddH2O. After 4 weeks of withdrawal, the hamsters of the ZSP-3 group did not recover from the increase in ALP. Histopathology showed the presence of inflammatory lesions in each group after 12 weeks, especially in the ZSP-1/3 groups, and the number of apoptotic cells in the ZSP-3 group was higher than that in the other groups, without any recovery after withdrawal of the drug. At 12 weeks, the MDA in the ZSP-1 group was higher than that in the control group and the ZSP-2 group, but the difference disappeared after drug withdrawal because the MDA in the ZSP-1/3 groups decreased. Conclusions ZSP-2 possessed a chemopreventive effect against oral cancer by inhibiting inflammation, proliferation of tumor cells, generation of microvessels and by promoting tumor cell apoptosis. In addition, hepatotoxicity of ZSP-2, which might be related to oxidative stress injury, was reduced to some extent.

Fine-grained software vulnerability detection is an important and challenging problem. Ideally, a detection system (or detector) not only should be able to detect whether or not a program contains vulnerabilities, but also should be able to pinpoint the type of a vulnerability in question. Existing vulnerability detection methods based on deep learning can detect the presence of vulnerabilities (i.e., addressing the binary classification or detection problem), but cannot pinpoint types of vulnerabilities (i.e., incapable of addressing multiclass classification). In this paper, we propose the first deep learning-based system for multiclass vulnerability detection, dubbed $\mu$VulDeePecker. The key insight underlying $\mu$VulDeePecker is the concept of code attention, which can capture information that can help pinpoint types of vulnerabilities, even when the samples are small. For this purpose, we create a dataset from scratch and use it to evaluate the effectiveness of $\mu$VulDeePecker. Experimental results show that $\mu$VulDeePecker is effective for multiclass vulnerability detection and that accommodating control-dependence (other than data-dependence) can lead to higher detection capabilities., Comment: To be published in IEEE Transactions on Dependable and Secure Computing

The micro-grooving technology/micro-ruling technology is a special and efficient manufacturing technology and generally used to machine the cylindrical surface and micro grooved structures array. This paper investigates the fabrication of different types of micro structures by ruling. Experiment is conducted to machine a multi-layer micropillar array with a sharp diamond cutting tool by micro-grooving. Experimental results show that micro-grooving technology is feasible for the machining of multi-layer micropillar array with submicrometer form accuracy.

Nursing home residents are at a higher risk of suicidal ideation, and depressive symptoms and limitations on activities of daily living (ADL) are presumed to be contributory factors, whereas resilience may buffer the negative effects of risk factors. This study aimed to investigate the prevalence of suicidal ideation and the moderating effect of resilience on suicidal ideation to dilute the adverse contribution of ADL limitation and depressive symptoms. A stratified random sampling was used to recruit 538 residents from 37 nursing homes in China. Participants' suicidal ideation, resilience, depressive symptoms, and ADL limitation were measured and tested by structural equation modeling. Statistics show that 14.9% of participants had suicidal ideation and the model where resilience moderated the effects of ADL limitation and depressive symptoms on suicidal ideation had the best model fit index. This suggests that positive psychological interventions for resilience building might be effective in reducing suicidal ideation.

The potential application of curcumin was heavily limited in biomedicine because of its poor solubility in pure water. To circumvent the detracting feature, two novel water-soluble amino acid modified curcumin derivatives (MLC and DLC) have been synthesized through the condensation reaction between curcumin and Nα-Fmoc-Ne-Boc-l-lysine. Benefiting from the enhanced solubility of 3.32×10-2g/mL for MLC and 4.66×10-2g/mL for DLC, the inhibition effects of the as-prepared derivatives on the amyloid fibrillation of lysozyme (HEWL) were investigated detaily in water solution. The obtained results showed that the amyloid fibrillation of HEWL was inhibited to a great extent when the concentrations of MLC and DLC reach to 20.139mM and 49.622mM, respectively. The fluorescence quenching upon the addition of curcumin to HEWL provide a support for static and dynamic recombination quenching process. The binding driving force was assigned to classical hydrophobic interaction between curcumin derivatives and HEWL. In addition, UV-Vis absorption and circular dichroism (CD) spectra confirmed the change of the conformation of HEWL.

The facile preparation of hyperbranched glycopolymers was performed without protecting group chemistry, where the methyl-6-O-methacryloyl-α-D-glucoside (6-O-MMAGlc) monomer was adopted as an AB3*-type inimer. The polymerization was initiated by the hydroxy/cerium(IV) redox process and could be named the self-condensing vinyl copolymerization/redox (SCVP/Redox) process. The oxygen radical (C–O˙), rather than the carbon radical (˙C–OH), was generated by the redox reaction of Ce(IV) with –OH groups on the pyranose in 6-O-MMAGlc, which was confirmed by NMR data. The formation of the branching point and linear chain growth were defined to give the degree of branching (DB). A linear increase of the DB was observed as the concentration of Ce(IV) increased, implying facile control of the DB. More interestingly, the hyperbranched glycopolymers on the amyloid fibrillation of hen egg-white lysozyme (HEWL) exhibited a greater inhibition activity than that of the linear analogue. This substantial study would provide more room to enrich the family of glycopolymers and extend their potential application in biomedicine and biomaterials.

PURPOSE/OBJECTIVE(S) The high intracranial efficacy of target therapy agents challenges the sequence of local radiation therapy (RT) and systematic tyrosine kinase inhibitors (TKI) in brain metastases (BM) patients. Therefore, we conducted a single institutional retrospective cohort study to demonstrate the appropriate treatment strategy of upfront RT or upfront TKI in these patients, including an assessment of its feasibility and toxicity. MATERIALS/METHODS Patients with brain metastases who received hypofractionated stereotactic radiotherapy (HFSRT) with/without whole brain radiotherapy (WBRT) at our institution from October 2010 to October 2020 were included in this study. The primary endpoint was intracranial progression-free survival (IPFS). The secondary endpoints were overall survival (OS), brain metastases specific survival (BMSS) and toxicity. Intracranial progression was estimated using the Fine-Gray competing risks model. Kaplan-Meier analysis and Log-rank tests were used to evaluate and compare OS and BMSS. Multivariate analysis was performed using Cox logistic regression analysis. RESULTS Among 885 patients, 570 patients enrolled in the study. 130 patients received upfront TKI with RT, 193 patients received upfront RT with TKI, and 247 patients received RT alone. The median follow-up time was 56.4 months. Upfront RT group showed lower intracranial progression risk with adjusted SHR 0.51 (95% CI, 0. 40- 0.667) than upfront TKI group (median IPFS, 17.2 months vs. 8.5 months; P

PURPOSE/OBJECTIVE(S) To compare the prognostic predictive power of the 11th Japan Esophageal Society (JES) system with the 8th American Joint Committee on Cancer (AJCC) system in patients with thoracic esophageal squamous cell carcinoma (TESCC), and to estimate the survival benefits of postoperative radiotherapy (PORT) based on substage of the JES system. MATERIALS/METHODS Area under the curve (AUC) values of receiver operating characteristic curve were calculated to evaluate prognostic efficacy. Propensity score matching (PSM) analysis was conducted to balance the two groups (surgery only [S group] or surgery plus postoperative radiotherapy [S+RT group]) across substages of the 11th JES system according to independent prognostic factors for overall survival (OS) identified using the Cox proportional hazards regression. RESULTS A total of 2960 patients were eligible. The 5-year OS AUC for the 8th AJCC system was significantly higher than that for the 11th JES system (0.701 vs. 0.675, P < 0.001). Before PSM, PORT significantly improved 5-year OS rates for patients in stage III and IVA by 9.1% (P < 0.001) and 21.1% (P < 0.001), respectively. After PSM, the 5-year OS rates in stage II, III, and IVA of the S+RT group were significantly higher than those in the S group (70.9%, 39.7%, and 35.1% vs. 57.8%, 27.2%, and 10.3%, respectively; P < 0.001). CONCLUSION The 11th JES system was less capable of predicting prognosis than the 8th AJCC system and patients in stage III of the JES system were highly recommended to undergo PORT.

Purpose/Objective(s) To create a radiomics model of prognostic prediction for soft-tissue sarcoma (STS) of the extremities and trunk treated with neoadjuvant radiotherapy. Materials/Methods we used a dataset of 62 STS patients treated with neoadjuvant radiotherapy from our institution between January 2015 and December 2019 (n = 20) and the NCI's Cancer Imaging Archive between November 2004 and November 2011(TCIA, n = 42). After tumor segmentation and preprocessing, 851 radiomic features were extracted from pretreatment fat saturated T2-weighted MRI image. The Radiomics-score was to be constructed based on the least absolute shrinkage and selection operator (LASSO) regression results. Kaplan-Meier analysis (log-rank test) and Cox's proportional hazards regression model were used to evaluate the prognostic factor of the 2-years disease-free survival (DFS). The nomogram model was established based on log-rank test and Cox's proportional hazards regression model. The Harrell's concordance index (C-index), receiver operating characteristic curve (ROC) analysis and calibration curves were used to evaluate the nomogram models. Decision curve analysis (DCA) was performed to analyze the clinical usefulness of the model. Results The cohort included 62 patients (30 females (48.4%), mean age: 50.9 ± 19.1 years). The most frequent histotypes were liposarcoma (24.2%) and undifferentiated sarcoma (22.6%). Most of tumors were deep-seated (74.2%) and located in the extremity (88.5%). A total of 851 radiomic features were extracted from T2-FS images. After data dimension reduction with LASSO, 42 most valuable features remained and their coefficients were from lasso-cox regression. The radiomics-score calculation formula consisted of these features. The univariate survival analysis showed that tumor location (P = 0.032), clinical stage (P = 0.022), tumor size (P = 0.005) and radiomics-score were correlated with DFS (P Conclusion The radiomics-score based pretreatment MRI was an independent prognostic factor for DFS of the extremities and trunk STS patients. The combined clinical-radiomics model added accuracy to predict DFS and thus contributed to the individual selection of neoadjuvant therapy.

A novel ratiometric fluorescent probe 1, consisting of Boranil derivative as the fluorophore and picolinate as the recognition site for Cu2+, was designed and synthesized. 1 was found to display ratiometric response while interacting with Cu2+ by undergoing a Cu2+-promoted hydrolysis of the picolinate moiety for the release of its precursor, 2. We observed that 1 not only showed quick response time (within 10 min), high sensitivity (detection limit of 0.52 μM), and high selectivity for Cu2+ over other metal ions, but also allowed us to detect Cu2+ in a convenient way of observing fluorescence color change under a 365 nm UV lamp using naked eyes. Our study introduced the first ratiometric fluorescent probe for Cu2+ based on Boranil derivative.

Fengyun-3C (FY-3C) is a second-generation meteorological satellite of China that was launched on 23 September 2013. The on board Visible and Infrared Radiometer (VIRR) can be used to observe global sea surface temperature (SST). In this paper, the VIRR SST products are compared with MODIS SST products and buoy measurements from 2015 to 2019. The collocations of VIRR, MODIS, and buoy SST are generated separately during the day and night with the spatial window of 0.05° × 0.05°. The comparison results show that the biases of VIRR SST minus buoy SST during the day and night are −0.21 and −0.13 °C with a corresponding robust standard deviation (RSD) of 0.58 and 0.59 °C, respectively. The mean differences between VIRR and MODIS are −0.10 and 0.08 °C with RSDs of 0.53 and 0.58 °C for the daytime and nighttime, respectively. The consistency of VIRR SST accuracy from 2015 to 2019 and the dependence of VIRR SST error on SST and latitude are also investigated.

In diamond cutting of polycrystalline metals, the influence of size effect and microstructure on the cutting force is prominent due to the trans-scale variation of undeformed chip thickness (UDCT) from microscale to nanoscale. This study proposes a trans-scale cutting force model for diamond cutting of polycrystalline metals with the full consideration of microstructure, material elastic recovery, size effect and round-tool-edge effect. Specifically, by corelating micro-forming theory and crystal plastic theory, a hybrid slip-line model (HSLM) is developed to determine the flow stress in the primary deformation zone, which can quantify the influence of size effect and microstructure, such as grain size, grain boundary and crystal anisotropy, on flow stress. Then, the normal cutting force and frictional cutting force are determined by analysing the stress distribution and frictional states at tool-chip interface using a tool-chip contact model. The rubbing force induced by material elastic recovery at very small UDCT is determined based on indentation theory. Through diamond cutting of polycrystalline copper with different grain sizes, it is experimentally demonstrated that the proposed HSLM can capture the cutting mechanism transformation phenomenon from shearing (tensile stress) to ploughing (compressive stress) with increasing size factor. Besides, the proposed force model has the improved estimation accuracy compared with the conventional force models developed based on Johnson-Cook constitutive equation.

Identification of geometric errors of translational axis is a key step to improve the accuracy of machine tools. However, during the procedure of measurement, installation errors of instruments are inevitable and should influence the measurement results. In order to avoid this and improve the reliability and accuracy of measurement, a novel identification measurement method is proposed. The errors of positioning and straightness of translational axis are measured by a laser interferometer in four installation positions. Twelve measured results are obtained, and then are used to identify six geometric errors of translation axis, based on the homogeneous transformation matrix and the least square method. Furthermore, an optimization method based on sensitivity analysis of the identification matrix is presented to obtain the optimum installation positions of the laser interferometer, to diminish the influence of the installation errors. Finally, simulations and experiments are conducted to validate the correctness and effectiveness of proposed method. The results indicate that the optimization identification method proposed is effective and accurate.

Hypergraph is an effective method used to represent the contextual correlation within hyperspectral imagery for clustering. Nevertheless, how to discover the closely correlated samples to form hype...

Five previously undescribed hemiterpene glycosides, cibotiumbarosides E-I, and two known hemiterpene glucosides, were isolated from the rhizome of Cibotium barometz (L.) J. Sm. The structures of cibotiumbarosides E-I were established by 1D and 2D NMR spectroscopic analyses and HRMS. The absolute configuration of the aglycone of cibotiumbaroside E was assigned by calculated ECD with the TDDFT method. Cibotiumbarosides F and I both exhibited remarkable hepatoprotective activity against APAP-induced acute liver damage in vitro, which were more effective than the positive control, bicyclol. On the other hand, seven hemiterpene glycosides were all inactive in assays of cytotoxicity, neuroprotection, antidiabetes and anti-inflammation.

The air-dried twigs of Litsea cubeba, a traditional Chinese medicinal tree, afforded 10 new aromatic glycosides (1–10) and 26 known analogues. Their structures were assigned by extensive 1D and 2D NMR experiments, and the absolute configurations were resolved by chemical methods, electronic circular dichroism, specific rotation, and X-ray crystallographic analysis. Compound 4 is the first example of a naturally occurring homoneolignan glucoside. Compounds 4, 6–8, and the known neolignan glucosides (11, 12, and 14) at respective 10 μM concentrations were found to reduce acetaminophen-induced HepG2 cell injury with 30.5–46.0% inhibitions. Furthermore, compounds 12 and 15 demonstrated moderate inhibitory activities against HDAC1, with IC50 values of 3.6 and 4.6 μM, respectively.

C20H28BCl3F4Ru2, triclinic, P1̄ (no. 2), a = 7.7061(15) Å, b = 12.654(3) Å, c = 13.993(3) Å, α = 68.25(3)°, β = 78.71(3)°, γ = 88.89(3)°, V = 1240.8(5) Å3, Z = 2, R gt(F) = 0.0686, wR ref(F 2) = 0.2017, T = 293(2) K.

BackgroundDevelopmental disorders (DDs) are early onset disorders affecting 5%–10% of children worldwide. Chromosomal microarray analysis detecting CNVs is currently recommended as the first-tier test for DD diagnosis. However, this analysis omits a high percentage of disease-causing single nucleotide variations (SNVs) that warrant further sequencing. Currently, next-generation sequencing can be used in clinical scenarios detecting CNVs, and the use of exome sequencing in the DD cohort ahead of the microarray test has not been evaluated.MethodsClinical exome sequencing (CES) was performed on 1090 unrelated Chinese DD patients who were classified into five phenotype subgroups. CNVs and SNVs were both detected and analysed based on sequencing data.ResultsAn overall diagnostic rate of 41.38% was achieved with the combinational analysis of CNV and SNV. Over 12.02% of patients were diagnosed based on CNV, which was comparable with the published CMA diagnostic rate, while 0.74% were traditionally elusive cases who had dual diagnosis or apparently homozygous mutations that were clarified. The diagnostic rates among subgroups ranged from 21.82% to 50.32%. The top three recurrent cytobands with diagnostic CNVs were 15q11.2-q13.1, 22q11.21 and 7q11.23. The top three genes with diagnostic SNVs were: MECP2, SCN1A and SCN2A. Both the diagnostic rate and spectrums of CNVs and SNVs showed differences among the phenotype subgroups.ConclusionWith a higher diagnostic rate, more comprehensive observation of variations and lower cost compared with conventional strategies, simultaneous analysis of CNVs and SNVs based on CES showed potential as a new first-tier choice to diagnose DD.

Roll-to-Roll imprint process is considered to be the most promising technology for manufacturing large-area micro-structured surface. However, the traditional turning technique was considered to be incapable of machining radial Fresnel lenses on roller mold. This study deals with the problem of machining the radial Fresnel lens on a roller mold, which is achieved by using the diamond cutting tools mounted on a multiple axis control ultra-precision machining center. In addition, this study simulates the effect of the deviation of the tool tip position from the rotation center of the platform and the deviation from the vertical plane of the roller axis on the machining results.

This paper investigated the impact of fairness concerns on the formation of the inventory transshipment strategy alliance through its impact on the ordering decisions and profits of two retailers. The paper introduced reference point dependency to describe the retailer&rsquo, s fairness concerns utility function, and modeled the strategic alliance system consisting of two retailers involved in transshipment. The conditions for the existence of Nash equilibrium solutions were given. The paper solved the impact of the fairness parameters on order quantities and profits by the implicit function theorem. Based on the theoretical analysis and numerical examples, this paper investigated the formation of a strategic alliance under asymmetric and symmetric fairness concerns. The results are as follows: (1) under asymmetric fairness concerns, when the transshipment price of the retailer with no fairness concerns is no more than the transshipment price of the retailer with fairness concerns, an inventory transshipment strategy alliance can be formed. Otherwise the retailer with no fairness concerns may need to pay the retailer with fairness concerns certain fees in order to form a strategic alliance, (2) under symmetric fairness concerns, two completely symmetric retailers can form strategic alliances.

Object detection is a hot topic with various applications in computer vision, e.g., image understanding, autonomous driving, and video surveillance. Much of the progresses have been driven by the availability of object detection benchmark datasets, including PASCAL VOC, ImageNet, and MS COCO. However, object detection on the drone platform is still a challenging task, due to various factors such as view point change, occlusion, and scales. To narrow the gap between current object detection performance and the real-world requirements, we organized the Vision Meets Drone (VisDrone2018) Object Detection in Image challenge in conjunction with the 15th European Conference on Computer Vision (ECCV 2018). Specifically, we release a large-scale drone-based dataset, including 8, 599 images (6, 471 for training, 548 for validation, and 1, 580 for testing) with rich annotations, including object bounding boxes, object categories, occlusion, truncation ratios, etc. Featuring a diverse real-world scenarios, the dataset was collected using various drone models, in different scenarios (across 14 different cities spanned over thousands of kilometres), and under various weather and lighting conditions. We mainly focus on ten object categories in object detection, i.e., pedestrian, person, car, van, bus, truck, motor, bicycle, awning-tricycle, and tricycle. Some rarely occurring special vehicles (e.g., machineshop truck, forklift truck, and tanker) are ignored in evaluation. The dataset is extremely challenging due to various factors, including large scale and pose variations, occlusion, and clutter background. We present the evaluation protocol of the VisDrone-DET2018 challenge and the comparison results of 38 detectors on the released dataset, which are publicly available on the challenge website: http://www.aiskyeye.com/. We expect the challenge to largely boost the research and development in object detection in images on drone platforms.

It is a common phenomenon that when a motor runs, there is a sound. In addition, when the motor accelerates or decelerates, the sound changes. The underlying reason is surmised to be that the speed is a complex function of the sound. Usually, sound is expressed by amplitude and frequency, according to the Fourier transform. Therefore, the aforementioned problem is changed to find the exact expression of the function with respect to frequency. If the function were known, it would be meaningful to find a novel method to estimate the speed from the sound only. This paper investigated the potential mechanism of the phenomenon, and discovered a quantitative relationship between sound and speed. The application area of the framework was novel. Another contribution offered in this paper was the virtual dominant frequency which was proposed to replace the dominant frequency.

Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM). Hepatic stellate cells (HSCs) are the primary cells that produce ECM in response to hepatic injury, and transforming growth factor-beta (TGF-β) has been regarded as the central stimulus responsible for HSC-mediated ECM production. In the present study, we attempted to identify a critical factor in HSC activation and the underlying mechanism. By analyzing online microarray expression profiles, we found that the expression of high-affinity cationic amino acid transporter 1 (CAT1) was upregulated in hepatic fibrosis models and activated HSCs. We isolated and identified mouse HSCs (MHSCs) and found that in these cells, CAT1 was most highly upregulated by TGF-β1 stimulation in both time- and dose-dependent manners. In vitro, CAT1 overexpression further enhanced, while CAT1 silencing inhibited, the effect of TGF-β1 in promoting MHSC activation. In vivo, CAT1 silencing significantly improved the hepatic fibrosis induced by both CCl4 and non-alcoholic fatty liver disease (NAFLD). In summary, CAT1 was significantly upregulated in TGF-β1-activated MHSCs and mice with hepatic fibrosis. CAT1 silencing inhibited TGF-β1-induced MHSC activation in vitro and fibrogenic changes in vivo. CAT1 is a promising target for hepatic fibrosis treatment that requites further investigation in human cells and clinical practice.

Curcumin is the physiologically and pharmacologically active component of turmeric (Curcuma longa L.) with attractive fluorescent property. However, the applications in live cell imaging field are restricted mainly due to the water-insolubility and cytotoxicity. To overcome this problem, curcumin-incorporated glycopolymers are synthesized by free radical copolymerization in this study. The glycopolymers are well-characterized by infrared spectroscopy (IR), nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), UV-Vis absorption spectroscopy and photoluminescence spectroscopy. Furthermore, obtained glycopolymers are assayed by MTT assay and cell imaging for supporting the potential bio application. The MTT result indicates that the introduction of carbohydrate units can reduce the cytotoxicity of curcumin unit. The live cell imaging investigations reveal that the curcuminincorporated glycopolymers are good candidates for cell imaging and may find broad applications in biological areas such as biological diagnosis, imaging, and detection.

Two novel Boc-L-isoleucine-functionalized curcumin derivatives have been synthesized and characterized, which exhibited enhanced solubility in water compared with the natural curcumin. The solubility could reach 2.12mg/mL for the monosubstituted compound and 3.05mg/mL for the disubstituted compound, respectively. Their anti-amyloidogenic capacity on the model protein, hen egg white lysozyme (HEWL), was examined in aqueous solution. ThT fluorescence assay showed that the operation concentration was only 0.5mM when the inhibition ratio was above 70%. Meanwhile, the inhibitory capacity of monosubstituted curcumin derivative on the formation of HEWL amyloid fibrils was found to be superior to that of disubstituted derivative, suggesting that the phenolic hydroxyl group might contribute to the anti-amyloidogenic activity. Interaction study showed that both curcumin derivatives could bind with HEWL near tryptophan residues and form new ground-state complex before HEWL self-assemblies into amyloid fibrils and thus inhibits the formation of amyloid fibrils. Both of the two cucumin derivatives have displayed low cytotoxicity with HeLa cell.

Background A bran-new landscape of immuno-oncology (IO) is arising in China rapidly, with IO development a hotspot in biopharmaceutical industries. Moreover, a paucity of data on the panorama of IO clinical trials in China inspired us to present the systemic analysis for stakeholders in this field. Methods Based on the Platform for Registry and Publicity of Drug Clinical Trials, a national authoritative database by China Food and Drug Administration, the trials for IO agents issued from 2013 to 2018 were explored using newly developed agents (by six types of mechanism and targets) and the number of initiated trials as key indicators. The clinical development stages of all agents were presented by targets. In addition, time trends in annually initiated trials and cumulative indication distribution were investigated. Results There were 62 IO agents and 230 initiated trials in China from 2013 to 2018, with 46 (74.2%) agents and 154 (67.0%) trials from domestic firms. The 62 agents modulated 18 targets focusing on PD-1 (17, 27.4%), PD-L1 (12, 19.4%) and unspecified tumor-associated antigens (5, 8.1%). Only 8 agents of cell therapy were ever developed for registration purpose. PD-1/L1 targets were most extensively investigated with a total of 180 (78.3%) trials and 4 agents approved. The annual number of trials showed an upward trend, and the sharp increase for trials of T-cell targeted immuno-modulators was seen with an average growth rate of 199.1% since 2016. In terms of cancer types, solid tumor (56, 24.3%), non-small cell lung cancer (45, 19.6%) and hepatocellular cancer (20, 8.7%) were the most common. Only 14 (6.1%) trials applied a biomarker enrichment strategy. Table . 1293P The landscape of immuno-oncology targets in clinical development in China since 2013 Types Targets Agents N = 62 (%) Trials N = 230 (%) Total Phase I Phase II/III Approv ed T-cell targeted immuno- modulator PD-1 17 (27.4) 6 7 4 129 (56.1) PD-L1 12 (19.4) 5 7 51 (22.2) CTLA-4 3 (4.8) 1 2 11 (4.8) IDO1/TDO 2 2 2 IDO1 1 1 1 CD137 1 1 1 LAG3 1 1 1 OX40 1 1 1 PD-1/CTLA-4 1 1 1 PD-L1/CTLA-4 1 1 1 PD-L1/ TGF-βRII 1 1 1 Other immuno- modulator Unspecified 1 1 5 (2.2) CD47 1 1 1 MUC1 1 1 1 Cancer vaccine TLR 2 2 2 EGF 1 1 1 MUC1 1 1 1 Cell Therapy Unspecified 4 (6.5) 2 2 4 (1.7) CD19 3 (4.8) 3 3 (1.3) BCMA 1 1 1 Oncolytic virus GM-CSFR 4 (6.5) 1 3 9 (3.9) CD3-targeted bispecific mAb CD19 1 1 1 HER2 1 1 1 Conclusions Though a gap exists in the number of agents and targets between China and the global pipeline, the rising capability of IO has been achieved in China recently. Efforts should be further made in novel targets, cell therapy for registration purpose, Chinese unique cancers and new trial designs. Legal entity responsible for the study National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Gene therapy has shown promise in antitumor strategies for advanced cancer. However, efficient and safe delivery of potent therapeutic gene expressing in specific tumor tissues remains elusive, especially when there exist stromal obstacles. Here we report a non-viral gene delivery approach targeting pancreatic stellate cells (PSCs) as the transfection host in the fibroblast-enriched tumor microenvironment of pancreatic cancer. Plasmid DNA (pDNA) encapsulated in branched polyethylenemine (BPEI) was found to selectively transfect PSCs rather than pancreatic cancer cells and other fibroblast cell lines. Mechanism investigations reveal that the highly expressed fibroblast growth factor receptors (FGFRs) in PSCs facilitated the cellular uptake of polyplexes in PSCs. This delivery platform carrying gene encoding of TNF-related apoptosis-inducing ligand (TRAIL) displayed effective by-stander effect and tumor cell-selective cytotoxicity. More importantly, the therapeutic efficacy was proved in a PSC-enriched orthotopic pancreatic tumor model. Thus, this gene delivery strategy smartly converts PSCs as the microenvironment obstacle for drug delivery into the producer and reservoir of selective tumor-killing proteins.

Correction on Formation of Academic Mobility of Future Foreign Language Teachers by Means of Media Education Technologies

Alum-processing is a traditional method to attenuate the toxicity of Pinelliae Rhizoma (tubers of Pinellia ternate, PT). The present study aimed at investigating the chemical and cytotoxic changes during alum processing. Metabolomic profiles of raw and alum-processed PT were studied based on ultra-performance liquid chromatography coupled with Orbitrap mass spectrometry. More than 80 chemicals in positive MS mode and 40 chemicals in negative MS mode, such as organic acids, amino acids, glucosides and nucleosides, were identified after multivariate statistical analysis, including principal component analysis and orthogonal partial least-square discriminant analysis. Almost all of the identified chemical markers were significantly decreased ~10- to 100-fold after alum processing. Meanwhile, the correlations between the chemical markers were assimilated to a positive coefficient from disorderly distribution during the processing. Raw PT extracts could inhibit the proliferation of human carcinoma cells (HCT-116, HepG2, and A549) at the rate of 40.5, 24.8 and 31.6% more strongly than processed PT. It was concluded that the alum processing of PT could decrease the number of actively water-soluble principles at the same time as decreasing toxicity. Given the water-insoluble property of toxic calcium oxalate raphides in PT, we suggest that a more scientific processing method should be sought.

The removal of sulfapyridine (SPY) by ferrate(VI) in aqueous solutions under a broad range of reaction conditions, including ferrate(VI) dosage, solution pH, natural organic matter and coexisting inorganic ions, was systematically investigated and the oxidation pathway of SPY by ferrate(VI) was deeply explored. Results showed that 500 µg/L of SPY was efficiently decomposed (86%) within 1 min by 5 mg/L ferrate(VI) at pH 5.6. The increment in ferrate(VI) dosage was surely favorable for SPY removal. The best SPY degradation was achieved at pH 5.6, under or above which the removal decreased. The introduction of inorganic ions in solutions retarded SPY removal. Ten oxidation intermediates were identified and the cleavages of C-S and S-N bonds might be the primary ways of SPY oxidation by ferrate(VI).

The automatic detection of software vulnerabilities is an important research problem. However, existing solutions to this problem rely on human experts to define features and often miss many vulnerabilities (i.e., incurring high false negative rate). In this paper, we initiate the study of using deep learning-based vulnerability detection to relieve human experts from the tedious and subjective task of manually defining features. Since deep learning is motivated to deal with problems that are very different from the problem of vulnerability detection, we need some guiding principles for applying deep learning to vulnerability detection. In particular, we need to find representations of software programs that are suitable for deep learning. For this purpose, we propose using code gadgets to represent programs and then transform them into vectors, where a code gadget is a number of (not necessarily consecutive) lines of code that are semantically related to each other. This leads to the design and implementation of a deep learning-based vulnerability detection system, called Vulnerability Deep Pecker (VulDeePecker). In order to evaluate VulDeePecker, we present the first vulnerability dataset for deep learning approaches. Experimental results show that VulDeePecker can achieve much fewer false negatives (with reasonable false positives) than other approaches. We further apply VulDeePecker to 3 software products (namely Xen, Seamonkey, and Libav) and detect 4 vulnerabilities, which are not reported in the National Vulnerability Database but were "silently" patched by the vendors when releasing later versions of these products; in contrast, these vulnerabilities are almost entirely missed by the other vulnerability detection systems we experimented with.