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Yujin Mei,1 Xue Yang,1 Yuqing Li,1 Xiaoyun Zhang,1 Jiaofeng Gui,1 Ying Wang,1 Wenyue Chen,1 Mingjia Chen,1 Changjun Liu,2 Lin Zhang3 1School of Nursing, Wannan Medical College, Wuhu City, Anhui Province, People’s Republic of China; 2School of Marxism, Jinzhou Medical University, Jinzhou City, Liaoning Province, People’s Republic of China; 3Department of Internal Medicine Nursing, Wannan Medical College, Wuhu City, Anhui Province, People’s Republic of ChinaCorrespondence: Lin Zhang, Email yaoran2008@163.comBackground: In China, diabetes has become a serious healthcare problem that plagues individuals and the government because of its high mortality rate and social burden, with type 2 diabetes mellitus (T2DM) accounting for the vast majority (about 90%) of cases. T2DM patients face a huge medication burden and it is imperative to find appropriate tools to assess the medication burden for patients. This study aimed to translate the original Diabetes Treatment Burden Questionnaire (DTBQ) into Chinese and assessed the reliability and validity of the DTBQ concerning the burden of medication treatment in patients with type 2 diabetes.Methods: A total of 329 T2DM patients were recruited to participate in the survey. The original version scale was first translated into Chinese using the backward and forward translation procedures. The internal consistency reliability of the scale was measured by the Cronbach alpha coefficient, the test-retest reliability, and the item-total correlation. The validity of the scale was assessed by the content validity index, exploratory factor analysis and confirmatory factor analysis.Results: The content validity index of the scale was 0.920. Cronbach alpha coefficient for the scale was 0.831. Exploratory factor analysis (EFA) supported a 15-item and 3-factor structure of the translated questionnaire. Confirmatory factor analysis (CFA) showed in the model fitness index, the chi-square degree of freedom was 3.575, the incremental fit index (IFI) was 0.917, the comparative fit index(CFI) was 0.916, the Tucker Lewis Index(TLI) was 0.900, all within acceptable limits. The retest reliability was 0.892, and the corrected item-total correlations for the items ranged from 0.293 to 0.729.Conclusion: Verification results showed that the Chinese version of the 15-item DTBQ had reliable reliability and validity. Therefore, it can be considered as an appropriate tool to assess the burden of drug treatment for patients with type 2 diabetes in China.Keywords: diabetes treatment burden questionnaire, T2DM, reliability, validity

Background: Hypertension is prevalent in China. Hypertensive patients suffered from many health problems in life. As time goes by, this will cause them to lack of healthy beliefs. Nevertheless, one’s beliefs about managing their hypertension level and a battery of health habits it is still indistinct. So, it is extremely vital to find a suitable instrument to comprehend the health beliefs of patients and provide seasonable help to keep their body and mind healthy. This Study intended to translate the Hypertension Belief Assessment Tool (HBAT) into Chinese and to explore the validity and reliability of the Chinese version in hypertensive patients. Methods: This is a cross-sectional study. We translated the HBAT into Chinese, and tested the validity and reliability of the Chinese version among 325 hypertensive patients. Results: The Cronbach’s α coefficient of the scale was 0.803. Exploratory factor analysis (EFA) supported a six-factor structure block for the HBAT, and the model was qualified in our confirmatory factor analysis. With modified confirmatory factor analysis, the fit indices were chi-square/degree of freedom (CMIN/DF) =2.491, comparative fit index (CFI)=0.952, incremental fit index (IFI)=0.952, root-mean-square error of approximation (RMSEA)=0.068, Tucker Lewis index (TLI)=0.941. The high score group (27%) and low score group (27%) all showed significant differences (PConclusion: The HBAT has good validity and reliability and it can evaluate the beliefs of Chinese hypertensive patients.

Objective: The quality of life of diabetes patients is associated with their disease or surrounding social environment. How to deal with psychological changes and adjust psychological stress response is worth further discussion. The researchers constructed moderated mediation models to test the impact of psychological resilience on the quality of life of people with diabetes, as well as the mediating role of stigma and the moderating role of empowerment. Method: From June to September 2022, data were collected by multi-stage stratified sampling. Firstly, the First Affiliated Hospital of Wannan Medical College was randomly selected from all tertiary hospitals in Wuhu, Anhui Province. Secondly, two departments were randomly selected from this hospital: endocrinology and geriatrics. Thirdly, survey points were set up in each department, and T2DM patients were randomly selected for questionnaire surveys. In addition, we used the Connor-Davidson Elasticity Scale (CD-RISC) to measure the psychological resilience of patients, and used the Stigma Scale for Chronic Illness (SSCI) to measure stigma. Empowerment was measured by the Diabetes Empowerment Scale (DES). Quality of Life was assessed by the Diabetes Quality of Life Scale (DQoL). We used SPSS (version 21) and PROCESS (version 4.1) for data analysis. Results: (1) Psychological resilience was negatively correlated with stigma and quality of life, and positively correlated with empowerment. Stigma was positively associated with empowerment and quality of life. Empowerment was negatively correlated with quality of life. (2) The mediation analysis showed that psychological resilience had a direct predictive effect on the quality of life, and stigma partially mediated the relationship; Empowerment moderates the first half of "PR→ stigma → quality of life"; Empowerment moderates the latter part of "PR→ stigma → quality of life." Conclusion: Under the mediating effect of stigma, psychological resilience can improve quality of life. Empowerment has a moderating effect on the relationship between psychological resilience and stigma, and it also has a moderating effect on the relationship between stigma and quality of life. These results facilitate the understanding of the relationship mechanisms between psychological resilience and quality of life.

It is challenging to treat multidrug-resistant tumors because such tumors are resistant to a broad spectrum of structurally and functionally unrelated drugs. Herein, treatment of multidrug-resistant tumors using red-light-responsive metallopolymer nanocarriers that are conjugated with the anticancer drug chlorambucil (CHL) and encapsulated with the anticancer drug doxorubicin (DOX) is reported. An amphiphilic metallopolymer PolyRuCHL that contains a poly(ethylene glycol) (PEG) block and a red-light-responsive ruthenium (Ru)-containing block is synthesized. Chlorambucil is covalently conjugated to the Ru moieties of PolyRuCHL. Encapsulation of DOX into PolyRuCHL in an aqueous solution results in DOX@PolyRuCHL micelles. The DOX@PolyRuCHL micelles are efficiently taken up by the multidrug-resistant breast cancer cell line MCF-7R and which carries DOX into the cells. Free DOX, without the nanocarriers, is not taken up by MCF-7R or pumped out of MCF-7R via P-glycoproteins. Red light irradiation of DOX@PolyRuCHL micelles triggers the release of chlorambucil-conjugated Ru moieties and DOX. Both act synergistically to inhibit the growth of multidrug-resistant cancer cells. Furthermore, the inhibition of the growth of multidrug-resistant tumors in a mouse model using DOX@PolyRuCHL micelles is demonstrated. The design of red-light-responsive metallopolymer nanocarriers with both conjugated and encapsulated drugs opens up an avenue for photoactivated chemotherapy against multidrug-resistant tumors.

The detection and localization of hydrogen releases are of vital importance in large confined spaces to enable safe commercial penetration of hydrogen energy into society. In the present study, a hydrogen leak localization system was developed based on measured concentration data and a machine learning system. A scale parking garage model was used to experimentally model fuel cell vehicle leaks in a confined space with helium used as a surrogate of hydrogen for safety reasons. Twelve gas sensors were placed along the ceiling to measure the helium concentrations. The leak position was changed in each test to gather a range of concentration data. Then, the measured helium concentrations were used as input data to train the machine learning models. Two machine learning algorithms were used to locate the leak position, an artificial neural network (ANN) and the K-DTW algorithm. The helium concentrations recorded by the twelve sensors at a specific time point were used as the input data for the ANN model, while time-series concentration data was used as the input for the K-DTW algorithm. The results show that the ANN model can predict leak locations that were not included in the training datasets and that the K-DTW algorithm can classify the unknown leak location to the given location label. The ANN prediction accuracy was 78.4%. The K-DTW algorithm identified the leak location with 87.5% accuracy. The localization technology developed in the present work can provide safe monitoring of large parking garages and the model accuracy can be improved by feeding more training data to the machine learning models.

Hydrogen is likely to be stored and transported as a liquid with high densities to have sufficient hydrogen on-site and for efficient distribution. Thus, cryogenic hydrogen jets and dispersion characteristics need to be studied to quantify the risks of accidental releases. The present study modeled cryogenic hydrogen jets with stagnation temperatures around 50 K released from round nozzles at stagnation pressures of 2–10 bar. The instantaneous flow fields were modeled using the Large Eddy Simulation (LES) turbulence model to accurately and efficiently capture the flow characteristics. The numerical models were validated with experimental data. The concentration and velocity distributions show that the centerline mass fraction and velocity decay at similar rates to the decays for room temperature jets. The radial distributions of the mass fraction, temperature and velocity are Gaussian and self-similar. Additionally, the numerical model can reproduce the shock structures near the nozzle for these underexpanded cryogenic hydrogen jets. The location of the first normal shock was predicted to be closer to the nozzle than for room temperature jets. The present work can be used to develop and revise safety codes and standards for liquid hydrogen facilities.

Most previous studies of hydrogen fuel cell vehicle (HFCV) releases in garages have focused on residential garages. However, hydrogen releases in large underground parking garages can be completely different with more concerns about public safety. In the present work, unintended hydrogen releases were studied in a scaled-down underground parking garage model to fill the knowledge gap concerning hydrogen dispersion in a large confined space. Helium was used in place of hydrogen for safety reasons. Gas sensors were used to measure the helium concentrations along the ground and the ceiling. The nearfield concentration distributions were studied to show that the leak jet was strongly affected by the buoyancy, so the gas concentration was very low along the floor with a flammable gas mixture only appearing right under the leaking car. The gas plume driven by the buoyancy reached the ceiling and spread in all directions resulting in a flammable layer along the ceiling. The effects of neighboring cars and walls were also investigated to show that the obstacles affected the nearfield gas dispersion but did not significantly affect the farfield concentration distributions. The concentration increased linearly with the release flow rate for the flow rates in this study. The gas dispersion during the release showed self-similar characteristics, which could be used for leak detection. This database will be useful for model validation for modeling HFCV releases in large underground parking garages and also provides guidelines for gas sensor placement in large confined spaces.

In this paper, we present a deep learning approach for cross-domain retrieval of 3D shape and 2D sketch image. Cross-domain retrieval has received significant attention to flexibly find information across different modalities of data. Effective measuring the similarity between different modalities of data is the key of cross-domain retrieval. Different modalities such as shape and sketch have imbalanced and complementary relationships, which contain unequal amount of information when describing the same semantics. Existing methods based on deep learning networks mostly construct one common space for different modalities, and these nets usually loss exclusive modality-specific characteristics. To address this problem, we propose a novel Cycle CNNs to estimate the cross-domain mapping between the space of 3D shape descriptors and the one of 2D sketch features. First, we employ the existing networks to construct independent feature spaces for each modality. For each feature space, modality-specific properties within one modality are fully exploited. Next, we use the designed Cycle CNNs to learn the mapping function between different feature spaces. This network can capture the mapping relationship between 3D shape feature space and 2D sketch feature domain. Finally, we use the explored mapping between the feature spaces of different modalities to perform cross-domain retrieval. We demonstrate a variety of promising results, where our method achieves better retrieval accuracy than existing state-of-the-art approaches.

We introduce EdgeNet, a metric learning architecture for extracting semantic local shape features, directly applicable to a wide range of shape analysis applications such as point matching, object classification, shape segmentation, and partial registration. EdgeNet is based on a novel technique to keep edge-wise correspondences in the deep feature space and encodes the local structure into the learned features. It is trained under the supervision of edge-wise correspondences by using the 3D coordinates. The training loss combines a bi-triplet loss to enforce feature variations between the semantic matching points in the feature space, a transformation loss to encourage consistency between corresponding edges after alignment transformation, and a smoothness loss guarantees the flatness between the nearest points in the feature space. The learned features are proved to encode local content, structure, and asymmetry for 3D shapes. Our network can be adapted to either 3D meshes or point clouds. We compare the performance of the EdgeNet with existing state-of-the-art approaches and demonstrate the efficiency and efficacy of EdgeNet in three shape analysis tasks, including shape segmentation, partial matching, and shape retrieval.

The development and revision of safety codes and standards for hydrogen infrastructure requires a solid scientific basis, including studies of unignited releases from high pressure systems for various scenarios. Most hydrogen releases are modeled as axisymmetric jets, but real leaks are more likely to be non-axisymmetric jets issuing from high aspect ratio cracks or slots. In the present study, underexpanded hydrogen jets from square and rectangular nozzles with aspect ratios of 1–16 were numerically modeled for stagnation pressures up to 20 MPa. The near and far flow fields were modeled separately using two sequential computational domains to accurately and efficiently capture the flow characteristics. The numerical models were first validated with experimental data from a previous experimental study and literature data. The mass fraction and velocity distributions show that the centerline decay rates increase as the nozzle aspect ratio increases, but this increase is dependent on the pressure. This means that the canonical decay law of round turbulent jets and plumes no longer applies to the slot nozzle jets for high pressures. The radial profiles collapse onto a Gaussian curve in the major axis plane, but neither collapse, nor are they Gaussian in the minor axis plane with peaks away from the jet centerline. Different shock patterns were identified along the major and minor axes and the axis switching phenomenon seen in the literature was also reproduced. The axis switching resulted in significantly wider flattened concentration distributions compared with the axisymmetric jet which may require consideration during safety analyses for non-circular nozzles. A scaling factor taking both the nozzle shape and pressure effects into account was then developed to better scale the centerline decay rates for jets from both the square and rectangular nozzles. The present study demonstrates that the nozzle shape effects on the jet spreading should not be overlooked and proper scaling factors are required to collapse the data and calculate decay rates.

Background To analyze and summarize the etiological distribution of pertussis-like syndrome in children and to provide a basis for clinical treatment. Methods A retrospective analysis was conducted of 756 children with pertussis-like syndrome hospitalized at the Department of Pediatric Respiratory Medicine of Chengdu Women's and Children's Central Hospital, 2015 to 2019. The etiological features were classified and reviewed. Results Among 756 children with pertussis-like syndrome, 439 cases were positive for etiological agents Among the 439 cases, 268 cases were positive for bacterial agents (positive rate 35.45%), including 174 cases (65.25%) positive for Haemophilus influenza (H. influenza). There were 75 cases (9.92%) positive for viral antibodies, including 29 cases (accounting for 38.67% of all cases positive for viral infection) positive for the respiratory syncytial virus (RSV). There were 243 cases (32.14%) positive for Mycoplasma pneumoniae (M. pneumoniae) antibodies. As to the general distribution of infections, cases with infections caused by a single type of bacteria accounted for 20.63%; cases with M. pneumoniae infection accounted for 18.78%; and cases with bacterial infection combined with M. pneumoniae infection accounted for 8.73%. Conclusions H. influenza, RSV, and M. pneumoniae were important pathogens causing pertussis-like syndrome in children. Bacterial infection, M. pneumoniae infection, and mixed infection caused by the two pathogens were the primary causes of pertussis-like syndrome in children.

Background: Erenumab is a novel monoclonal calcitonin gene-related peptide receptor antibody that is used for the preventive treatment of migraine. Objectives: This study aimed to evaluate the overall safety, efficacy, and dose-response relationship of erenumab in patients with episodic migraine and patients with prior migraine treatment failures. Objectives : To evaluate overall safety and efficacy and dose-response relationship of erenumab in patients with episodic migraine and patients with prior migraine treatment failures. Methods: We searched randomized clinical trials on PUBMED, EMBASE database, and Cochrane Library database. A pair-wise meta-analysis and Bayesian network analysis were performed. Results: For efficacy outcomes, the network meta-analysis suggests that in comparison to erenumab 70 mg, participants who received erenumab 140 mg reported a significant decrease in monthly acute Migraine-Specific Medication Days (MSMD) and 50% increase in response rate, and erenumab was most likely to be ranked first for Monthly Migraine Days (MMD), MSMD, and 50% response rate. For safety outcomes, the network meta-analysis has found no significant difference between the 70 mg group and the 140 mg group measured by adverse events and serious adverse events. In the 140 mg erenumab group, a significant decreased in MMD and MSMD and 50% and 75% increased in response rate were reported in patients with ≥ 2 treatment failures compared to placebo. For safety outcomes, no significant difference was found between the 140 mg erenumab group and the placebo group. Conclusion: Erenumab was effective in patients with episodic migraine. A total of 140 mg erenumab was associated with better efficacy outcomes without any increased risk for developing adverse events compared to 70 mg erenumab. Furthermore, 140 mg erenumab was effective in patients with prior migraine treatment failures.

Nucleosides/nucleotides are building blocks of nucleic acids, parts of cosubstrates and coenzymes, cell signaling molecules, and energy carriers, which are involved in many cell activities. Here, we describe a rapid and reliable method for the absolute qualification of nucleoside/nucleotide contents in plants. Briefly, 100 mg of homogenized plant material was extracted with 1 mL of extraction buffer (methanol, acetonitrile, and water at a ratio of 2:2:1). Later, the sample was concentrated five times in a freeze dryer and then injected into an HPLC-MS/MS. Nucleotides were separated on a porous graphitic carbon (PGC) column and nucleosides were separated on a C18 column. The mass transitions of each nucleoside and nucleotide were monitored by mass spectrometry. The contents of the nucleosides and nucleotides were quantified against their external standards (ESTDs). Using this method, therefore, researchers can easily quantify nucleosides/nucleotides in different plants.

In an HVDC system, the power line carrier noise filter, or the PLC filter for short, is mainly used to eliminate the interference of high-frequency harmonics generated by the converter valve to AC line carrier communication. There had been several burning accidents of PLC filter tuning elements in HVDC projects, which profoundly reduced the availability of the HVDC system. To solve this problem, in this paper, the operating parameters of PLC filter components were simulated and analyzed with the variation of harmonic power supply frequency firstly, with the fault weak points of tuned components being found. Then, according to the structures of the PLC communication filters and the tuning elements, three optimization schemes of the PLC filter were proposed. The feasibility of these schemes are compared by simulation and calculation from two aspects: the effect of reducing high-frequency harmonic interference and the influence on the running capacity of the equipment. Finally the risk of these schemes are pointed out.

Background Erenumab is a novel monoclonal calcitonin gene–related peptide receptor antibody that is used for the preventive treatment of migraine.Objectives To evaluate overall safety and efficacy and dose-response relationship of erenumab in patients with episodic migraine and patients with prior migraine treatment failures.Methods We searched randomized clinical trials on PUBMED, EMBASE database, and Cochrane Library database. A pair-wise meta-analysis and Bayesian network analysis were performed.Results For efficacy outcomes, the network meta-analysis suggests that compared with erenumab 70 mg, participants received erenumab 140 mg reported significantly decreased MSMD and increased 50% response rate, and erenumab was most likely to be ranked first for MMD, MSMD and 50% response rate. For safety outcomes, the network meta-analysis has found no significant difference between the 70 mg group and the 140 mg group measured by AE and SAE. For patients with ≥2 treatment failures, 140mg erenumab group, patients with ≥2 treatment failures reported significantly reduced MMD and MSMD, increased 50%, and 75% response rate, compared with placebo. For safety outcomes, no significant difference was found between 140 mg erenumab group and the placebo group.Conclusion Erenumab was effective in patients with episodic migraine. 140 mg erenumab was associated with better efficacy outcomes without increased risk for developing adverse events compared with 70 mg erenumab, and 140 mg erenumab was effective in patients with prior migraine treatment failures.Registration number: CRD42020198985

Coronaviruses are identify in different species of animals, including camels, bats and avian. Avian infectious bronchitis virus (IBV) always infect and invade from the respiratory tract, where submucosal dendritic cells (DCs) are the first guard to defend it. However, different IBV subtypes, such as QX and M41, could suppress the function of dendritic cells and escape the degradation and presentation, which might help coronaviruses to transfer and migrant. Hence, it is necessary to illustrate the uncovered mechanisms how IBV inhibited the antigen-presentation of avian DCs. Initially, we compared two types IBV's function in activating avian bone marrow dendritic cells (BMDCs) and found that both IBV (QX and M41) did not significantly increase the expression of MHCII. Subsequent global analyses identified 21 significantly different expressed (DE) microRNAs and 2888 DE long non-coding RNAs (lncRNAs) in IBV M41 stimulated group, while IBV (QX) stimulation only identified 4 DE microRNAs and 1782 DE lncRNAs. Moreover, GO and KEGG analysis of microRNAs target and lncRNAs lead to endocytosis and cytokine-cytokine receptor interaction, which might contribute to the differences in pathogenicity of QX and M41. Meantime, a significant decrease of the m 6 A modification level in mRNA, but an increased in the ut RNA were observed in avian BMDCs upon the prevalent IBV (QX) infection. Interestingly, an opposite consequence was seen in avian BMDCs during the IBV (M41) infection. Further study found that both non-structural protein 7 (NSP7) and NSP16 inhibited the maturation and cytokines secretion of BMDCs, as well as their antigen-presentation ability. Lastly, we found that gga-miR21, induced and increased by both NSP7 and NSP16, inhibited the antigen presentation of avian BMDCs. Taken together, our results illustrated how IBV inhibited the antigen-presentation of avian DCs and provide a clue for the systemic transmission of the COVID-19. Funding Statement: This work was supported by the National Key Research and Development Program of China (2017YFD500706), the Jiangsu Excellent Youth Natural Science Foundation (BK20190077), the National Natural Science Foundation of China (No. 31702197) to J.L. Moreover, this work was also supported by National Natural Science Foundation of China (31930109 and 31772777), the Fundamental Research Funds for the Central Universities (JCQY201906) and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) to Q.Y and Q.HY. Furthermore, this work was financially supported by the Fundamental Research Funds for the Central Universities (KJQN202060), the National Natural Science Foundation of China (31900907), the Natural Science Foundation of Jiangsu Province (BK20190528) to M.C Declaration of Interests: The authors of this editorial have no conflicts of interest to declare. The authors have no other relevant affiliations or financial involvement in any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Ethics Approval Statement: This study was approved by the Ethics Committee of Animal Experiments center of Nanjing Agricultural University. All animal studies were approve by the Institutional Animal Care and Use Committee of Nanjing Agricultural University (SYXK-2017-0007), and followed the National Institutes of Health guidelines for the performance of animal experiments.

Ubrogepant is a small molecular calcitonin gene–related peptide receptor antagonist that is used for the acute treatment of migraine. The aim was to conduct a meta-analysis to systematically evaluate the efficacy and safety of ubrogepant for the treatment of episodic migraine compared with placebo in the adult population. We systematically searched PubMed, EMBASE, and the Cochrane Library Central Register of Controlled Trials for relevant randomized clinical trials, from the earliest available date to November 10, 2019, to evaluate the efficacy and safety of short-term ubrogepant use. Inclusion criteria were (1) randomized clinical trial; (2) enrolled adult participants diagnosed with episodic migraine; (3) compared ubrogepant with placebo at doses that were evaluated in phase III clinical trials; (4) enrolled more than 100 patients in each group; and (5) provided any information on primary or secondary outcomes. Trials were excluded if their participants were diagnosed with chronic migraine. A total of three multicenter, randomized clinical trials with 3326 patients were included. Ubrogepant use was associated with a significantly higher percentage of patients with pain freedom (ubrogepant 20.8%; placebo 12.6%; relative risk [RR] 1.65, 95% confidence interval [CI] 1.38–1.98) and absence of the most bothersome migraine-associated symptoms (ubrogepant 37.3%; placebo 27.6%; RR 1.35, 95% CI 1.20–1.53) at 2 h post-dose compared with placebo. Ubrogepant increased the rate of absence of migraine-associated symptoms at 2 h post-dose compared with placebo (photophobia: RR 1.30 [95% CI 1.18–1.44], I2 = 49%; phonophobia: RR 1.20 [95% CI 1.11–1.29]; nausea: RR 1.07 [95% CI 1.02–1.13]), and patients were more likely to function normally at 2 h post-dose compared with placebo (RR 1.30 [95% CI 1.16–1.45]). No significant difference was found for treatment-related adverse events within 48 h or 30 days for ubrogepant compared with placebo (48 h: RR 1.07 [95% CI 0.85–1.35]; 30 days: RR 1.03 [95% CI 0.79–1.34]). Subgroup analysis demonstrated that compared to placebo, ubrogepant led to greater rates of freedom from pain at 2 h with 25-mg, 50-mg, and 100-mg doses and absence of the most bothersome symptoms with 50-mg and 100-mg doses. The use of ubrogepant as an acute treatment of episodic migraine in adults led to a greater percentage of freedom from pain and absence of the most bothersome symptoms at 2 h post-dose. Short-term use of ubrogepant was not related to an increased risk for adverse events. Further studies are needed to evaluate efficacy and safety for long-term use and in specific subgroups of patients.

Background Fremanezumab (TEV-48125) is a fully humanized immunoglobulin G isotype 2a selective monoclonal antibody that potently binds to calcitonin gene-related peptide (CGRP). It is one of novel therapeutic drugs for the prevention of migraine, which is one of the most common neurological diseases worldwide. Several clinical trails have been conducted to investigate the safety and efficacy of fremanezumab, but there is no systematic review of existing literature has been performed. Hence, we performed a meta-analysis to investigate the efficacy and safety of fremanezumab for prevention of migraine. Method Pubmed (MEDLINE), Embase, and Cochrane Library were searched from January 2001 to August 2019 for randomized controlled trials (RCTs). Five RCTs with 3379 patients were finally included in our study. Result We pooled 3379 patients from 5 RCTs, the primary endpoints were mean monthly migraine and headache days, baseline to week 12. We found that fremanezumab led to a significant reduction in migraine days (P < 0.0001) and headache days (P < 0.0001) during 12 weeks compared with placebo. In addition, after using fremanezumab, the risk of at least one adverse event (P=0.001) or related to the trail regimen (P=0.0005) significantly increase compared with placebo. Conclusions Fremanezumab has good efficacy for the prevention of migraine. The administration of fremanezumab can cause some mild adverse events but not serious adverse events.

N(6)-methylated adenine (m(6)A) is the most frequent posttranscriptional modification in eukaryotic mRNA. Turnover of RNA generates N(6)-methylated AMP (N(6)-mAMP), which has an unclear metabolic fate. We show that Arabidopsis thaliana and human cells require an N(6)-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N(6)-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. A phylogenetic, structural, and biochemical analysis revealed that many fungi partially or fully lack MAPDA, which coincides with a minor role of N(6)A-RNA methylation in these organisms. MAPDA likely protects RNA from m(6)A misincorporation. This is required because eukaryotic RNA polymerase can use N(6)-mATP as a substrate. Upon abrogation of MAPDA, root growth is slightly reduced, and the N(6)-methyladenosine, N(6)-mAMP, and N(6)-mATP concentrations are increased in Arabidopsis. Although this will potentially lead to m(6)A misincorporation into RNA, we show that the frequency is too low to be reliably detected in vivo. Since N(6)-mAMP was severalfold more abundant than N(6)-mATP in MAPDA mutants, we speculate that additional molecular filters suppress the generation of N(6)-mATP. Enzyme kinetic data indicate that adenylate kinases represent such filters being highly selective for AMP versus N(6)-mAMP phosphorylation. We conclude that a multilayer molecular protection system is in place preventing N(6)-mAMP accumulation and salvage.

Previously studies of hydrogen releases have focused on hydrogen jets through round nozzles, but leaks are more likely to result in jets through slots. In this study, the concentration decays along the jet centerline were measured for underexpanded jets from rectangular slot nozzles with aspect ratios (AR) of 1–12.6 for storage pressures up to 3.7 MPa. The mass fractions along the jet centerlines decay inversely with distance from the nozzle as with axisymmetric jets but with a faster decay rate. All the data collapses onto a single curve when normalized by the proper factor of the downstream location, except for the jets from square nozzles (AR1). The decay rates for jets from rectangular nozzles with AR greater than unity are significantly larger than for the jets from square nozzles. The jets from square nozzles behave somewhat like the circular jets from circular nozzles due to the symmetric geometry, so the decay rate is closer to that of circular jets relative to the jets from the other rectangular nozzles. This database will be useful for model validations for the modeling of jets from rectangular nozzles.

Informative and discriminative feature descriptors play a crucial role in a large variety of shape analysis and processing applications, including shape matching, retrieval, segmentation, recognition, and synthesis. In this paper, in order to obtain more discriminative shape descriptors in an automated fashion, we develop a novel approach to jointly learning shape descriptors and their correspondence in deep triplet convolutional neural networks (CNNs). We first extract geometrically informative multi-scale features based on classical diffusion theories on manifold and kernel function on shapes. During the training process, the deep triplet CNNs is trained in an unsupervised manner by using a larger pool of extracted multi-scale features serving as the networks' inputs. One key component of our triplet CNNs is a delicate and unique design of the loss function favoring good matches while penalizing mis-matches simultaneously. Our newly-learned shape descriptors have better discriminative power than any existing kernel-based descriptors and could give rise to more accurate shape matching subject to various shape deformation constraints (e.g., isometric deformations and non-isometric deformations). To our best knowledge, this is the first attempt to learn more discriminative shape descriptors and more accurate shape correspondence jointly using the triplet CNNs. Extensive experiments have confirmed that our newly-learned shape descriptors have many attractive properties, including being concise, discriminative, and robust, and we demonstrate the superior performance of our approach over other state-of-the-art methods.

Photoactivatable ruthenium (Ru) complexes are promising compounds for anticancer phototherapy. They must be stable under physiological conditions before they are transported to cancer cells. In this paper, we systematically studied the stabilities of two Ru-containing block copolymers (Ru complexes as side group or in main chain, respectively) and their corresponding Ru complexes in different media, including saline, bovine serum albumin (BSA) solution, Dulbecco's Modified Eagle's Medium (DMEM, pH 6.5) and DMEM (pH 5.5) with 1.0 mM glutathione (GSH). Their stabilities were studied by monitoring the metal-to-ligand charge transfer (MLCT) bands of the Ru moieties via UV–Vis absorption spectroscopy. The MLCT bands of Ru complexes changed to varying degrees within a day in the above-mentioned media, indicating that they were instable. In contrast, the MLCT bands of Ru-containing polymer assemblies did not change significantly under the same conditions. These results showed that the self-assembled nanostructures protected the Ru moieties and improved their stability. In addition, these nanostructured polymer assemblies could be activated by red light. Therefore, the studied Ru-containing polymer assemblies are more suitable for in vivo applications than their low-molecular weight analogues.

Pseudouridine (Ψ) is a frequent nucleoside modification that occurs in both noncoding RNAs and mRNAs. In pseudouridine, C5 of uracil is attached to the Rib via an unusual C-glycosidic bond. This RNA modification is introduced on the RNA by site-specific transglycosylation of uridine (U), a process mediated by pseudouridine synthases. RNA is subject to constant turnover, releasing free pseudouridine, but the metabolic fate of pseudouridine in eukaryotes is unclear. Here, we show that in Arabidopsis (Arabidopsis thaliana), pseudouridine is catabolized in the peroxisome by (1) a pseudouridine kinase (PUKI) from the PfkB family that generates 5′-pseudouridine monophosphate (5′-ΨMP) and (2) a ΨMP glycosylase (PUMY) that hydrolyzes ΨMP to uracil and ribose-5-phosphate. Compromising pseudouridine catabolism leads to strong pseudouridine accumulation and increased ΨMP content. ΨMP is toxic, causing delayed germination and growth inhibition, but compromising pseudouridine catabolism does not affect the Ψ/U ratios in RNA. The bipartite peroxisomal PUKI and PUMY are conserved in plants and algae, whereas some fungi and most animals (except mammals) possess a PUMY-PUKI fusion protein, likely in mitochondria. We propose that vacuolar turnover of ribosomal RNA produces most of the pseudouridine pool via 3′-ΨMP, which is imported through the cytosol into the peroxisomes for degradation by PUKI and PUMY, a process involving a toxic 5′-ΨMP intermediate.

Eukaryotic messenger RNA (mRNA) contains non-canonical nucleosides, which are modified mostly by methylation. Although some modifications are known for decades, advances in high-throughput sequencing and mass spectrometric techniques now have allowed to elucidate transcriptome wide methylation patterns. The discovery of methyltransferases that write and demethylases that erase methylations in a sequence-specific manner, as well as reader proteins that recognize these modifications leading to a specific biological response, has triggered wide attention converting the research field of mRNA methylation into a current hotspot in molecular biology.

An ideal tumor drug delivery platform should offer little release of the drug in a physiological environment and fast release of the drug once endocytosis into the tumor tissues occurs. Therefore, we have developed a new kind of core-crosslinked copolymers (mPEG-St-SeSex) based on mPEGylated starch and diselenide bonds for rapid drug release. The corresponding core-crosslinked analogs mPEG-St-SSx and mPEG-St-CCx copolymers using 3,3′-dithiodipropionic acid and octanedioic acid as crosslinkers, respectively, were synthesized and used as controls. The results displayed that all amphiphilic core-crosslinked copolymers could form micelles with spherical structures in aqueous solution, showing advanced stability compared to non-crosslinked micelles (mPEG-St) in physiologically related and ultra micelle destabilization conditions. The disassembly of micelles triggered by DTT, combined with in vitro drug release assay and intracellular drug release studies using confocal laser scanning microscopy (CLSM), indicated that the DOX-loaded mPEG-St-SeSex micelles showed higher activity and could be more quickly disrupted than the DOX-loaded mPEG-St-SSx and mPEG-St-CCx micelles in reducing environment and subsequently rapidly released drug. These results, in addition to cell cytotoxicity studies, demonstrated that the mPEG-St-SeSex micelles have the potential to develop controlled drug-delivery systems for cancer therapy.

At present, diselenide bonds have been considered as a novel dual redox-sensitive linkage. Nevertheless, few studies have focused on diselenide-linked polysaccharide as new biological materials. In this work, the diselenide-linked mPEGylated starch amphiphilic copolymers (mPEG-SeSe-St), which combined the biocompatibility of polysaccharide and the stimuli-responsiveness of diselenide linkages, were developed as a novel type of PEG-detachable drug vector for rapid drug release. The amphiphilic design of the mPEG-SeSe-St enabled the formation of self-assembled micelles with spherical core–shell structures in aqueous solution. The data of well-ordered appraisals demonstrated that mPEG-SeSe-St could be disrupted in the presence of a low concentration of hydrogen peroxide (H2O2, 0.1% (v/v)) or glutathione (GSH, 1 mM). The process of diselenide bonds' more rapid degradation than disulfide bonds led to a synergistically enhanced release of loaded anticancer drugs (DOX) in cellular environments. These results, combined with cell viability measurements and confocal laser scanning microscopy (CLSM), indicated that mPEG-SeSe-St micelles might have appeared as a refined platform for cancer therapy.

Traditional photodynamic phototherapy is not efficient for anticancer treatment because solid tumors have a hypoxic microenvironment. The development of photoactivated chemotherapy based on photoresponsive polymers that can be activated by light in the “therapeutic window” would enable new approaches for basic research and allow for anticancer phototherapy in hypoxic conditions. This work synthesizes a novel Ru‐containing block copolymer for photoactivated chemotherapy in hypoxic tumor environment. The polymer has a hydrophilic poly(ethylene glycol) block and a hydrophobic Ru‐containing block, which contains red‐light‐cleavable (650–680 nm) drug–Ru complex conjugates. The block copolymer self‐assembles into micelles, which can be efficiently taken up by cancer cells. Red light induces release of the drug–Ru complex conjugates from the micelles and this process is oxygen independent. The released conjugates inhibit tumor cell growth even in hypoxic tumor environment. Furthermore, the Ru‐containing polymer for photoactivated chemotherapy in a tumor‐bearing mouse model is applied. Photoactivated chemotherapy of the polymer micelles demonstrates efficient tumor growth inhibition. In addition, the polymer micelles do not cause any toxic side effects to mice during the treatment, demonstrating good biocompatibility of the system to the blood and healthy tissues. The novel red‐light‐responsive Ru‐containing polymer provides a new platform for phototherapy against hypoxic tumors.

A novel amphiphilic polymer (mPEGylated starch-deoxycholic acid, mPEG-St-DCA) was successfully prepared by grafting hydrophobic deoxycholic acid (DCA) into mPEGylated starch. According to the characterization of 1H NMR and FTIR, mPEG-St-DCA polymers could self-assemble into micelles with spherical core–shell structures. With the degree of substitution (DS) of DCA increasing, the average size of micelles (pH 7.4) decreased to below 200 nm. Correspondingly, the critical micelle concentration (CMC) decreased from 0.048 to 0.022 mg mL−1. And zeta potential values were near −2 mV. But under the condition of pH 6.5, the size and CMC showed an increasing trend. Doxorubicin (DOX), a model anticancer drug, was efficiently loaded into mPEG-St-DCA micelles, and in vitro release exhibited that DOX-loaded micelles had a good in vitro pH-induced drug release. MTT assays confirmed that mPEG-St-DCA micelles were biocompatible with HeLa cells, and DOX-loaded micelles had a relatively better cytotoxicity against HeLa cells with a remarkably high IC50 of 5.74 μg mL−1. Confocal laser scanning microscopy (CLSM) analyses demonstrated that mPEG-St-DCA micelles could be internalized efficiently by HeLa cells to realize intracellular DOX release, which further enhanced the inhibition of cell proliferation. On the basis of the above results, it was indicated that novel amphiphilic mPEG-St-DCA micelles with pH-response could be used as drug delivery carriers for cancer therapy.

Our studies indicate a potential important elicitor candidate which can aid in the fight against a worldwide disease, rice blast. In this study, we report the purification, identification, characterization, and gene cloning of a novel hypersensitive response-inducing protein elicitor (MoHrip2) secreted from an important pathogenic fungus, Magnaporthe oryzae. The protein fraction was isolated from the culture filtrate of M. oryzae and identified by de novo sequencing. The elicitor-encoding gene mohrip2 was cloned following sequence comparison and PCR amplification. This 459-bp gene encodes a 152-residue polypeptide that contains an 18-residue signal peptide and exhibits a pI of 4.72 and an apparent molecular mass of 16 kDa. The hypothetical protein, MoHrip2, was expressed in Escherichia coli, and both the recombinant and the endogenous protein caused necrotic lesions in tobacco leaves. In addition to phenolic compound deposition and alkalization of the extracellular medium, MoHrip2 also induced hydrogen peroxide production and nitric oxide accumulation in tobacco cells. Moreover, rice seedlings treated with MoHrip2 exhibited pronounced resistance to M. oryzae compared with control seedlings.

Aims: To determine the global transcriptional response of Bacillus subtilis to an antimicrobial agent, xenocoumacin 1 (Xcn1). Methods and Results: Subinhibitory concentration of Xcn1 applied to B. subtilis was measured according to Hutter’s method for determining optimal concentrations. cDNA microarray technology was used to study the global transcriptional response of B. subtilis to Xcn1. Real-time RT–PCR was employed to verify alterations in the transcript levels of six genes. The subinhibitory concentration was determined to be 1 μg ml−1. The microarray data demonstrated that Xcn1 treatment of B. subtilis led to more than a 2·0-fold up-regulation of 480 genes and more than a 2·0-fold down-regulation of 479 genes (q ≤ 0·05). Conclusions: The transcriptional responses of B. subtilis to Xcn1 were determined, and several processes were affected by Xcn1. Additionally, cluster analysis of gene expression profiles after treatment with Xcn1 or 37 previously studied antibiotics indicated that Xcn1 has similar mechanisms of action to protein synthesis inhibitors. Significance and Impact of the Study: These microarray data showed alterations of gene expression in B. subtilis after exposure to Xcn1. From the results, we identified various processes affected by Xcn1. This study provides a whole-genome perspective to elucidate the action of Xcn1 as a potential antimicrobial agent.