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Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce lipids. In 2020, we reported a chimeric camelid-human heavy chain antibody VHH-B11-Fc targeting PCSK9. Recently, it was verified that VHH-B11 binds one linear epitope in the PCSK9 hinge region. To enhance its druggability, we have developed a novel biparatopic B11-H2-Fc Ab herein. Thereinto, surface plasmon resonance (SPR) confirmed the epitope differences in binding-PCSK9 among VHH-B11, VHH-H2 and the approved Repatha. Additionally, SPR revealed the B11-H2-Fc exhibits an avidity of approximately 0.036 nM for PCSK9, representing a considerable increase compared to VHH-B11-Fc (~ 0.69 nM). Moreover, we found the Repatha and B11-H2-Fc exhibited > 95% PCSK9 inhibition efficiency compared to approximately 48% for the VHH-Fc at 7.4 nM (P 0.05). These findings provide the first evidence of the efficacy of a novel Ab targeting PCSK9 in the field of lipid-lowering drugs.

Abstract Named entity recognition and relation extraction are two important fundamental tasks in natural language processing. The joint entity-relationship extraction model based on parameter sharing can effectively reduce the impact of cascading errors on model performance by performing joint learning of entities and relationships in a single model, but it still cannot essentially get rid of the influence of pipeline models and suffers from entity information redundancy and inability to recognize overlapping entities. To this end, we propose a joint extraction model based on the decomposition strategy of pointer mechanism is proposed. The joint extraction task is divided into two parts. First, identify the head entity, utilizing the positive gain effect of the head entity on tail entity identification.Then, utilize a hierarchical model to improve the accuracy of the tail entity and relationship identification. Meanwhile, we introduce a pointer model to obtain the joint features of entity boundaries and relationship types to achieve boundary-aware classification. The experimental results show that the model achieves better results on both NYT and WebNLG datasets.

Hydroxychloroquine (HCQ) has gained significant attention as a therapeutic option for systemic lupus erythematosus (SLE) because of its multifaceted mechanism of action. It is a lipophilic, lysosomotropic drug, that easily traverses cell membranes and accumulates in lysosomes. Once accumulated, HCQ alkalizes lysosomes within the cytoplasm, thereby disrupting their function and interfering with processes like antigen presentation. Additionally, HCQ has shown potential in modulating T-cell responses, inhibiting cytokine production, and influencing Toll-like receptor signaling. Its immunomodulatory effects have generated interest in its application for autoimmune disorders. Despite its established efficacy, uncertainties persist regarding the optimal therapeutic concentrations and their correlation with adverse effects such as retinal toxicity. Therefore, standardized dosing and monitoring guidelines are crucial. In this study, we provide a comprehensive review of the mechanisms, efficacy, dosing variations, and retinal toxicity profiles of HCQ, which are essential to optimize SLE treatment protocols and ensure patient safety.

Carotid free⁃floating thrombus (CFFT) is significantly associated with ischemic stroke. Thrombosis occludes the artery or falls off, leading to massive cerebral infarction or multiple embolism. In severe cases, cerebral hernia or even death may occur. The diagnosis of CFFT is gradually based on CT angiography (CTA). Early identification can help in etiological treatment. This article reviews the progress of the diagnosis and treatment of CFFT, in order to improve chinical diagnosis and treatment.

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset that seriously affects human health. Plant‐derived peptides have been found to hinder the development of AD pathologies, which is an excellent candidate for preventing AD. However, due to the excessively complicated pathogenesis of AD and the fact that most studies on the activity of plant‐derived peptides are single and not deep enough, which restricted the development and application of plant‐derived AD‐prevention peptides (PADPs). This review summarized the currently available means of obtaining PADPs, in vitro and in vivo AD‐prevention activity validation protocols, molecular pathways of PADPs, the structure–activity relationship between plant‐derived peptides and AD‐prevention activity, and some perspectives of current advanced technologies. This paper will help to develop the foundation for the production and exploitation of PADPs.

As the crucial part of a transmission assembly, the monitoring of the status of the crankshaft is essential for the normal working of a reciprocating machinery system. In consideration of the interaction between crankshaft system components, the fault vibration feature is typically non-stationary and nonlinear, and the single-scale feature extraction method cannot adequately assess the fault features, therefore a novel impact feature extraction method based on genetic algorithms to optimize multi-scale permutation entropy is proposed. Compared with other traditional feature extraction methods, the proposed method illustrates good robustness and high adaptability in the signal processing of crankshaft vibrations. Firstly, the improved complete ensemble empirical mode decomposition with adaptive noise (ICEEMDAN) method is developed on the signal to obtain several intrinsic mode function (IMF) components, and the IMF components with a large kurtosis are selected for array reorganization. Then, the parameters of multi-scale permutation entropy (MPE) are optimized based on genetic algorithm (GA), the multi-scale permutation entropy is calculated and the feature vector set is constructed. The feature vector set is input into the support vector machine (SVM) and optimized by a particle swarm optimization (PSO) model for training and final pattern recognition, where the Variational Mode Decomposition(VMD)-GA-MPE with a PSO-SVM recognition model and the ICEEMDAN-MPE with PSO-SVM recognition model without GA optimization are constructed for a comparison with the proposed method. The research result illustrates that the proposed method, which inputs the genetic algorithm optimized multi-scale permutation entropy extracted from the ICEEMDAN decomposition into the PSO-SVM, performs well in impact feature extraction and the pattern recognition of crankshaft vibrations.

Energy stress activates AMPK leading to metabolic plasticity and therapy resistance in cancer. Here, the authors show that AMPK activation decreases Prospero-related homeobox 1 (PROX1) levels impairing branched amino acid metabolism and tumourigenesis in liver and lung cancer models.

Abstract An advanced automatic crash notification (AACN) system can predict the injuries of a vehicle's occupants when the vehicle is involved in a collision accident. The rear‐seat occupants are at significant risk in collision accidents owing to an inferior protection system and the absence of mandatory seat belt laws. However, only a few studies have focused on the injury prediction for rear‐seat occupants, which can be used in AACN system. Therefore, an injury prediction algorithm is proposed for rear‐seat occupants. Initially, a rear‐seat occupant simulation model is established and verified and the relationship between the head, neck, and chest injury levels and velocity variation is examined. Then, a rear‐seat occupant injury prediction algorithm is developed and AACN terminal is constructed to analyse the effects of the algorithm. The comparison of the obtained results with actual accident data validated that the proposed algorithm can effectively evaluate the injury levels of rear‐seat occupants. The study findings can enhance the prediction accuracy of all occupants’ injury levels based on their positions inside the vehicle and improve the efficiency of rescue operations, particularly in the case of rear‐seat occupants.

Abstract Developing Ohmic contact systems or achieving low contact resistance is significant for high‐performance semiconductor devices. This work comprehensively investigates the interfacial properties of CrX2N4 (X = C, Si) based field‐effect transistors (FETs) with different metal (Ag, Au, Cu, Ni, Pd, Pt, Ti, and graphene) electrodes by using electronic structure calculations and quantum transport simulations. It is highlighted that the stronger interlayer coupling allows CrC2N4 to form an n‐type Ohmic contact with Ti electrode in the vertical direction. Furthermore, the absence of tunneling barrier at the CrC2N4–Ti interface greatly improves the electron injection efficiency. On the other hand, the studied metals form Schottky contact with CrC2N4 at the lateral interface due to Fermi level pinning (FLP) effects. Surprisingly, the strong FLP effects restrict the Schottky barrier heights of CrSi2N4‐metal contacts to a narrow range. Where Ag, Au, Ni, Pd, Pt, Ti electrodes and Ag, Ti electrodes form ideal ohmic contact with CrSi2N4 in the vertical and lateral directions, respectively, while the other metals form quasi‐ohmic contact. Ti exhibits the highest contact performance as the electrode in both CrC2N4 and CrSi2N4 based FETs. The findings may provide fundamental understanding for designing high‐performance and energy‐efficient FETs based on CrX2N4.

Background The current standard of care for the treatment of patients with primary mitral regurgitation (MR) is surgical mitral valve repair. Transcatheter edge‐to‐edge repair with the MitraClip device provides a less invasive treatment option for patients with both primary and secondary MR. Worldwide, >150 000 patients have been treated with the MitraClip device. However, in the United States, MitraClip is approved for use only in primary patients with MR who are at high or prohibitive risk for mitral valve surgery. The REPAIR MR (Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery) trial is designed to compare early and late outcomes associated with transcatheter edge‐to‐edge repair with the MitraClip and surgical repair of primary MR in older or moderate surgical risk patients. Methods and Results The REPAIR MR trial is a prospective, randomized, parallel‐controlled, open‐label multicenter, noninferiority trial for the treatment of severe primary MR (verified by an independent echocardiographic core laboratory). Patients with severe MR and indications for surgery because of symptoms (New York Heart Association class II–IV), or without symptoms with left ventricular ejection fraction ≤60%, pulmonary artery systolic pressure >50 mm Hg, or left ventricular end‐systolic diameter ≥40 mm are eligible for the trial provided they meet the moderate surgical risk criteria as follows: (1) ≥75 years of age, or (2) if

Introduction: A common problem in bone tissue engineering is that the burst release of active osteogenic factors is not beneficial for osteogenesis. This study aimed to prepare naringin (Ng) liposomes to reduce the burst release of Ng and improve new bone formation.Methods: We synthesized Ng liposomes using the thin-film hydration method. Drug-encapsulation efficacy experiments were conducted using the ultracentrifugation technique. The morphology and size distributions of freezedried liposomes were determined by transmission electron microscopy and dynamic light scattering. The Ng liposomes and Ng-lipo/sucrose acetate isobutyrate (SAIB) depots were characterized using Fourier transform infrared spectroscopy and in vitro release studies. After implantation of the Ng-lipo/SAIB depots, in vitro osteoblast-liposome interactions and in vivo osteogenesis were tested.Results: The formulation of freeze-dried Ng liposomes via an optimized recipe yielded nanosized (136.9 nm) negatively charged particles with a high encapsulation efficiency (~76.3%). Their chemical structure did not change after adding SAIB to the Ng liposomes. The burst release was reduced dramatically from 74.4% to 23.7%. In vivo, after 8 weeks, the new bone formation rate in the calvarial defects of Sprague-Dawley rats receiving Ng-lipo/SAIB was 57% compared with 25.18% in the control group (p = .0003).Discussion: Our results suggested that Ng-lipo/SAIB hybrid depots could serve as candidate materials for drug delivery in bone regeneration applications.

Abstract Based on comparison between age sets in Africa and the social age structure of the Dai people in China, this paper examines the forms, functions and evolution of the age groups of the De’ang people in Yunnan Province, China. The age groups of De’ang people are unique in that only two distinct age grades (the youth and the elderly) are organized, both of which have different social functions. This pattern provides an important reference for further discussion on the relationships between age sets and age grades, as well as forms and types of age-class systems.

In this study, three typical and most extreme precipitation events in the history of North China are analyzed and compared in terms of accumulated precipitation and synoptical circulation using surface station observations of China and the ERA5 dataset. The three events happened in August 1963 (“63.8” event, hereafter), August 1975 (“75.8” event), and July 2021 (“21.7” event), respectively, mainly in Hebei and Henan Provinces of North China. The results show that the maximum daily and 4-day accumulated precipitation of all three events exceeded 500 mm and 800 mm, with many stations’ daily precipitation ranking Top 1. The “63.8” event persisted for the longest time, affected the largest area, and rained the most in 7 days (over 1000 mm). The “75.8” event was characterized by the most extreme daily precipitation and a concentrated area. All three events characterize a normal northward subtropical high that was located in North China and Northeast China. At 500 hPa, the area from South China to the South China Sea was dominated by a uniform pressure field. In the upper levels, there were troughs and divergence anomalies in all three events. In the low levels, there were anomalous low-level jets and the associated water vapor flux anomalies, which were located at different levels and came from different directions. Stable synoptical circulation and persistent jet and water vapor flux anomalies are the key factors in these extreme events.

In order to improve the rescue efficiency of the advanced automatic crash notification (AACN) system,a driver injury prediction algorithm was proposed,and the overall design of the AACN system terminal was conducted based on this algorithm.First,the amount of speed change,the direction of the accident,the driver′s age,gender,whether to wear the seat belt,and whether the driver′s side airbag inflated were selected as the influencing factors of the driver′s injury.Next,a Logistic regression model was analyzed and developed based on traffic accident data.The effectiveness of the model was verified by using the Hosmer-Lemeshow test table,and the best trigger threshold was obtained through sensitivity analysis.Then,the AACN system terminal was designed.Finally,an actual case was used to test the accuracy of the injury prediction algorithm and the effectiveness of AACN system terminal.The results of the case study show that the proposed driver injury prediction algorithm and the AACN system are highly accurate,which can effectively predict the driver′s injury and help the rescue center work out an active rescue plan.The research results can be used to solve the problem that existing centralized AACN systems′ efficiency is not high and their accuracy is greatly affected by human factors.Consequently,they provide a reference for the design of driver injury prediction algorithm in the decentralized AACN system.

With the widespread use of digital technologies such as big data, cloud computing and artificial intelligence in higher education, how to establish a scientific and systematic evaluation system to turn the traditional classroom with the one-way transmission of knowledge into an interactive space for exchanging ideas and inspiring wisdom has become an essential task for human resource management in universities, and a key to improving teaching quality. However, due to the debate between scientism and humanism in teaching evaluation, studies related to teaching performance have been isolated from human resource management, resulting in the lack of a systematic vision and framework for such studies. Relevant studies are still limited to the evaluation contents of different evaluation subjects. Evaluations also tend to focus only on the teaching process, ignoring the objectives of talent training, making it difficult for evaluations to play a goal-oriented role and hindering the further development of relevant studies. Therefore, this paper draws on human resource management methodologies and analyzes knowledge teaching evaluation system characteristics in colleges and universities in a big data context to construct a “multiple evaluations, trinity and four-step closed-loop” big data-based knowledge teaching evaluation system. “Trinity” represents evaluation from three performance dimensions: teaching effect, teaching behavior and teaching ability. “Multiple evaluations” represents the design of teaching performance indicators based on teaching data, breaking the barriers between different evaluation subjects. “Four-step closed-loop” draws on performance management theory to standardize the teaching performance management process from four aspects: planning, implementation, evaluation, and feedback. This evaluation system provides a systematic methodology for unifying the theory and practice of innovative knowledge teaching evaluation system in universities in a big data context.

Jiangsu Province is located in the middle coastal area of East China, and has a relatively developed economy and a large population density. Severe convection often occurs in Jiangsu Province, and the lightning activities may cause great economic losses and social impact in this region. Based on the theory of natural disaster risk assessment, this study investigates the risk of hazard factors, the sensitivity of hazard-pregnant environment, and the frangibility of a hazard-bearing body in Jiangsu Province. Then, we select thunderstorm days, cloud-to-ground (CG) lightning density, CG lightning current intensity, altitude, topographic relief, soil-electric conductivity, drainage density, population density, gross domestic product (GDP) per land area, and soil utilization type as the influencing factors, and then we use the analytic hierarchy process and entropy weight method to calculate the weights of the influencing factors. Furthermore, all the factors are weighted stacked in ArcGIS, and finally the lightning disaster risk zoning map (1 × 1 km of Jiangsu Province is presented. The results show that the risk of lightning disaster in Jiangsu is low in the north and high in the south. The area of different risk level increases with the decrease in risk level. High-risk areas are mainly in the middle of Nanjing, eastern Changzhou, eastern Wuxi, and the middle of Suzhou. Medium-risk areas are mainly in northern Nanjing, eastern Changzhou, eastern Suzhou, the Tongshan District of Xuzhou City, the Chongchuan District of Nantong City, Lianyun District of Lianyungang City, and the Xiangshui County, Sheyang County, and Dafeng District of Yancheng City. The sub–low-risk areas are mainly in Xuzhou, Suqian, Huai’an, and the middle of Yangzhou City. The low-risk areas are mainly in Lianyungang, Yancheng, northern Nantong, Taizhou, Zhenjiang, southern Nanjing, western Changzhou, western Wuxi, and western Suzhou. We hope this study could provide some references for the lightning disaster prevention and mitigation in Jiangsu Province and East China.

At present, autonomous mobile robots are widely used in industrial and commercial fields. However, although the global path searched by existing mobile robot path planning methods has no collision with obstacles, there is a problem in that the path is close to obstacles and is not smooth, and there is a collision safety risk when the robot is actually moving. To solve the above problems, this paper proposes a global path planning method based on minimizing the risk index. Firstly, the distance calculation method of the heuristic function of the traditional graph search algorithm is improved to reduce the number of nodes in the search space. Additionally, by selecting the appropriate search neighborhood, the search efficiency and path smoothness of the algorithm are improved. Thirdly, to increase the distance between the original search path and obstacles, the risk index path search strategy is proposed. Finally, the minimized snap trajectory smoothing method with a safe corridor is used to smooth the original waypoint. Both simulation and real robot experimental results show that the minimum distance between waypoints and obstacles is increased by 43.72% on average, and the number of trajectory inflection points are reduced by 75.12% on average after optimization. As such, the proposed method can fully guarantee safety and generate smooth mobile robot paths in global trajectory planning tasks.

Plastic energy dissipation is a key factor in the response of inelastic structures subjected to seismic input, and is often regarded as a primary source of structural damage due to the inelastic deformation of structural components. Accurately predicting a structure’s plastic energy dissipation is essential for efficient energy-based design and seismic assessment. While a single-degree-of-freedom (SDOF) system provides a simple and effective method for estimating plastic energy dissipation, few studies have explored the use of nonlinear analysis methods or equivalent SDOF systems for this purpose. Based on the principle-of-force-analogy method, firstly, the formulas of plastic energy dissipation of a multi-degree-of-freedom (MDOF) system and its equivalent SDOF system were established. Secondly, two estimation methods of plastic energy dissipation of MDOF systems were proposed. Finally, numerical simulations were performed on several multi-story and high-rise structures with varying heights and spans to compare the plastic energy dissipation of MDOF systems and the equivalent SDOF systems of different modes. The simulation results demonstrate that the proposed methods and formulas accurately estimate plastic energy dissipation in multi-story and high-rise structures, while also requiring fewer calculations and less storage.

Two kinds of rectangular mini-channels of different sizes were designed and fabricated for testing the convective heat transfer characteristics of graphene nanofluids. The experimental results show that the average wall temperature decreases with the increases in graphene concentration and Re number at the same heating power. Within the experimental Re number range, the average wall temperature of 0.03% graphene nanofluids in the same rectangular channel decreases by 16% compared with that of water. At the same heating power, the convective heat transfer coefficient increases with the increase in the Re number. The average heat transfer coefficient of water can be increased by 46.7% when the mass concentration of graphene nanofluids is 0.03% and the rib-to-rib ratio is 1:2. In order to better predict the convection heat transfer characteristics of graphene nanofluids in small rectangular channels of different sizes, the convection heat transfer equations applicable to graphene nanofluids of different concentrations in small rectangular channels with different channel rib ratios were fitted, based on factors such as flow Re number, graphene concentration, channel rib ratio, Pr number, and Pe number; the average relative error (MRE) was 8.2%. The mean relative error (MRE) was 8.2%. The equations can thus describe the heat transfer characteristics of graphene nanofluids in rectangular channels with different groove-to-rib ratios.

There are numerous prospects for automated unmanned forklifts in the fields of intelligent logistics and intelligent factories. However, existing unmanned forklifts often operate according to offline path planning first followed by path tracking to move materials. This process does not meet the needs of flexible production in intelligent logistics. To solve this problem, we proposed an optimized online motion planner based on the output of the state grid as the original path. Constraints such as vehicle kinematics; dynamics; turning restriction at the end of the path; spatial safety envelope; and the position and orientation at the starting point and the ending point were considered during path optimization, generating a precise and smooth trajectory for industrial forklifts that satisfied non-holonomic vehicle constraints. In addition, a new rapid algorithm for calculating the spatial safety envelope was proposed in this article, which can be used for collision avoidance and as a turning-angle constraint term for path smoothing. Finally, a simulation experiment and real-world tray-insertion task experiment were carried out. The experiments showed that the proposal was effective and accurate via online motion planning and the tracking of automated unmanned forklifts in a complicated environment and that the proposal fully satisfied the needs of industrial navigation accuracy.

Meiyu-front rainstorm is one of the main disastrous weather events in summer in East China. In this study, seven assimilation experiments of multi-type observation data such as wind profile data, microwave radiometer data and radiosonde sounding data are designed to forecast the Meiyu-front rainstorm on 15 June 2020. The results show that the seven experiments can basically simulate the orientation of rain belt. The comprehensive experiment which assimilates all types of observations performs the best in simulating the location of heavy rainstorm and shows good performance in simulating the precipitation above moderate rain. For the comprehensive experiment, the forecast deviation of rainstorm and heavy rainstorm is small, and the equitable threat score has also been greatly improved compared with other experiments. It is found that the convective available potential energy is enhanced after the assimilation of surface observation data. In addition, the wind convergence and water vapor transportation are modified after assimilating wind profile data. Accordingly, the precipitation efficiency is improved in the comprehensive experiment. The profiles of pseudo-equivalent potential temperature, vorticity and divergence show that, the assimilation of new-types observation data from wind profiler radar and microwave radiometer increases the instability of atmospheric stratification and enhances the ascending motion in the heavy precipitation center. The above results show that the introduction of various some new-type data before the numerical simulation can reduce the forecast deviation. In addition, the combined assimilation of microwave radiometer and sounding data presents better performance than single data assimilation, which indicates that data mutual complementation is essential to improving forecast accuracy.

Tocopherols are essential nutrients for human health known as vitamin E. Vitamin E deficiency can have a profound effect on human health, including the central nervous system and cardiovascular and immune protection. Multiple enzymatic steps are involved in the conversion between different forms of tocopherols. Among them, γ-tocopherol methyltransferase encoded by gene VTE4 catalyzes the conversion of γ- to α-tocopherol or δ- to β-tocopherol isoforms. However, the gene copies and their functional contribution of VTE4 homologs in Brassica napus were not elucidated. To this end, different mutation combinations of four putative BnVTE4 homologous copies were generated by using CRISPR/Cas9 genome editing technology. Editing of those BnVTE4 homologs led to a significant change of the α-tocopherol content and the ratio between α- and γ-tocopherol compared with wide-type control. Analysis of the different combinations of BnVTE4-edited homologs revealed that the contribution of the BnVTE4 individual gene displayed obvious functional differentiation in α-tocopherol biosynthesis. Their contribution could be in order of VTE4.C02-2 (BnaC02G0331100ZS) > VTE4.A02-1 (BnaA02G0247300ZS) > VTE4.A02-2 (BnaA02G0154300ZS). Moreover, the VTE4.A02-1 and VTE4.A02-2 copies might have severe functional redundancies in α-tocopherol biosynthesis. Overall, this study systemically studied the different effects of BnVTE4 homologs, which provided a theoretical basis for breeding high α-tocopherol content oilseed rape.

Lacunopsis Deshayes, 1876 is restricted to South Asia and shows a remarkable regional distribution. Fifteen species have been reported from the lower Mekong River area of Laos, Cambodia, Thailand and Vietnam. Two species Lacunopsis auris Y.-Y. Liu, Y.-X. Wang & W.-Z. Zhang, 1980 and L. yunnanensis Y.-Y. Liu, Y.-X. Wang & W.-Z. Zhang, 1980 occurred in the Yunnan Province of China. The most recent treatments of Lacunopsis date back to the 1970's and the 1980's, therefore detailed information on anatomy and DNA analysis is lacking.A new species of freshwater snail (Gastropoda, Pomatiopsidae), L. yuxiensis sp. nov., is described, based on samples collected from Fuxian Lake (Yunnan, China). The new species is characterized by a solid shell and dark red and yellow spiral ribs on the whorls, reminiscent of marine gastropods of the family Trochidae. In addition to a description of the shell morphology and radula, molecular data are presented for the first time. This compilation of faunal and taxonomic data provides relevant information for use in conservation efforts. Additional molecular data may prove helpful for both refining current knowledge on the morphological variability within this species and verifying the degree of cryptic diversity of this genus.

Abstract Background Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes mellitus that has a considerable impact on quality of life, but there are few effective therapeutic strategies. The aim of this trial is to determine the efficacy and safety of manual acupuncture (MA) versus sham acupuncture (SA) for DPN. Methods/design This is a study protocol for a randomized, placebo-controlled clinical trial. A total of 118 patients with DPN will be recruited and randomly assigned in a 1:1 ratio to either the MA group or SA group. All patients will receive 24 sessions over 12 weeks. Participants will complete the trial by visiting the research center at month 6 for a follow-up assessment. The primary outcome is peroneal motor nerve conduction velocity (peroneal MNCV) at week 12 compared with baseline. Secondary outcomes include peroneal motor nerve action potential amplitude (peroneal MNAP) and latent period (peroneal MNLP), sural sensory nerve conduction velocity (sural SNCV), action potential amplitude (sural SNAP) and latent period (sural SNLP), fasting plasma glucose (FPG), 2-h postprandial blood glucose (2hPG), glycated hemoglobin (HbAlc) at week 12 compared with baseline, Michigan Neuropathy Screening Instrument (MNSI) score and Diabetes Specific Quality of Life scale (DSQL) at week 12 and month 6 compared with baseline. Safety will be assessed during the whole trial. Masking effectiveness will be assessed by patients. Discussion This trial may provide high-quality evidence for evaluating the efficacy and safety of MA treatment for DPN compared with SA treatment. Results of this study will be published in peer-reviewed journals. Trial registration Chinese Clinical Trials Registry ChiCTR1800020444. First registered on 29 December 2018, retrospectively registered, http://www.chictr.org.cn/showproj.aspx?Proj=31063 .

An artificial ground freezing method is often applied to highly permeable gravel formations. Seepage flow increases energy consumption and engineering accidents under this condition. Based on the physical modeling tests, the numerical simulations were conducted. The physical modeling test examined the development of the temperature and frozen wall. Numerical modeling integrated with the ACO algorithm was established to optimize the layout parameters of the freezing pipes. The results indicate that the flowing water prolongs the closure time of the frozen wall. Meanwhile, the total thickness of the frozen wall is also reduced by the flowing water. There are significant differences in the development rates of the frozen wall in different zones. The thickness of the entire frozen wall is nonuniform owing to the seepage flow. Following optimization using the proposed algorithm, the closure time was shortened from 82.4 d to 56.9 d for the frozen wall. Moreover, the freezing efficiency increased by 30.95% after optimization, and consequently, the entire frozen wall was more uniform with a nonweak zone. A case study showed that this optimization system is an effective method for artificial ground freezing operations in geotechnical engineering.

A physical model for the footwall slope of Nanfen open-pit mine, China was established using a self-developed deep geological engineering disaster model test system. A thermosensitive similar material, paraffin, was selected to simulate a weak structural plane in the slope to reproduce the landslide process. From an experimental perspective, the variation trend of shear strength parameters of weak structural plane and the mechanical support characteristics of NPR (negative Poisson’s ratio) anchor cable under the condition of a large landslide deformation and failure were examined. The results of this model test showed that slope failure has four distinct stages: (1) soil compaction stage, (2) crack generation stage, (3) crack propagation stage, and (4) sliding plane transfixion stage. According to the test results, the rock mechanics parameters of weak surface in the footwall slope of Nanfen open-pit mine were calculated. The cohesion is approximately 1.35 × 105 Pa, and the internal friction angle is approximately 6.33°. During slope failure, the NPR anchor cable experiences a large deformation but no damage occurs, indicating that the NPR anchor cable can be continuously monitored and reinforced during the deformation and failure of landslide. The stress characteristics of NPR anchor cables during the test are consistent with the monitoring results of Newtonian force at the landslide site, proving that NPR anchor cables are effective and reasonable in landslide monitoring and early warning.

Heterogeneous populations of basal cells in the prostate epithelium contain stem cells. Here the authors show that Zeb1 marks a pool of prostate epithelial stem cells that self-renew, generate prostate glandular structures with all 3 epithelial cell types and are required for prostate basal cell development.

Abstract Background White spot lesions (WSLs) are common adverse effects in fixed orthodontic treatment. Remineralising agents are widely used to prevent WSLs formation and are the first-line treatment for existing WSLs. Previous systematic reviews have evaluated the effectiveness of remineralisation agents in the management of WSLs. However, their conclusions were contradictory. The objective of this study will be to compare the effectiveness and safety of current remineralising agents used in the management of WSLs in patients treated with fixed orthodontic appliances in any orthodontic setting. Methods Literature searches will be conducted in several electronic databases (from inception onwards): MEDLINE (via Ovid), Scopus, Embase, the Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL), among others. Grey literature will be identified through searching clinical trials registries. Randomised controlled trials that compared the effectiveness of different remineralisation agents in the prevention and treatment of WSLs will be included. Two researchers will independently screen all citations, full-text articles, and abstract data. The study risk bias will be appraised using an appropriate tool. The primary outcomes will be WSLs incidence and severity of WSLs. Secondary outcomes will be subjective measures of WSLs and adverse effects. The mean difference (MD) and relative risk (RR) with corresponding 95% confidence intervals (CI) will be chosen as effect measures for continuous and binary outcomes, respectively. If feasible, fixed and random-effects pairwise meta-analyses and frequentist network meta-analyses will be conducted where appropriate. Discussion This network meta-analysis will compare the effectiveness of remineralising agents in the prevention and treatment of orthodontically induced WSLs. By integrating the evidence from direct and indirect comparisons and ranking all evaluated interventions, our findings have the potential to help clinicians make more accurate treatment decisions. Systematic review registration PROSPERO CRD42019116852, registered on March 15, 2019

Summary: New carbon forms that exhibit extraordinary physicochemical properties can be generated from nanostructured precursors under extreme pressure. Nevertheless, synthesis of such fascinating materials is often not well understood. That is the case of the C60 precursor, with irreproducible results that impede further progress in the materials design. Here, the semiconducting amorphous carbon, having band gaps of 0.1–0.3 eV and the advantages of isotropic superhardness and superior toughness over single-crystal diamond and inorganic glasses, is produced from fullerene at high pressure and moderate temperatures. A systematic investigation of the structure and bonding evolution is carried out with complementary characterization methods, which helps to build a model of the transformation that can be used in further high-pressure/high-temperature (high p,T) synthesis of novel nano-carbon systems for advanced applications. The amorphous carbon materials produced have the potential of accomplishing the demanding optoelectronic applications that diamond and graphene cannot achieve.

Leaf water status determination based on mechanical and electrophysiological properties helps determine the inherent as well as instantaneous leaf dehydration tolerance synchronously. The leaf water potential (ΨL), physiological capacitance (CP) and gripping force (F) were determined with leaves of Broussonetia papyrifera (L.) Vent. and Morus alba L. Real-time leaf stiffness (LCSrt) and maximum leaf stiffness (LCSmax) were investigated by compressing a leaf with external gripping force. Results indicated that LT displayed good correlation with F. Compared to M. alba, a better instantaneous dehydration tolerance or pressure resistance in B. papyrifera was correlated to its persistent stronger LCSrt or LCSmax, respectively. B. papyrifera showed better flexibility and tolerance to wider range of pressure than M. alba. The higher leaf mechanical strength helped to maintain a higher outward pulling force of cell walls; thus, the subsequent negative pressure effectively inhibited cellular water loss. B. papyrifera exhibited better drought resistance than M. alba.

Mutants lacking functional HYD2 homoeologs showed improved seedling growth, but comparable or increased susceptibility to salt stress in tillering plants, suggesting a developmentally restricted role of HYD2 in salt response. Salinity stress threatens global food security by reducing the yield of staple crops such as wheat (Triticum ssp.). Understanding how wheat responds to salinity stress is crucial for developing climate resilient varieties. In this study, we examined the interplay between carotenoid metabolism and the response to salt (NaCl) stress, a specific form of salinity stress, in tetraploid wheat plants with mutations in carotenoid β-hydroxylase 1 (HYD1) and HYD2. Our investigation encompassed both the vulnerable seedling stage and the more developed tillering stage of wheat plant growth. Mutant combinations lacking functional HYD2 homoeologs, including hyd-A2 hyd-B2, hyd-A1 hyd-A2 hyd-B2, hyd-B1 hyd-A2 hyd-B2, and hyd-A1 hyd-B1 hyd-A2 hyd-B2, had longer first true leaves and slightly enhanced root growth during germination under salt stress compared to the segregate wild-type (control) plants. Interestingly, these mutant seedlings also showed decreased levels of neoxanthin and violaxanthin (xanthophylls derived from β-carotene) and an increase in β-carotene in roots. However, tillering hyd mutant and segregate wild-type plants generally did not differ in their height, tiller count, and biomass production under acute or prolonged salt stress, except for decreases in these parameters observed in the hyd-A1 hyd-B1 hyd-A2 hyd-B2 mutant that indicate its heightened susceptibility to salt stress. Taken together, these findings suggest a significant, yet developmentally restricted role of HYD2 homoeologs in salt-stress response in tetraploid wheat. They also show that hyd-A2 hyd-B2 mutant plants, previously demonstrated for possessing enriched nutritional (β-carotene) content, maintain an unimpaired ability to withstand salt stress.

Automatic crash notification systems (ACNSs) play a key role in post-accident safety. To improve the accuracy and efficiency of ACNSs, a method to correct the velocity variation information of ACNSs was established. First, after the acceleration data of sled crash tests were analysed, the factors affecting the accuracy of the velocity variation information were determined, and the influence of the discrimination threshold and acceleration curve shape on the velocity variation information was examined. Second, according to the acceleration data generated by the simulation model of a sled crash, the correlation between the accuracy of the velocity variation information and influencing factors was modelled. Third, an automatic crash notification algorithm involving a velocity variation correction function (VVCF) was proposed based on the correlation model. Finally, to verify its reliability, the improved algorithm was applied to an automatic crash notification system (ACNS) terminal. The validation results show that the ACNS terminal can accurately identify collisions and transmit accident information. Moreover, more accurate velocity variation information can be retrieved.

Mesoscale convective vortices (MCVs) often cause rainstorms. To deepen our understanding of MCV formation mechanisms, reanalysis data from the National Centers for Environmental Prediction and the Weather Research and Forecasting model were used to simulate MCV activity in East China in August 2009. The simulations could reproduce the MCV and associated convective activities well. The vorticity budget and MCV formation mechanisms were then analyzed. The results show that the planetary vorticity advection is much smaller than other terms of the vorticity equation. The MCV initiates in the convective precipitation region and below 800 hPa. When the MCV initiates, there are vorticity-variation couplets within the vortex, and the MCV moves towards the positive vorticity-variation direction. In positive vorticity-variation areas, the divergence term and the tilting term are the vorticity source. The equilibrium response to diabatic heating is one of the forming mechanisms of this MCV. The latent-heating level is relatively low in this MCV case, and the MCV-forming level is also relatively low. Another forming mechanism of this MCV is the tilting of the horizontal vortex tube caused by the upward motion. At the MCV initiation, the perturbation scale of the vortex is found to be larger than the Rossby deformation radius, and thus the MCV could have a long duration.

Innovation can include creativity, innovation mechanisms, and entrepreneurship. The ability to innovate is an important indicator of economic and social development, and creativity is an educational indicator of learning effectiveness. This article explores creativity and innovation from an educational perspective and proposes a sustainability-oriented creativity, innovation, and entrepreneurship education framework that uses creative problem solving. This framework contains four layers and three dimensions. The first layer concerns the thinker and basic structure, and the second layer contains the catalyst of sustainable development goals (SDGs). The third layer is the advanced structure of cultivating SDG thinkers. The final layer is the generation of students who will attempt to start up social enterprises. The three aspects apply the creative nature of diffuse thinking to social innovation; apply demand expansion to extend individual needs to societal needs; and apply educational goal development to encourage sustainability. We expect this framework, which can turn thinkers into doers through creativity and social innovation, to apply to different disciplines. This article provides suggestions for (1) designing curriculum in creativity, innovation, and entrepreneurship education (CIE) for different education level and (2) transitioning technical and vocational education in developing economies on the road to sustainable development.

Myofibrils are huge cytoskeletal assemblies embedded in the cytosol of muscle cells. They consist of arrays of sarcomeres, the smallest contractile unit of muscles. Within a muscle type, myofibril diameter is highly invariant and contributes to its physiological properties, yet little is known about the underlying mechanisms setting myofibril diameter. Here we show that the PDZ and LIM domain protein Zasp, a structural component of Z-discs, mediates Z-disc and thereby myofibril growth through protein oligomerization. Oligomerization is induced by an interaction of its ZM domain with LIM domains. Oligomerization is terminated upon upregulation of shorter Zasp isoforms which lack LIM domains at later developmental stages. The balance between these two isoforms, which we call growing and blocking isoforms sets the stereotyped diameter of myofibrils. If blocking isoforms dominate, myofibrils become smaller. If growing isoforms dominate, myofibrils and Z-discs enlarge, eventually resulting in large pathological aggregates that disrupt muscle function.

The rapid economic development in East Asia has led to serious air pollution problems in the near-surface layer. Studies have shown that there is an interaction between air pollution and the East Asian upper-level jet, which is an important weather system controlling the climate in East Asia. Therefore, it is of great significance to study the relationship between the surface layer air pollutants and the upper-level jet stream in East Asia. Based on the daily wind and vertical velocity data provided by the National Centers for Environmental Prediction/National Center for Atmospheric Research as well as the surface pollutant and meteorological variable data provided by the Science Data Bank, we use statistical analysis methods to study the relationship between the East Asian upper-level jet and the high-concentration area of near-surface air pollutants in summer. Meanwhile, the mechanisms of the interaction are preliminarily discussed. The results show that the North China Plain and the Tarim Basin are the high-value areas of the particulate matter (PM) in summer during 2013–2018, and the ozone (O3) concentration in the near-surface atmospheric layer in the North China Plain is also high. The average concentrations of the PM2.5, PM10 and O3 in the North China Plain are 45.09, 70.28 and 131.27 μg·m−3, respectively, and the days with the concentration exceeding the standard reach 401, 461 and 488, respectively. During this period, there is an increasing trend in the O3 concentration and a decreasing trend in the PM concentration. The average ratio of the PM2.5 to PM10 is approximately 0.65 with a decreasing trend. The air pollutant concentration in this region has a significant relationship with the location of the East Asian upper-level jet. The low wind speed at the surface level under the control of the upper-level jet is the main reason for the high pollutant concentration besides the pollutant emission. They relate to each other through the surface humidity and the meridional and zonal wind. Meanwhile, the concentrations of the PM2.5 and PM10 are high in the near-surface layer in the Tarim Basin, and the average concentrations are 45.19 and 49.08 μg·m−3, respectively. The days with the concentration exceeding the standard are 265 and 193, respectively. The interannual variation in the PM concentration shows an increasing trend first and then a decreasing trend. The average ratio of PM2.5 to PM10 in this region reaches approximately 0.9. The ratio reaches the highest in 2013 and 2014 and then decreases to and maintains at approximately 0.85. The concentration of air pollutants in the basin has a significant relationship with the intensity of the upper-level jet in East Asia. The weakening of the upper-level jet will lead to a decrease in the surface humidity in the northern part of the basin, an increase in the surface temperature in the western part of the basin and a decrease in the surface zonal wind in the eastern part of the basin, which will result in a higher PM concentration.

Purpose: The importance of multidimensional and engaging instruction for sustainable development goals (SDGs) in higher education cannot be overstated. Such instructions should motivate students not only to memorize and contemplate these goals but also to actively participate in addressing SDG-related challenges. Consequently, this study aims to develop practical and appropriate instructional approaches to education for sustainable development (ESD) in higher education to enhance students' knowledge, attitudes and behaviors concerning sustainability. Design/methodology/approach: By using a quasi-experimental design, this ESD study was conducted at a university in central Taiwan. A total of 121 students from diverse academic backgrounds participated in the 16-week experiment, which was divided into three groups. Lecturing, thematic teaching and design-thinking strategies were applied to these respective groups. Findings: The thematic-teaching and design-thinking groups displaying improved cognitive performance. However, the quantity results revealed that the design-thinking group surpassed the other two groups in sustainability knowledge, attitudes, behaviors and mind map tasks. The qualitative findings further indicated that design thinking - through multiple practical problem-solving activities - guided college students to think independently and sustainably, as well as enabled them to internalize the value of sustainable development. By implementing these effective approaches, the core goals of ESD-related personal and societal transformations may be realized. Practical implications: This study proposed a goal-oriented ESD instructional model for educators, demonstrating the efficacy of design thinking in cultivating higher-order thinking and affection for ESD in students. Additionally, this study introduced an innovative evaluation approach - mind mapping - to the ESD domain, which may compensate for the limitations of the survey method. Originality/value: This study provides empirical evidence for the effectiveness of design thinking and thematic-based pedagogies in sustainable development higher education. Additionally, it also offers a practical ESD instructional model with reference value for scholars and multi-domain instructors. Moreover, the study highlights that by examining organizational governance from the perspectives of design thinking and higher-order affection, sustainable and economic development need not be mutually exclusive concepts. Instead, pursuing SDGs can be viewed as investment opportunities for organizations rather than mere costs.

In November 2019, tropical cyclone (TC) frequency over the western North Pacific reached its record high. In this study, the possible causes and formation mechanisms of that record high TC frequency are investigated by analyzing the effect of large-scale environmental factors. A comparison between the extremely active TC years and extremely inactive TC years is performed to show the importance of the large-scale environment. The contributions of several dynamic and thermodynamic environmental factors are examined on the basis of two genesis potential indexes and the box difference index that can measure the relative contributions of large-scale environmental factors to the change in TC genesis frequency. Results indicate that dynamical factors played a more important role in TC genesis in November 2019 than thermodynamic factors. The main contributions were from enhanced low-level vorticity and strong upward motion accompanied by positive anomalies in local sea surface temperature, while the minor contribution was from changes in vertical wind shear. Changes in these large-scale environmental factors are possibly related to sea surface temperature anomalies over the Pacific (e.g., strong Pacific meridional mode).

Objective To detect the genotype of ABO blood group by SNaPshot technology. Methods DNA were extracted from the peripheral blood samples with known blood groups （obtained by serology） of 107 unrelated individuals in Yunnan. Six SNP loci of the 261th, 297th, 681th, 703th, 802th, and 803th nucleotide positions were detected by SNaPshot Multiplex kit, and relevant genetics parameters were calculated. Results In 107 blood samples, the allele frequencies of types A, B, OA, and OG were 0.355 1, 0.168 2, 0.230 0 and 0.247 6, respectively, while that of types AG and cis AB were not detected. The genotyping results of ABO blood group were consistent with that of serologic testing. Conclusion SNaPshot technology can be adapted for genotyping of ABO blood group.

Low-dimensional systems exhibit unique optical properties. Yuanet al. demonstrate one-dimensional organic-inorganic hybrid metal halide perovskites with highly efficient bluish white-light emission due to efficient exciton self-trapping in the quantum-confined structure.

C17H15N3, monoclinic, P21/c (no. 14), a = 11.6325(11) Å, b = 7.8196(7) Å, c = 15.5644(11) Å, β = 106.288(2)°, V = 1358.9(2) Å3, Z = 4, Rgt(F) = 0.0363, wRref(F2) = 0.0975, T = 296(2) K.

Based on the scientific calculation of agricultural carbon emissions in Henan Province, the Tapio decoupling model is used to analyze its relationship with economic development, and its driving factors are analyzed in combination with the LMDI model. The results show that the total amount of agricultural carbon emissions in Henan Province from 2010 to 2019 is on the rise, of which chemical fertilizers are the largest source of carbon emissions. The decoupling analysis shows that before 2019, the weak decoupling between agricultural carbon emissions and the total output value of the planting industry was mainly weak, and a strong decoupling state appeared for the first time in 2019. This means that the level of agricultural economic development is the main force driving the growth of carbon emissions.