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Abstract Hydraulic actuated quadruped robots have bright application prospects and significant research values in unmanned area investigation, disaster rescue and other scenarios, due to the advantages of high payload and high power to weight ratio. Among these fields, inevitable collision of robots may occur when contact with unknown objects, step on empty objects, or collapse, all of which have an impact on the working hydraulic system. To overcome the unknown external disturbances, this paper proposes an active disturbance rejection control (ADRC) strategy of double vane hydraulic rotary actuators for the hip joints of the quadruped robots. Considering the order of the valve-controlled actuator model, a three-stage tracking differentiator, a four-stage extended state observer, and a state error feedback controller are designed relatively, and the extended state observer is adopted to observe and compensate the uncertainty of external load torque of the system. The effectiveness of the ADRC method is verified in simulation environment and a single joint experimental platform. Moreover, the impact experiments of the limb leg unit are carried out after introducing the proposed ADRC strategy into hip joint, the limb leg unit of quadruped robots presents better impact resistance ability.

Abstract High-end equipment always operate in low-speed and heavy-load working environments, highlighting the need for cam-lobe hydraulic motors with excellent speed stability (< 1 r/min) and ultrahigh-power rotary output (> 1 MW). The successful operation of cam-lobe hydraulic motors relies on the circulation supply of high- and low-pressure oil. However, the switching between high-/low-pressure oil controlled by the oil distributor inevitably causes an obvious pressure impact and speed pulsation, which directly reduces the speed stability of hydraulic motors. Therefore, an optimization design approach for the oil distributor port is proposed to minimize the speed pulsation of cam-lobe hydraulic motors. In the proposed approach, a simulation model that links the oil distributor port structural parameters with the hydraulic motor speed pulsation was developed to clarify the effect of the oil distributor structural parameters on speed pulsation. Then, an orthogonal analysis method was used to identify the optimized oil distributor port structural parameters while minimizing the hydraulic motor’s speed pulsation as much as possible. Finally, several experiments were conducted to validate the effectiveness and accuracy of the proposed optimization design approach. The experimental results indicate that the pulsation rate of the hydraulic motor equipped with the optimized oil distributor was 62.5% lower than that of the original motor at a working pressure of 25 MPa, which is consistent with the simulation results using the proposed optimization design approach. The findings of this study offer a feasible and effective approach to guide the design optimization of the oil distributor port for low-pulsation hydraulic motors.

Abstract Cam-lobe radial-piston hydraulic motors are widely used as rotation driving units for various marine machinery owing to their ultrahigh output torque (more than 100 kN m). A multi-row cam roller bearing (MCRB) is the key component that directly determines the fatigue life of a cam-lobe radial-piston hydraulic motor. However, compact geometry and complex loads render MCRB susceptible to fatigue failure, highlighting the need for an optimized MCRB to achieve longer fatigue life and higher reliability. Therefore, this study proposes an innovative geometry optimization method for an MCRB to improve its fatigue life. In this method, a quasi-static model was developed to calculate the load distribution, with the fatigue life of the MCRB calculated using both basic dynamic loading and load distribution. Subsequently, a genetic algorithm was used to obtain the optimized geometry parameters, which significantly improved the fatigue life of the MCRB. Finally, a loading test was conducted on a hydraulic motor installed with both the initial and optimized MCRB to validate the effectiveness of the proposed optimization method. This study provides a theoretical guideline for optimizing the design of MCRB, thereby increasing the fatigue life of hydraulic motors.

Abstract Background An imbalance in lipid metabolism has been linked to the development of AMD, but the causal relationship between AMD and plasma fatty acids (FAs) remains controversial. Using a two-sample Mendelian randomization (MR) approach, we sought to evaluate the impact of specific FA plasma levels on the risk of different AMD subtypes. Methods We analysed genome-wide association data of circulating FAs from 115,006 European-descended individuals in the UK Biobank. These data were used in a two-sample MR framework to assess the potential role of circulating FAs in developing wet and dry AMD. Sensitivity analyses were conducted to ensure the robustness of our findings. Additional multivariable and locus-specific MR analyses were conducted to evaluate direct effects of FA on AMD subtypes, minimizing biases from lipoprotein-related traits and triglycerides. Results Mendelian randomization revealed associations of omega-3 was associated with decreased wet (OR 0.78, 95%CI 0.66–0.92) and dry AMD (0.85, 0.74–0.97) risk, showed a protective effect on AMD. Notably, the omega-6 to omega-3 ratio showed potential causal effects on both wet (1.27, 1.03–1.56) and dry AMD (1.18, 1.02–1.37). Multivariable MR suggested that the causal relationship of omega-3, omega-6 to omega-3 ratio on wet AMD persists after conditioning on HDL, LDL and triglycerides, albeit with slightly diminished evidence strength. Locus-specific MR linked to omega-3(FADS1, 0.89, 0.82–0.98; FADS2, 0.88, 0.81–0.96) and omega-6 to omega-3 ratio (FADS1, 1.10, 1.02–1.20; FADS2, 1.11, 1.03–1.20) suggests causal effects of these factors on wet AMD. Conclusions The associations between plasma FA concentrations and AMD, suggest potential causal role of omega-3, and the omega-6 to omega-3 ratio in wet AMD. These results underscore the impact of an imbalanced circulating omega-3 and omega-6 FA ratio on AMD pathophysiology from MR perspective.

ABSTRACT: Goose astrovirus (GoAstV) is an emerging avian pathogen that induces gout in goslings with a mortality of up to 50%. Organ damage caused by GoAstV infection was considered the cause of gout, but it is still unclear whether other factors are involved. Human and murine studies have linked the gut microbiome-derived urate and gout, thus we hypothesized that gut microbiome may also play an important role in gout induced by GoAstV infection. This study tested the pathogenicity of our isolated GoAstV genotype 2 strain on goslings, while the appearance of clinical signs, histopathological changes, viral distribution and the blood level of cytokines were monitored for 18 d postinfection (dpi). The dynamics in the gut microbiome were profiled by 16S sequencing and then correlated with GoAstV infection. Results showed that this study successfully developed an experimental infection model for studying the pathogenicity of the GoAstV infection which induces typical symptoms of gout. GoAstV infection significantly altered the gut microbiome of goslings with the enrichment of potential proinflammatory bacteria and depletion of beneficial bacteria that can produce short-chain fatty acids. More importantly, the microbial pathway involved in urate production was significantly increased in goslings infected with GoAstV, suggesting that gut microbiome-derived urate may also contribute to the gout symptoms. Overall, this study demonstrated the role of gut microbiome in the pathogenesis of GoAstV infection, highlighting the potential of gut microbiome-based therapeutics against gout symptoms.

Abstract Quantitative cultural studies have witnessed a surge with the rapid development of computer technology in recent years. Since ancient literature constitutes a long-time-span repository for human culture, with quantitative methods and ancient texts, scholars can study the genesis and progression of human history and society across historical epochs from digital perspectives. Nevertheless, traditional humanities scholars often lack the requisite technical skills, creating a demand for interactive platforms. This paper introduces the Evol platform—an online tool designed for the quantitative analysis of ancient literature. Equipped with various analysis functions and visualization tools, the Evol platform allows users to quantify literary documents through intuitive online interaction. Using this platform, we investigated three cases of cultural evolution in ancient Chinese history: (1) the changing attitude of the government towards nomadic ethnic groups; (2) the formulation and propagation of an allusion phrase related to the Battle of Muye; (3) the influence of the Book of Changes across diverse cultural domains. By showcasing cases across diverse semantic units and topics, Evol demonstrates its potential in providing efficient and low-cost experimental tools catering to the realms of culturomics, history, and philology.

Path planning is a critical process in mobile robot navigation. Sampling-based path planning algorithms represented by Rapidly Exploring Random Tree star (RRT*) have gained widespread adoption due to their asymptotic optimality and proven efficiency. However, when applied to intricate environments, characterized by narrow passages and cluttered obstacles, these algorithms encounter challenges in both the initial solution generation and the convergence towards the optimal path, mainly caused by the inefficient sampling strategy, thereby impeding its overall effectiveness. To address these limitations, we introduced Agile-RRT* (A-RRT*), an advancement of RRT* algorithm. Our contributions are twofold: firstly, we introduce an adaptive goal-biased sampling strategy, which employs an adaptive principle for determining the step size on the basis of the goal-biased strategy. This avoids getting trapped in local minima and enhances the efficiency of the initial solution generation. Secondly, we introduce a path optimization approach using a secondary tree and subset-informed sampling, to accelerate the convergence toward the optimal path. It optimizes the path by gradually shrinking the designed elliptical planning space around local states, which effectively narrows down the search space. The experimental results demonstrated that the proposed A-RRT* diminishes the initial solution search time by 71.00% and the sub-optimal solution search time by 82.86% in comparison to RRT*. The A-RRT* exhibits superior performance over RRT*, Informed-RRT*, P-RRT* and Quick-RRT* in terms of soundness and efficiency in narrow and intricate environments. This method could expedite efficient motion planning for drones and mobile robots in complex environments.

Abstract Human social interactions tend to vary in intensity over time, whether they are in person or online. Variable rates of interaction in structured populations can be described by networks with the time-varying activity of links and nodes. One of the key statistics to summarize temporal patterns is the inter-event time, namely the duration between successive pairwise interactions. Empirical studies have found inter-event time distributions that are heavy-tailed, for both physical and digital interactions. But it is difficult to construct theoretical models of time-varying activity on a network that reproduce the burstiness seen in empirical data. Here we develop a spanning-tree method to construct temporal networks and activity patterns with bursty behavior. Our method ensures any desired target inter-event time distributions for individual nodes and links, provided the distributions fulfill a consistency condition, regardless of whether the underlying topology is static or time-varying. We show that this model can reproduce burstiness found in empirical datasets, and so it may serve as a basis for studying dynamic processes in real-world bursty interactions.

Children diagnosed with autism spectrum disorder (ASD) are at an increased risk of experiencing gastrointestinal (GI) discomfort, which has been linked to dysfunctions in the microbiome–gut–brain axis. The bidirectional communication between gut and brain plays a crucial role in the overall health of individuals, and alterations in the gut microbiome can contribute to immune activation and gut–brain dysfunction in ASD. Despite the limited and controversial results of pre-/probiotic applications in ASD, this review comprehensively maps the association between ASD clinical symptoms and specific bacterial taxa and evaluates the efficacy of pre-/probiotics in modulating microbiota composition, reducing inflammatory biomarkers, alleviating difficulties in GI distress, sleep problems, core and other ASD-associated symptoms, as well as relieving parental concerns, separately, in individuals with ASD. Beyond simply targeting core ASD symptoms, this review highlights the potential of pre-/probiotic supplementations as a strategy to modulate gut homeostasis and immune response, and to delineate the potential mechanisms by which its direct or mediating effects can alleviate gut–brain dysfunction and poor nutritional status in ASD management. Further well-designed randomized controlled trials are needed to strengthen the existing evidence and establish optimal protocols for the use of pre-/probiotics in the context of ASD.

Advanced glycation end product (AGE) accumulation due to diabetes causes vascular and neurological lesions, delaying healing. The use of stem cells could overcome these problems. Although many studies have shown the potential beneficial effects of stem cell therapies in the treatment of chronic and refractory skin ulcers, their delivery methods are still under investigation. Human periodontal ligament stem cells (hPDLSCs) can spontaneously differentiate into myofibroblasts in specific cultures; therefore, they have the potential to effectively treat diabetic wounds and may also have applications in the field of medical cosmetics. The myofibroblastic differentiation ability of hPDLSCs in the presence of AGEs was evaluated by the expression of α-SMA and COL1A1 using RT-qPCR and WB technology. Wound healing in diabetic mice, induced by streptozotocin (STZ) and assessed using H&E staining, Masson staining, and immunohistochemical (IHC) and immunofluorescence (IF) staining, was used to validate the effects of hPDLSCs. In the wound tissues, the expression of α-SMA, COL1A1, CD31, CD206, iNOS, and vimentin was detected. The findings indicated that in H-DMEM, the expression of COL1A1 exhibited a significant decrease, while α-SMA demonstrated an increase in P7 cells, ignoring the damage from AGEs (p < 0.05). In an STZ-induced diabetic C57BL/6J mice whole-skin defect model, the healing rate of the hPDLSCs treatment group was significantly higher than that in the models (on the 7th day, the rate was 65.247% vs. 48.938%, p < 0.05). hPDLSCs have been shown to spontaneously differentiate into myofibroblasts in H-DMEM and resist damage from AGEs in both in vivo and in vitro models, suggesting their potential in the field of cosmetic dermatology.

Abstract Soft and stretchable electronics have emerged as highly promising tools for biomedical diagnosis and biological studies, as they interface intimately with the human body and other biological systems. Most stretchable electronic materials and devices, however, still have Young’s moduli orders of magnitude higher than soft bio-tissues, which limit their conformability and long-term biocompatibility. Here, we present a design strategy of soft interlayer for allowing the use of existing stretchable materials of relatively high moduli to versatilely realize stretchable devices with ultralow tissue-level moduli. We have demonstrated stretchable transistor arrays and active-matrix circuits with moduli below 10 kPa—over two orders of magnitude lower than the current state of the art. Benefiting from the increased conformability to irregular and dynamic surfaces, the ultrasoft device created with the soft interlayer design realizes electrophysiological recording on an isolated heart with high adaptability, spatial stability, and minimal influence on ventricle pressure. In vivo biocompatibility tests also demonstrate the benefit of suppressing foreign-body responses for long-term implantation. With its general applicability to diverse materials and devices, this soft-interlayer design overcomes the material-level limitation for imparting tissue-level softness to a variety of bioelectronic devices.

Abstract Being recognized among the cradles of human civilization, ancient China nurtured the longest continuous academic traditions and humanistic spirits, which continue to impact today’s society. With an unprecedented large-scale corpus spanning 3000 years, this paper presents a quantitative analysis of cultural evolution in ancient China. Millions of intertextual associations are identified and modelled with a hierarchical framework via deep neural network and graph computation, thus allowing us to answer three progressive questions quantitatively: (1) What is the interaction between individual scholars and philosophical schools? (2) What are the vicissitudes of schools in ancient Chinese history? (3) How did ancient China develop a cross-cultural exchange with an externally introduced religion such as Buddhism? The results suggest that the proposed hierarchical framework for intertextuality modelling can provide sound suggestions for large-scale quantitative studies of ancient literature. An online platform is developed for custom data analysis within this corpus, which encourages researchers and enthusiasts to gain insight into this work. This interdisciplinary study inspires the re-understanding of ancient Chinese culture from a digital humanities perspective and prompts the collaboration between humanities and computer science.

ABSTRACTIrritable bowel syndrome (IBS) is a heterogeneous condition with multifactorial pathogenesis. We studied deeply phenotyped individuals with microbiota sequencing enrolled in the American Gut Project. The IBS subjects were matched by age, gender, body mass index, geography, and dietary patterns with non-IBS controls. A total of 942 subjects with IBS-Diarrhea (IBS-D), IBS-Constipation (IBS-C), unclassified IBS (IBS-U), and 942 non-IBS controls were included. We compared taxonomic and functional composition of gut microbiota based on 16S sequencing data and linked them with clinical characteristics and dietary factors. Subjects with IBS-D or IBS-U but not IBS-C showed significantly reduced bacterial diversity (Shannon; p

Abstract Few‐layer black phosphorus (FL‐BP) shows great potential in infrared polarization‐sensitive photodetection due to its narrow bandgap and strong in‐plane anisotropy. However, FL‐BP is easy to be oxidized and degraded, which severely restricts its applications. Herein, a simple and scalable in situ interfacial passivation method based on pentacene film is reported to enhance the ambient stability of FL‐BP as well as achieve n‐type doping for improved polarization‐sensitive photoimaging. High crystal quality FL‐BP flakes with intrinsic anisotropy are prepared by electrochemical exfoliation. The morphology and Raman spectra of FL‐BP/pentacene exhibit excellent stability 28 days after passivation. In addition, the hole mobility is significantly enhanced and dark current is substantially suppressed due to the interfacial passivation and n‐type doping effect. The FL‐BP/Pentacene based photodetector shows a broadband response from visible to near‐infrared with good stability. The photoresponsivity under 915 nm illumination is calculated as 2.2 mA W−1 with an anisotropy ratio of 1.29. Furthermore, the polarization imaging under the irradiation at zigzag and armchair directions directly reveals the strong infrared polarization‐sensitive imaging capability of FL‐BP/pentacene. This work also opens up new avenues to enhance the photoresponse and stability of various optoelectronics based on similarly unstable 2D materials.

Abstract The treatment of myocardial infarction (MI) remains a substantial challenge due to excessive inflammation, massive cell death, and restricted regenerative potential, leading to maladaptive healing process and eventually heart failure. Current strategies of regulating inflammation or improving cardiac tissue regeneration have limited success. Herein, a hybrid hydrogel coassembled by acellular cardiac extracellular matrix (ECM) and immunomodulatory glycopeptide is developed for endogenous tissue regeneration after MI. The hydrogel constructs a niche recapitulating the architecture of native ECM for attracting host cell homing, controlling macrophage differentiation via glycopeptide unit, and promoting endotheliocyte proliferation by enhancing the macrophage‐endotheliocyte crosstalk, which coordinate the innate healing mechanism for cardiac tissue regeneration. In a rodent MI model, the hybrid hydrogel successfully orchestrates a proreparative response indicated by enhanced M2 macrophage polarization, increased angiogenesis, and improved cardiomyocyte survival, which alleviates infarct size, improves wall thicknesses, and enhances cardiac contractility. Furthermore, the safety and effectiveness of the hydrogel are demonstrated in a porcine MI model, wherein proteomics verifies the regulation of immune response, proangiogenesis, and accelerated healing process. Collectively, the injectable composite hydrogel serving as an immunomodulatory niche for promoting cell homing and proliferation, inflammation modulation, tissue remodeling, and function restoration provides an effective strategy for endogenous cardiac repair.

Cardiac magnetic resonance imaging analysis has been a useful tool in screening patients for heart disease. Early, timely and accurate diagnosis of diseases of the heart series is the key to effective treatment. MRI provides important material for the diagnosis of cardiac diseases. The rise of deep learning has transformed computer-aided diagnostic systems, especially in the field of medical imaging. Existing work on cardiac structure segmentation models based on MRI imaging mainly relies on convolutional neural networks (CNNs), which lack model diversity and limit the prediction performance. This paper introduces Visual Transformer with Feature Recombination and Feature Distillation(ViT-FRD), a novel learning pipeline that combines a visual transformer (ViT) and a CNN through knowledge refinement. The training procedure allows the student model, i.e., ViT, to learn from the teacher model, i.e., CNN, by optimizing distillation losses. Meanwhile, ViT-FRD provides two performance boosters to increase the efficacy and efficiency of training. The proposed method is validated on two cardiac MRI image datasets. The findings demonstrate that ViT-FRD achieves SOTA and outperforms the widely used baseline model.

Here, using fecal metagenomics data of 2,320 individuals, the authors develop a microbiome-based machine learning approach showing high accuracy for multi-class disease diagnosis, highlighting its potential application in improving noninvasive diagnostics and monitor responses to therapy.

Here, by performing an integrative multi-omics analysis coupled to clinical features of COVID-19 patients prospectively followed for up to 6 month, the authors identify specific gut microbiome patterns associated with disease severity and development of post-acute COVID-19 syndrome.

The accuracy of Monte Carlo (MC) simulations in estimating the computed tomography radiation dose is highly dependent on the accuracy of CT scanner model. A system was developed to observe the 3D model intuitively and to calculate the X-ray energy spectrum and the bowtie (BT) filter model more accurately in Monte Carlo N-particle (MCNP). Labview's built-in Open Graphics Library (OpenGL) was used to display basic surfaces, and constructive solid geometry (CSG) method was used to realize Boolean operations. The energy spectrum was calculated by simulating the process of electronic shooting and the BT filter model was accurately modeled based on the calculated shape curve. Physical data from a study was used as an example to illustrate the accuracy of the constructed model. RMSE between the simulation and the measurement results were 0.97% and 0.74% for two filters of different shapes. It can be seen from the comparison results that to obtain an accurate CT scanner model, physical measurements should be taken as the standard. The energy spectrum library should be established based on Monte Carlo simulations with modifiable input files. It is necessary to use the three-segment splicing modeling method to construct the bowtie filter model.

Radioresistance reduces the antitumor efficiency of radiotherapy and further restricts its clinical application, which is mainly caused by the aggravation of immunosuppressive tumor microenvironment (ITM). Especially tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype during high-dose fractional radiotherapy mediating radiotherapy resistance. Herein, the toll like receptor agonist TLR7/8a was conjugated with radiosensitive peptide hydrogel (Smac-TLR7/8 hydrogel) to regulate TAMs repolarization from M2 type into M1 type, thus modulating the ITM and overcoming the radioresistance. The Smac-TLR7/8 hydrogel was fabricated through self-assembly with nanofibrous morphology, porous structure and excellent biocompatibility. Upon γ-ray radiation, Smac-TLR7/8 hydrogel effectively polarized the macrophages into M1 type. Notably, combined with radiotherapy, TAMs repolarization regulated by Smac-TLR7/8 hydrogel could increase tumor necrosis factor secretion, activate antitumor immune response and effectively inhibit tumor growth. Moreover, TAMs repolarization rebuilt the ITM and elicited the immunogenic phenotypes in solid tumors, thus enhanced the PD1-blockade efficacy through increasing tumor infiltrating lymphocytes (TILs) and decreasing Treg cells in two different immune activity tumor mice models. Overall, this study substantiated that recruiting and repolarization of TAMs were critical in eliciting antitumor immune response and overcoming radioresistance, thus improving the efficacy of radiotherapy and immunotherapy.

Abstract The hypoxia of the tumor microenvironment (TME) seriously restricts the photodynamic therapy (PDT) effect of conventional type‐II photosensitizers, which are highly dependent on O2. In this work, a new type‐I photosensitizer (TPE‐TeV‐PPh3) consisting of a tetraphenylethylene group (TPE) as a bioimaging moiety, triphenyl‐phosphine (PPh3) as a mitochondria‐targeting group, and telluroviologen (TeV2+) as a reactive oxygen species (O2•−, •OH) generating moiety is developed. The luminescence intensity of TPE‐TeV‐PPh3 increased significantly after specific oxidation by excess H2O2 in the TME without responding to normal tissues via the formation of Te═O bond, which can be used for monitoring abnormal H2O2, positioning, and imaging of tumors. TPE‐TeV‐PPh3 with highly reactive radicals generation and stronger hypoxia tolerance realizes efficient cancer cell killing under hypoxic conditions, achieving 88% tumor growth inhibition. Therefore, TPE‐TeV‐PPh3 with low phototoxicity in normal tissue achieves tumor imaging and effective PDT toward solid tumors in response to high concentrations of H2O2 in the TME, which provides a new strategy for the development of type‐I photosensitizers.

ABSTRACT: The epidemic of goose astrovirus (GoAstV) caused huge losses to the poultry industry. Epidemiological studies in China revealed 2 circulating genotypes of GoAstV, but there is a lack of differential diagnosis tools. By analyzing all published genomes of GoAstV, this study designed specific PCR primers and Taqman probes to recognize different genotypes of GoAstV. After optimization and verification, this study developed a Taqman-based real-time quantitative PCR method that is capable of differential diagnosis. The established qPCR exhibited detection limitations of 100 copies/μL or 10 copies/μL, respectively, for GoAstV genotype 1 and genotype 2, and showed no false positive for other common avian viruses. This method was then used to analyze 72 samples collected from different regions in Jiangxi, and the results were verified by genome sequencing and phylogenetic analysis. These results revealed a complex coinfection of GoAstV different genotypes in China, highlighting the importance of long-term focus on the prevalence and genome evolution of GoAstV.

【Objective】The study was conducted to investigate the growth, protease and chitinase activities of a strain of Purpureocillium lilacinum isolated from the stroma of Aschersonia aleyrodis on citrus under different culture conditions, with a view to providing a theoretical basis for the use of P. lilacinum as a biocontrol agent.【Method】The strains of the stroma of A. aleyrodis from Hongjiang orange leaves were isolated and purified by tissue isolation, identified by a combination of morphological characteristics and molecular methods, and their protease and chitinase activities were determined by the Folin-phenol and DNS method.【Result】The strain ZJPL1812 was identified as P. lilacinum by morphological observation and ITS sequence analysis. The best culture temperature for the strain was 30℃, and the suitable pH value was 5.0-9.0. The best mycelial growth was achieved when ammonium dihydrogen phosphate and maltose were used as the nitrogen and carbon sources; the highest protease activity was produced when peptone and sucrose were used as the nitrogen and carbon sources; and the highest chitinase activity was achieved when ammonium nitrate and soluble starch were used as the nitrogen and carbon sources.【Conclusion】The strain can use many different kinds of nitrogen and carbon sources, with a wide range of acid-base adaptability and strong environmental adaptability. And it produces high protease and chitinase activities, indicating that it has some potential in biological control.

Abstract As a type of hydraulic rotary actuator, a helical hydraulic rotary actuator exhibits a large angle, high torque, and compact structure; hence, it has been widely used in various fields. However, its core technology is proprietary to several companies and thus has not been disclosed. Furthermore, the relevant reports are primarily limited to the component level. The dynamic characteristics of the output when a helical rotary actuator is applied to a closed-loop system are investigated from the perspective of driving system design. Two main aspects are considered: one is to establish a reliable mathematical model and the other is to consider the effect of system parameter perturbation on the output. In this study, a detailed mechanical analysis of a helical rotary hydraulic cylinder is first performed, factors such as friction and load are considered, and an accurate dynamic model of the actuator is established. Subsequently, considering the nonlinear characteristics of pressure flow and the dynamic characteristics of the valve, a dynamic model of a valve-controlled helical rotary actuator angle closed-loop system is described based on sixth-order nonlinear state equations, which has never been reported previously. After deriving the system model, a sensitivity analysis of 23 main parameters in the model with a perturbation of 10% is performed under nine operating conditions. Finally, the system dynamics model and sensitivity analysis results are verified via a prototype experiment and co-simulation, which demonstrate the reliability of the theoretical results obtained in this study. The results provide an accurate mathematical model and analysis basis for the structural optimization or control compensation of similar systems.

The mixed infection of duck Tembusu virus (DTMUV) and goose astrovirus (GoAstV) is an important problem that endangers the goose industry. Although quantitative PCR has been widely used in monitoring these two viruses, there is no reliable method to detect them at the same time. In this study, by analyzing the published genomes of DTMUV and goose astrovirus genotype 2 (GoAstV-2) isolated in China, we found that both viruses have high conservation, showing 96.5 to 99.5% identities within different strains of DTMUV and GoAstV, respectively. Subsequently, PCR primers and TaqMan probes were designed to identify DTMUV and GoAstV-2, and different fluorescent reporters were given to two probes for differential diagnosis. Through the optimization and verification, this study finally developed a duplex TaqMan qPCR method that can simultaneously detect the above two viruses. The lower limits of detection were 100 copies/μL and 10 copies/μL for DTMUV and GoAstV-2 under optimal condition. The assay was also highly specific in detecting one or two viruses in various combinations in specimens, and provide tool for clinical diagnosis of mixed infections of viruses in goose.

The Jinsha River, upstream of the Yangtze River, flows through the southeastern margin of the plateau, providing an opportunity to study the plateau uplift relative to the Sichuan basin through fluvial geomorphology. Eight tributaries of the Jinsha River located at the transition boundary from the plateau to the basin were analyzed for the feature of longitudinal profile and its evolution. The spatial distribution of slope-break knickpoints in the catchment was determined by slope-area analysis and integration analysis. Further, the magnitude and timing of the base level lowering (i.e., uplift of the Tibetan Plateau) were estimated by reconstructing the river longitudinal profile. The results show that there are two levels of slope-break knickpoints, with average elevations of 2865 m and 1523 m, corresponding to base levels relatively lowering of 1400 m and 1100 m, respectively. With reference to the long-term downcutting rate of the Jinsha River, the timings of these two phases base level lowering and uplifts are estimated to be ∼21–24 and ∼7–13 Ma, respectively. These are close to the timing of two uplifts revealed by inversion modeling of river longitudinal profiles. Therefore, the uplift of the studied region on the Tibetan Plateau can be divided into two stages, the early stage (∼20 Ma) uplift from 1500 to 2900 m and the late stage (∼10 Ma) uplift from 2900 to 4000 m, which further supports the staged outside uplift of the Tibetan Plateau.

With the advancement in modern agricultural technologies, ensuring crop health and enhancing yield have become paramount. This study aims to address potential shortcomings in the existing chili disease detection methods, particularly the absence of optimized model architecture and in-depth domain knowledge integration. By introducing a neural architecture search (NAS) and knowledge graphs, an attempt is made to bridge this gap, targeting enhanced detection accuracy and robustness. A disease detection model based on the Transformer and knowledge graphs is proposed. Upon evaluating various object detection models on edge computing platforms, it was observed that the dynamic head module surpassed the performance of the multi-head attention mechanism during data processing. The experimental results further indicated that when integrating all the data augmentation methods, the model achieved an optimal mean average precision (mAP) of 0.94. Additionally, the dynamic head module exhibited superior accuracy and recall compared to the traditional multi-head attention mechanism. In conclusion, this research offers a novel perspective and methodology for chili disease detection, with aspirations that the findings will contribute to the further advancement of modern agriculture.

On 8 January 2022, a seismic event of significant magnitude (Mw 6.7, Ms 6.9) occurred in the northeastern region of the Tibetan Plateau. This earthquake was characterized by left-lateral strike-slip motion, accompanied by a minor reverse movement. The Menyuan earthquake resulted in the formation of two main ruptures and one secondary rupture. These ruptures were marked by a left-lateral step zone that extended over a distance of 1 km between the main ruptures. The length of the rupture zones was approximately 37 km. The surface rupture zone exhibited various features, including left-lateral offset small gullies, riverbeds, wire fences, road subgrades, mole tracks, cracks, and scarps. Through a comprehensive field investigation and precise measurement using unmanned aerial vehicle (UAV) imagery, 111 coseismic horizontal offsets were determined, with the maximum offset recorded at 2.6 ± 0.3 m. The analysis of aftershocks and the findings from the field investigation led to the conclusion that the earthquake was triggered by the Lenglongling fault and the Tuolaishan fault. These faults intersected at a release double-curved structure, commonly referred to as a stepover. During this particular process, the Lenglongling fault was responsible for initiating the coseismic rupture of the Sunan–Qilian fault. It is important to note that the stress applied to the Tuolaishan fault has not been fully relieved, indicating the presence of potential future hazards.

As a method of deep learning interpretability, class activation mapping (CAM) is efficient and convenient for extracting geographic objects supervised by image-level labels. However, in addition to the inherent problem of inaccuracy and incompleteness of CAM, we have to deal with the spectral and spatial variance of geographic objects when applying CAM methods to remote sensing images. To explore the capabilities of CAM methods on extracting various geographic objects, we make a comprehensive comparison of five commonly-used CAM methods, including original CAM, GradCAM, GradCAM++, SmoothGradCAM++, and ScoreCAM, in four aspects: efficiency; accuracy; effectiveness on dealing with the spectral and spatial variance; and performance of delineating different geographic object categories. The results demonstrate that the original CAM, GradCAM, and GradCAM++ achieves the highest efficiency, accuracy, and integrity for extracting geographic objects, respectively, which can help us choose the appropriate CAM methods according to the specific requirements of different extraction tasks. Benefiting from the capability in extracting various geographic objects and adaptability in complex scenes, GradCAM achieves the best performance in dealing with the spectral and spatial variance problem and shows the advantage of capturing object details and keeping object completeness at the same time. In addition to the comparison experiments and suggestions, we also provide the principle explanations of the performance differences. The findings of this article could contribute to a deep understanding of different CAM methods and benefit to selecting suitable CAM methods for extracting geographic objects from the perspectives of both principles and experiments.

Peptide vaccine targeting tumor-specific antigens is a promising cancer treatment regimen. However, peptide vaccines are commonly low-immunogenic, leading to suboptimal antitumor T-cell responses. Current peptide vaccination approaches are challenged by the variability of peptide physicochemical characters and vaccine formulations, flexibility, and the broad feasibility. Here, the supramolecular co-assembly of antigen epitope-conjugated peptides (ECPs) targeting CD8 or CD4 T-cell receptors was used to engineer a nanofibrious hydrogel vaccine platform. This approach provided precise and tunable loading of peptide antigens in nanofibers, which notably increased the antigen uptake, cross-presentation, and activation of dendritic cells (DCs). Immunization in mice indicated that the co-assembled peptide hydrogel did not induce local inflammation responses and elicited significantly promoted T-cell immunity by activating the MyD88-dependent NF-κB signaling pathway in DCs. Vaccination of mice using co-assembled peptide vaccine stimulated both enhanced CD8 and CD4 T cells against EG.7-OVA tumors without additional immunoadjuvants or delivery systems, and resulted in a more remarkable cancer immunotherapy efficacy, compared with free peptide vaccine or aluminum-adjuvanted peptide formulation. Altogether, peptide co-assembly demonstrated by three independent pairs of ECPs is a facile, customizable, and chemically defined approach for co-delivering peptide antigens in self-adjuvanting hydrogel vaccines that could induce stronger anticancer T-cell responses.

ObjectiveThis study intended to assess the efficacy of colchicine for prevention of post-operative atrial fibrillation (AF).BackgroundPost-operative AF is a common complication of surgery operations. Inflammation plays a crucial role in the pathogenesis of post-operative AF. Colchicine, a potent anti-inflammatory drug, may have a role in mitigating the incidence of post-operative AF.MethodsWe searched Cochrane Library, Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), Database of Chinese sci-tech periodicals (COVIP), and Wanfang Database for randomized controlled trials (RCTs) comparing colchicine versus placebo, or usual care for prevention of post-operative AF. The main outcome was the occurrence of AF post operation, which includes cardiac surgery, lung surgery, or pulmonary vein isolation. The estimated risk ratio (RR) for the occurrence of post-operative AF was evaluated using a random-effects model. The safety end point was the development of any side effects.ResultsA total of 12 RCTs with 2274 patients were eventually included in this meta-analysis, where 1141 patients received colchicine and 1133 patients received placebo or usual care. Perioperative colchicine treatment was related to a decreased incidence of post-operative AF (RR: 0.65; 95% confidence interval [CI]: 0.56 to 0.75, p

Dysbiosis of gut microbiota is well-described in patients with coronavirus 2019 (COVID-19), but the dynamics of antimicrobial resistance genes (ARGs) reservoir, known as resistome, is less known. Here, we performed longitudinal fecal metagenomic profiling of 142 patients with COVID-19, characterized the dynamics of resistome from diagnosis to 6 months after viral clearance, and reported the impact of antibiotics or probiotics on the ARGs reservoir. Antibiotic-naive patients with COVID-19 showed increased abundance and types, and higher prevalence of ARGs compared with non-COVID-19 controls at baseline. Expansion in resistome was mainly driven by tetracycline, vancomycin, and multidrug-resistant genes and persisted for at least 6 months after clearance of SARS-CoV-2. Patients with expanded resistome exhibited increased prevalence of Klebsiella sp. and post-acute COVID-19 syndrome. Antibiotic treatment resulted in further increased abundance of ARGs whilst oral probiotics (synbiotic formula, SIM01) significantly reduced the ARGs reservoir in the gut microbiota of COVID-19 patients during the acute infection and recovery phase. Collectively, these findings shed new insights on the dynamic of ARGs reservoir in COVID-19 patients and the potential role of microbiota-directed therapies in reducing the burden of accumulated ARGs.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in which neuroinflammation plays pivotal roles. An important mechanism of neuroinflammation is the NLRP3 inflammasome activation that has been implicated in PD pathogenesis. In this perspective, we will discuss the relationship of some key PD-associated proteins including α-synuclein and Parkin and their contribution to inflammasome activation. We will also review promising inhibitors of NLRP3 inflammasome pathway that have potential as novel PD therapeutics. Finally, we will provide a summary of current and potential in vitro and in vivo models that are available for therapeutic discovery and development.

Ti4+-ion-doped (n + 1)SrO − nCeO2 (n = 2) ceramic systems were prepared with the conventional solid-state reaction method, and the effects of the phase structures and compositions, sintering behaviors, microstructures and microwave dielectric properties of these ceramic systems were investigated in detail as a function of TiO2 content. The analytical results of the XRD patterns show that the pure (n + 1)SrO − nCeO2 (n = 2) system is a composite-phase ceramic system with coexisting SrCeO3 and Sr2CeO4 phases (represented as a SrCeO3 + Sr2CeO4 system), which belong to the orthogonal structures of the Pmcn (62) and Pbam (55) space groups, respectively. For the xTiO2-(1 − x) (SrCeO3 + Sr2CeO4) (x = 0.1–0.4) ceramic samples, the secondary phase Sr2TiO4 can also be detected within the range of the investigated components. Meanwhile, the Raman spectroscopy, SEM-EDS, and HRTEM (SAED) analysis results also verified the correctness and consistency of the phase structures and compositions for all the given specimens. In addition, complex impedance spectroscopy was used to detect the conductive behavior of these compound ceramic systems, and the calculation results show that the appropriate addition of Ti4+-ions can make the SrCeO3 + Sr2CeO4 system have better thermal stability. The composition of x = 0.2 multiphase structural ceramic sample sintered at 1330 °C for 4 h has a near zero τf value of ~−4.6 ppm/°C, a moderate εr of ~40.3 and a higher Q × f~44,020 GHz (at 6.56 GHz). The relatively superior-performing ceramics developed in this work are expected to provide a promising microwave dielectric material for communication components.

Abstract This paper proposes a textual analytics approach to the discovery of trends and variations in social development. Specifically, we have designed a linguistic index that measures the marked usage of gendered modifiers in the Chinese language; this predicts the degree of occupational gender segregation by identifying the unbalanced distribution of males and females across occupations. The effectiveness of the linguistic index in modelling occupational gender segregation was confirmed through survey responses from 244 participants, covering 63 occupations listed in the Holland Occupational Codes. The index was then applied to explore the trends and variations of gender equality in occupation, drawing on an extensive digital collection of materials published by the largest newspaper group in China for both longitudinal (from 1946 to 2018) and synchronic (from 31 provincial-level administrative divisions) data. This quantitative study shows that (1) the use of gendered language has weakened over time, indicating a decline in occupational gender stereotyping; (2) conservative genres have shown higher degrees of gendered language use; (3) culturally conservative, demographically stable, or geographically remote regions have higher degrees of gendered language use. These findings are discussed with consideration of historical, cultural, social, psychological, and geographical factors. While the existing literature on gendered language has been an important and useful tool for reading a text in the context of digital humanities, an innovative textual analytics approach, as shown in this paper, can prove to be a crucial indicator of historical trends and variations in social development.

Abstract Lung cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including reactive oxygen species (ROS) production, carbonic anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.

CRISPR-Cas9 is a gene editing tool that can be used to modulate gene expression. Here, the authors report the generation of a mouse model that express all components of the CRISPR-Cas9 guide directed Synergistic Activation Mediator (SAM), demonstrate that gene activation can be achieved with various delivery methods and include generation of a disease model of hypercholesterolemia

Hepatic carcinoma is one of the most common cancers worldwide, while its treatment remains a great challenge. Traditional therapeutic methods often have disadvantages such as limited therapeutic efficacy and potential side effects. In this study, we report the construction of bovine serum albumin (BSA)–stabilized manganese oxide (MnO2)/semiconducting polymer (SP) nanocomposites to combine photothermal therapy (PTT) and chemodynamic therapy (CDT) for treatment of hepatic carcinoma in living mouse models. Such nanocomposites are composed of BSA, SP, and MnO2 as the stabilizer, PTT, and CDT agent, respectively. SP produced local heat under near-infrared (NIR) laser irradiation for PTT, and MnO2 nanoparticles mediated CDT in the tumor microenvironment, leading to apoptosis of cancer cells. Such nanocomposite-mediated combinational therapy showed a much higher efficacy in inhibiting growth of subcutaneous HepG2 tumors in nude mice than sole treatment. This study thus provides a multifunctional nanoplatform for safe and effective treatment of hepatic carcinoma.

ABSTRACT Understanding the role of fecal microbiota transplantation (FMT) in the decolonization of multidrug-resistant organisms (MDRO) is critical. Specifically, little is known about virome changes in MDRO-infected subjects treated with FMT. Using shotgun metagenomic sequencing, we characterized longitudinal dynamics of the gut virome and bacteriome in three recipients who successfully decolonized carbapenem-resistant Enterobacteriaceae (CRE), including Klebsiella spp. and Escherichia coli, after FMT. We observed large shifts of the fecal bacterial microbiota resembling a donor-like community after transfer of a fecal microbiota dominated by the genus Ruminococcus. We found a substantial expansion of Klebsiella phages after FMT with a concordant decrease of Klebsiella spp. and striking increase of Escherichia phages in CRE E. coli carriers after FMT. We also observed the CRE elimination and similar evolution of Klebsiella phage in mice, which may play a role in the collapse of the Klebsiella population after FMT. In summary, our pilot study documented bacteriome and virome alterations after FMT which mediate many of the effects of FMT on the gut microbiome community. IMPORTANCE Fecal microbiota transplantation (FMT) is an effective treatment for multidrug-resistant organisms; however, introducing a complex mixture of microbes also has unknown consequences for landscape features of gut microbiome. We sought to understand bacteriome and virome alterations in patients undergoing FMT to treat infection with carbapenem-resistant Enterobacteriaceae. This finding indicates that transkingdom interactions between the virome and bacteriome communities may have evolved in part to support efficient FMT for treating CRE.

Chicken infectious anemia virus (CIAV) can be transmitted by contaminated live vaccines, and causes huge economic losses. This study evaluated the contamination status of CIAV in 24 batches of vaccines by recombinase-aided amplification assay (RAA), fluorescence quantitative PCR and dot blot assay, and then found a contaminated attenuated vaccine. The whole genome of the CIAV contaminant was then sequenced and named JS2020-PFV (Genbank accession number: MW234428, 2296bp). It showed 94.5 to 99.9% identities with reference strains and shared the closest evolution relationship with AB1K strain which was isolated from a chicken farm in Turkey. All of these suggested that the use of CIAV contaminated live vaccine may be one of the reason for its epidemic in poultry.

ObjectiveTo assess whether carotid artery ultrasonography and brachial-ankle pulse wave velocity (baPWV) measurement can accurately predict cardiovascular and cerebrovascular events, and all-cause mortality in patients with cardiovascular diseases (CVD).MethodsPatients from the Kailuan Study Stroke Cohort (Tangshan, China) who underwent carotid artery ultrasonography and baPWV measurement between June 2010 and June 2011 were included in this study. The effects of carotid plaque, baPWV, and their combination on cardiovascular events, including myocardial infarction (MI), cerebral ischemic stroke, cerebrovascular events, and all-cause mortality, were evaluated using Kaplan-Meier analysis and Cox proportional hazards regression.ResultsA total of 4,899 participants (59.7% males; 54.18 ± 11.52 years old) were analyzed. During a mean follow-up of 5.68 ± 0.66 years, the incidence of cardiovascular events and all-cause mortality were 4.94‰ person-years and 7.02‰ person-years, respectively; 32.8% of participants had both carotid artery atherosclerosis and increased arterial stiffness. A high baPWV alone was associated with an increased risk of CVD events [hazard ratio (HR): 2.68; 95% confidence interval (95% CI): 1.20–6.00; P = 0.007] and cerebral infarction (HR: 5.92; 95% CI: 1.76–19.93; P = 0.004), but not with MI or all-cause death. The presence of both carotid plaque and high baPWV was highly associated with an increased risk of CVD events (HR: 4.65; 95% CI: 2.06–10.45; P < 0.001) and cerebral infarction (HR: 9.21; 95% CI: 2.71–31.19; P < 0.001), but not with MI or all-cause death. Similar results were obtained by the Kaplan-Meier analyses.ConclusionThe presence of carotid plaque and high baPWV were associated with a high risk of CVD events and ischemic stroke. Moreover, the combination of carotid artery ultrasonography and baPWV measurement could predict the risk for CVD ability more accurately than a single measurement alone.

ABSTRACT: Avian leukosis virus (ALV) induces multiple tumors in chicken and is still prevalent in a lot of local flocks in China. In this study, we analyzed the ALV infection status in an Anyi tile-like gray chicken flock by DF1-cells isolation, virus identification, and genome sequencing. Results showed a 29% (29/100) ALV positive rate in this flock. Homology analysis based on env genes illustrated that all these stains belong to subgroup J (92–100% identities) and can be further divided into 5 batches, suggesting a higher diversity of ALV-J within the same flock. The whole-genome analysis of representative stains from each batch confirmed the close relationship between these isolated strains with previously reported strains from different regions (Guangxi, Shandong, and Heilongjiang), revealing the enrichment of different strains in Anyi tile-like grey chickens. This study provides the epidemiological data of ALV-J in a special chicken flock and a reference for the further eradication of ALV in China.

High transmembrane delivery efficiency of nanoparticles has attracted substantial interest for biomedical applications. It has been proved that the desired physicochemical properties of nanoparticles were efficient for obtaining a high cellular uptake capacity. On the other hand, biophysical stimuli from in situ microenvironment were also indicated as another essential factor in the regulation of cellular uptake capacity. Unfortunately, the influence of colony morphology on cellular uptake capacity was rarely analyzed. In this study, micropatterned PDMS stencils containing circular holes of 800/1,200 μm in diameter were applied to control colonies’ size. The amino-modified nanoparticles were cocultured with micropatterned colonies to analyze the influence of colonies’ morphology on the cellular uptake capacity of nanoparticles. Consequently, more endocytosed nanoparticles in larger colonies were related with a bigger dose of nanoparticles within a larger area. Additionally, the high cell density decreased the membrane–nanoparticles’ contacting probability but enhanced clathrin-mediated endocytosis. With these contrary effects, the cells with medium cell density or located in the peripheral region of the micropatterned colonies showed a higher cellular uptake capacity of nanoparticles.

The purpose of this study was to prepare a kind of Zearalenone fast quantitative test strip based on time-resolved fluorescence immunochromatographic assay.Europium nanoparticles were used as fluorescent probes to label anti-zearalenone monoclonal antibodies,and a quantitative immunochromatography method was established based on competitive inhibition principle.The results showed that the sensitivity of Zearalenone fluorescent detection strip was 0.1 ng/mL,the linear range was 0.1～5.0 ng/mL,the standard recovery rate of negative samples of corn and wheat was between 93.45% and 112.2%,and the coefficient of variation of 5 repeats for the same sample was less than 15%.The results show that the Zearalenone fluorescent test strip has the technical characteristics of high sensitivity,short reaction time and accurate quantification,which is suitable for the rapid quantitative detection of Zearalenone in grain and its products.

Abstract Avian leukosis caused by avian leukosis virus (ALV) is one of the most severe diseases endangering the poultry industry. When the eradication measures performed in commercial broilers and layers have achieved excellent results, ALV in some local chickens has gradually attracted attention. Since late 2018, following the re-outbreak of ALV-J in white feather broilers in China, AL-like symptoms also suddenly broke out in some local flocks, leading to great economic losses. In this study, a systematic epidemiological survey was carried out in eight local chicken flocks in Jiangxi Province, China, and 71 strains were finally isolated from 560 samples, with the env sequences of them being successfully sequenced. All of those new isolates belong to subgroup J but they have different molecular features and were very different from the strains that emerged in white feature broilers recently, with some strains being highly consistent with those previously isolated from commercial broilers, layers and other flocks or even isolated from USA and Russian, suggesting these local chickens have been acted as reservoirs to accumulate various ALV-J strains for a long time. More seriously, phylogenetic analysis shows that there were also many novel strains emerging and in a separate evolutionary branch, indicating several new mutated ALVs are being bred in local chickens. Besides, ALV-J strains isolated in this study can be further divided into ten groups, while there were more or fewer groups in different chickens, revealing that ALV may cross propagate in those flocks. The above analyses explain the complex background and future evolution trend of ALV-J in Chinese local chickens, providing theoretical support for the establishment of corresponding prevention and control measures.

The rare SLC30A8 mutation encoding a truncating p.Arg138* variant (R138X) in zinc transporter 8 (ZnT8) is associated with a 65% reduced risk for type 2 diabetes. To determine whether ZnT8 is required for beta cell development and function, we derived human pluripotent stem cells carrying the R138X mutation and differentiated them into insulin-producing cells. We found that human pluripotent stem cells with homozygous or heterozygous R138X mutation and the null (KO) mutation have normal efficiency of differentiation towards insulin-producing cells, but these cells show diffuse granules that lack crystalline zinc-containing insulin granules. Insulin secretion is not compromised in vitro by KO or R138X mutations in human embryonic stem cell-derived beta cells (sc-beta cells). Likewise, the ability of sc-beta cells to secrete insulin and maintain glucose homeostasis after transplantation into mice was comparable across different genotypes. Interestingly, sc-beta cells with the SLC30A8 KO mutation showed increased cytoplasmic zinc, and cells with either KO or R138X mutation were resistant to apoptosis when extracellular zinc was limiting. These findings are consistent with a protective role of zinc in cell death and with the protective role of zinc in T2D.

Cancer vaccines designed to initiate or amplify tumor-specific T-cell responses have been used as a key approach for effective cancer immunotherapy. Across the history of tumor antigens, now we are entering the era of personalized, antigenic epitope-based molecular cancer vaccine. Unfortunately, the immunotherapeutic efficiency of peptide vaccines in human patients is still limited. The weak immunogenicity of peptide antigens is a major limitation for inducing a satisfactory antitumor T-cell response, thus additional immunoadjuvants and delivery systems for non-covalent peptide encapsulation are commonly used in clinic. Beyond this approach, self-assembled molecular peptide vaccines by chemical conjugation of epitope to a self-assembling peptide or the construction of amphiphilic peptide conjugates hold great promise as next generation peptide vaccines to elicit stronger or broader cellular responses that can dramatically increase the immunotherapy efficiency of peptide vaccines. In this review, we summarize recent approaches and progresses for manufacturing self-assembled, self-adjuvanting, and fully synthetic peptide vaccines and their performance for cancer immunotherapy. We also propose multivalent nanovaccines prepared by co-assembly strategy as the future development of peptide cancer vaccines, as well as vaccination in combination with other treatments including immune checkpoint blockade, immunogenic chemo-/radio-therapy as novel synergetic therapies for cancer.

Abstract Background Fistulas have puzzled us all the time and stem cell therapy for it is still in its infancy. We conducted a meta-analysis and systematic review to evaluate the efficacy of stem cells and its potential mechanisms in the management of Crohn’s fistula. Methods Electronic databases were searched comprehensively for studies reporting the efficacy and safety of stem cells in patients with any form of Crohn’s fistula. A random-effects model was used, and all outcomes were calculated by SPSS 24.0. Results Twenty-nine articles with 1252 patients were included. It showed that stem cell group had a higher rate of fistula healing compared to placebo group in patients of Crohn’s fistula (61.75% vs 40.46%, OR 2.21, 95% CI 1.19 to 4.11, P