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Abstract Background The aim of this study is to explore the influence of GPs’information, motivation and behavior skills on EM prescribing behavior in urban and suburban districts. Method A cross-sectional study was conducted from June to November 2022 cross 3 urban districts and 4 suburban districts in Beijing. The structural equation model was used to analyze the factors influencing the essential medicine prescription behavior among general practitioners in urban and suburban districts. Results A total of 511 valid questionnaires were collected. There was a statistically significant difference in mean scores for personal motivation and behavioral skills between urban GPs and suburban GPs. For urban GPs, the path analysis revealed that the social motivation had a direct effect on the essential medicine prescribing behavior (β = 0.225, p

Abstract The immunoprotective components control COVID-19 disease severity, as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies across initial COVID-19 severity, remain unclarified. Here, we longitudinally analyzed SARS-CoV-2-specific immune effectors during the acute infection and convalescent phases of 165 patients with COVID-19 categorized by severity. We found that early and robust SARS-CoV-2-specific CD4+ and CD8+ T cell responses ameliorate disease progression and shortened hospital stay, while delayed and attenuated virus-specific CD8+ T cell responses are prominent severe COVID-19 features. Delayed antiviral antibody generation rather than titer level associates with severe outcomes. Conversely, initial COVID-19 severity imprints the long-term maintenance of SARS-CoV-2-specific adaptive immunity, demonstrating that severe convalescents exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate counterparts. Moreover, initial COVID-19 severity inversely correlates with SARS-CoV-2 reinfection risk. Overall, our study unravels the complicated interaction between temporal characteristics of virus-specific T cell responses and COVID-19 severity to guide future SARS-CoV-2 wave management.

Abstract Background As the number of elderly migrants in China continues to grow, it is necessary to pay closer attention to their health and health services. Some studies have confirmed that social capital plays a significant role in the utilization of health services. Therefore, an in-depth exploration of the relationship between social capital and the utilization of essential public health services (EPHS) by elderly migrants will not only contribute to improving their overall health but also facilitate a more balanced development of public health service system in China. Methods Based on the cross-sectional data from the 2017 China Migrants Dynamic Survey (CMDS), this study examined the impact of social capital on the utilization of EPHS among elderly migrants. We evaluated social capital at two distinct levels: the individual and the community, and considered two dimensions of social capital: structural social capital (SSC) and cognitive social capital (CSC). The study aimed to delve into the impact of these forms of social capital on the utilization of EPHS among elderly migrants, and whether the migration range moderates this impact by multilevel logistic regression analysis. Results A total of 5,728 migrant elderly individuals were selected. The health records establishment rate and health education acceptance rate were approximately 33.0% and 58.6%, respectively. Social capital influenceed the utilization of EPHS among elderly migrants. Specifically, individual-level SSC and CSC have impacts on both the establishment of health records (OR = 1.598, 95%CI 1.366–1.869; OR = 1.705, 95%CI 1.433–2.028) and the acceptance of health education (OR = 1.345, 95%CI 1.154–1.567; OR = 2.297, 95%CI 1.906–2.768) among elderly migrants, while community-level SSC only affected the acceptance of health education (OR = 3.838, 95%CI 1.328–11.097). There were significant differences in individual-level SSC, health records, and health education among different migration range subgroups among elderly migrants. Migration range moderated the effect of social capital on the utilization of EPHS, crossing provinces could weaken the relationship between SSC and health education. Conclusions Social capital is associated with a higher utilization rate of EPHS among elderly migrants. It is necessary to encourage them to actively participate in social activities, strengthen public services and infrastructure construction in the area, and improve their sense of belonging and identity.

BackgroundReaching movements are crucial for daily living and rehabilitation, for which Fitts' Law describes a speed-accuracy trade-off that movement time increases with task difficulty. This study aims to investigate whether cortical activation in motor-related areas is directly linked to task difficulty as defined by Fitts' Law. Understanding this relationship provides a physiological basis for parameter selection in therapeutic exercises.MethodsSixteen healthy subjects performed 2D reaching movements using a rehabilitation robot, with their cortical responses detected using functional near-infrared spectroscopy (fNIRS). Task difficulty was manipulated by varying target size and distance, resulting in 3 levels of index-of-difficulty (ID). Kinematic signals were recorded alongside cortical activity to assess the relationship among movement time, task difficulty, and cortical activation.ResultsOur results showed that movement time increased with ID by 0.2974s/bit across all subjects (conditional r2 = 0.6434, p < 0.0001), and all subjects showed individual trends conforming Fitts' Law (all p < 0.001). Neither activation in BA4 nor in BA6 showed a significant correlation with ID (p > 0.05), while both the target size and distance, as well as the interaction between them, showed a significant relationship with BA4 or BA6 activation (all p < 0.05).ConclusionThis study found that although kinematic measures supported Fitts' Law, cortical activity in motor-related areas during reaching movements did not correlate directly with task difficulty as defined by Fitts' Law. Additional factors such as muscle activation may call for different cortical control even when difficulty was identical.

Neutralization slag (NS) of copper smelting is a waste residue mainly composed of calcium sulfate, which is produced during the process of metal smelting. The large accumulation and storage of NS poses a significant threat to the environment. Therefore, it is imperative to explore a new economically and environmentally friendly approach for recycling NS. This study proposes a method for preparing a new eco-friendly geopolymer material by utilizing NS. A geopolymer with satisfactory mechanical properties was created by employing a hybrid solid activator consisting of CaO-Na2SiO3. The effects of hybrid solid alkali activators calcium oxide (CaO)/sodium silicate (Na2SiO3) ratio on the hydration properties of the NS-based geopolymer were studied, and its curing mechanism was discussed. The results show that, when the hybrid solid activator CaO/Na2SiO3 ratio was 3:1, the maximum 28 d compressive strength of the geopolymer reached 27.8 MPa. The solid activator at a suitable ratio can accelerate the hydration reaction, form higher amounts of C-A-S-H gel and ettringite, reduce the proportion of harmful macropores in the geopolymer, and improve the microstructure of the geopolymer. Toxicity characteristic leaching procedure (TCLP) test confirmed that the NS-based geopolymer had a solidification effect on heavy metals. The leaching concentration of elemental Pb from the neutralised slag feedstock was 7.241 mg/L, while the lowest concentration was 0.286 mg/L in the NS based geopolymer. As a green cementitious material, the NS-based geopolymer is expected to be applied in engineering practice.

Excavated rock from underground tunneling activities constitutes a significant portion of the overall construction and demolition (C&D) waste, yet its efficient reuse is challenging. Here we propose an integrated approach combining the utilization of the excavated rock and the production of an eco-friendly ultra-high performance concrete (UHPC). As the first steps to assess the feasibility of the approach, the workability, mechanical properties, fracture toughness test, phase stability and shrinkage of the UHPC were comprehensively studied. The results show that increasing excavated rock content in UHPC leads to a reduction in flowability but improves flexural performance with the enhancement of phase stability. However, this enhancement effect diminishes with larger excavated rock sizes. The compressive strength of the mixture with 400 kg/m³ dosage and 5–10 mm size range achieve 104.1 MPa, which is better than the reference UHPC. Meanwhile, elevated excavated rock content obviously reduces UHPC shrinkage, notably within size 5–10 mm. In addition, an overall assessment was performed to evaluate the UHPC from both environmental and economic perspectives. The results indicate that incorporating excavated rock as aggregates into UHPC can result in cost savings of up to 9.5%, an 11% reduction in embodied energy, and a 15.5% decrease in embodied carbon. Additionally, this integration can yield superior properties compared to reference UHPC. This approach also reduces dependence on natural aggregates, promoting sustainability.

In recent years, China's advanced light sources have entered a period of rapid construction and development. As modern X-ray detectors and data acquisition technologies advance, these facilities are expected to generate massive volumes of data annually, presenting significant challenges in data management and utilization. These challenges encompass data storage, metadata handling, data transfer and user data access. In response, the Data Organization Management Access Software (DOMAS) has been designed as a framework to address these issues. DOMAS encapsulates four fundamental modules of data management software, including metadata catalogue, metadata acquisition, data transfer and data service. For light source facilities, building a data management system only requires parameter configuration and minimal code development within DOMAS. This paper firstly discusses the development of advanced light sources in China and the associated demands and challenges in data management, prompting a reconsideration of data management software framework design. It then outlines the architecture of the framework, detailing its components and functions. Lastly, it highlights the application progress and effectiveness of DOMAS when deployed for the High Energy Photon Source (HEPS) and Beijing Synchrotron Radiation Facility (BSRF).

Abstract Schizophrenia (SCZ), a highly heritable mental disorder, is characterized by cognitive impairment, yet the extent of the shared genetic basis between schizophrenia and cognitive performance (CP) remains poorly understood. Therefore, we aimed to explore the polygenic overlap between SCZ and CP. Specifically, the bivariate causal mixture model (MiXeR) was employed to estimate the extent of genetic overlap between SCZ (n = 130,644) and CP (n = 257,841), and conjunctional false discovery rate (conjFDR) approach was used to identify shared genetic loci. Subsequently, functional annotation and enrichment analysis were carried out on the identified genomic loci. The MiXeR analyses revealed that 9.6 K genetic variants are associated with SCZ and 10.9 K genetic variants for CP, of which 9.5 K variants are shared between these two traits (Dice coefficient = 92.8%). By employing conjFDR, 236 loci were identified jointly associated with SCZ and CP, of which 139 were novel for the two traits. Within these shared loci, 60 exhibited consistent effect directions, while 176 had opposite effect directions. Functional annotation analysis indicated that the shared genetic loci were mainly located in intronic and intergenic regions, and were found to be involved in relevant biological processes such as nervous system development, multicellular organism development, and generation of neurons. Together, our findings provide insights into the shared genetic architecture between SCZ and CP, suggesting common pathways and mechanisms contributing to both traits.

Abstract Objective Preimplantation genetic testing for monogenic disorders (PGT-M) has been used for over 20 years to detect many serious genetic conditions. However, there is still a lack of reference materials (RMs) to validate the test performance during the development and quality control of PGT-M. Method Sixteen thalassemia cell lines from four thalassemia families were selected to establish the RMs. Each family consisted of parents with heterozygous mutations for α- and/or β-thalassemia and two children, at least one of whom carried a homozygous thalassemia mutation (proband). The RM panel consisted of 12 DNA samples (parents and probands in 4 families) and 4 simulated embryos (cell lines constructed from blood samples from the four nonproband children). Four accredited genetics laboratories that offer verification of thalassemia samples were invited to evaluate the performance of the RM panel. Furthermore, the stability of the RMs was determined by testing after freeze‒thaw cycles and long-term storage. Results PGT-M reference materials containing 12 genome DNA (gDNA) reference materials and 4 simulated embryo reference materials for thalassemia testing were successfully established. Next-generation sequencing was performed on the samples. The genotypes and haplotypes of all 16 PGT-M reference materials were concordant across the four labs, which used various testing workflows. These well-characterized PGT-M reference materials retained their stability even after 3 years of storage. Conclusion The establishment of PGT-M reference materials for thalassemia will help with the standardization and accuracy of PGT-M in clinical use.

Prosthetic hands are frequently rejected due to frustrations in daily uses. By adopting principles of human neuromuscular control, it could potentially achieve human-like compliance in hand functions, thereby improving functionality in prosthetic hand. Previous studies have confirmed the feasibility of real-time emulation of neuromuscular reflex for prosthetic control. This study further to explore the effect of feedforward electromyograph (EMG) decoding and proprioception on the biomimetic controller. The biomimetic controller included a feedforward Bayesian model for decoding alpha motor commands from stump EMG, a muscle model, and a closed-loop component with a model of muscle spindle modified with spiking afferents. Real-time control was enabled by neuromorphic hardware to accelerate evaluation of biologically inspired models. This allows us to investigate which aspects in the controller could benefit from biological properties for improvements on force control performance. 3 non-disabled and 3 amputee subjects were recruited to conduct a “press-without-break” task, subjects were required to press a transducer till the pressure stabilized in an expected range without breaking the virtual object. We tested whether introducing more complex but biomimetic models could enhance the task performance. Data showed that when replacing proportional feedback with the neuromorphic spindle, success rates of amputees increased by 12.2% and failures due to breakage decreased by 26.3%. More prominently, success rates increased by 55.5% and failures decreased by 79.3% when replacing a linear model of EMG with the Bayesian model in the feedforward EMG processing. Results suggest that mimicking biological properties in feedback and feedforward control may improve the manipulation of objects by amputees using prosthetic hands. Clinical and Translational Impact Statement: This control approach may eventually assist amputees to perform fine force control when using prosthetic hands, thereby improving the motor performance of amputees. It highlights the promising potential of the biomimetic controller integrating biological properties implemented on neuromorphic models as a viable approach for clinical application in prosthetic hands.

Despite the recent advances in understanding the water ingress at the interface of calcium silicate hydrate and epoxy, there are still open questions regarding the pore size and defects' dependence on the structure, dynamic and mechanical properties of the interfaces. In this paper, molecular dynamics simulations are carried out for perfect and defective interface models consisting of C-S-H and epoxy resins, respectively. Gaps of different sizes between epoxy and C-S-H are filled with water molecules, with a maximum spacing of 2.79 nm, to investigate the effect of water ingress on the structural, dynamic, and mechanical properties of the interface. The results indicate that in the interface formed by the defective structure, the calcium ions responsible for providing strength have been transformed into a free state due to the influence of water molecules. Consequently, they lose their ability to bridge between the epoxy and silicate tetrahedra, leading to the inability to establish interfacial strength. The defective structure, with its larger surface area and increased interaction with water, is more susceptible to degradation, especially noticeable in the tensile simulations. Furthermore, the interactions between water and C-S-H are the primary factors influencing the microstructure and dynamic behavior of the interface. As the number of water molecules increases, the interface strength weakens. This work provides new insight into understanding the bonding mechanism of the C-S-H/epoxy interface with water ingress. It contributes to the design and development of FRP reinforced concrete composites.

The water flow velocity is a crucial environmental physical factor that drastically impacts the survival and stock distribution of marine organisms. To facilitate the restoration of wild stocks of Pacific abalone (Haliotis discus hannai) and increase the success rate of release, abalones were monitored for 24 h without interruption in an experimental unit (developed in-house) to assess the flow velocity preferences of marine mollusks. Abalones tended to keep away from areas with higher flow velocities (> 5 cm/s) and they preferred to stay in areas with lower flow velocities (< 5 cm/s). Comparative study of the diurnal behavioral characteristics of abalones under seven different flow velocities (0, 5, 10, 15, 20, 25, and 30 cm/s) showed that the cumulative distance moved, movement duration, and feeding time decreased significantly as the flow velocity increased. At flow velocities over 20 cm/s, abalones barely moved or consumed food, and cosine rhythm analysis demonstrated that the diurnal rhythms of behavioral parameters disappeared and the peak movement phase occurred earlier than expected. In addition, increasing the flow velocity reduced the spacing between individuals and the polarity of movement was higher. Individuals changed their coordination levels in groups as an active adaptation to changes in the flow velocity. These findings provide new insights into the ecological habits of abalones. Based on the characteristic movement behaviors of abalones at different flow velocities, bottom-sowing should be conducted in areas with a flow velocity 20 cm/s to improve the efficiency of bottom-sowing stock enhancement.

Abstract Background Chamomile (Matricaria recutita L.) is an important economic crop after tobacco (Nicotiana tabacum L.) cultivation. The nicotine released into the soil during tobacco cultivation has an impact on various aspects of chamomile growth, including plant height, flowering period, flower yield, and flower quality. We aimed to examine the effects of physiological and metabolic response of chamomile under different concentrations of nicotine stress. Results The study revealed that chamomile growth was positively influenced by nicotine concentrations of 1.0 μg/g (N-1) and 10.0 μg/g (N-10). However, higher nicotine concentrations of 100.0 μg/g (N-100) and 500.0 μg/g (N-500) were found to induce stress as the highest levels of antioxidant enzyme activities and malondialdehyde (MDA) levels were observed under this treatment. In addition, it was observed that nicotine was transported from the roots to other organs during the entire growth period of chamomile and the nicotine levels reached saturation under N-100 treatment. A total of 1096 metabolites were detected by ultra-high-performance liquid chromatography-coupled tandem mass spectrometry (UHPLC–MS/MS) analysis, and 48 differentially expressed metabolites (DEMs) were identified among the groups via widely targeted metabolomics studies. The response of chamomile flowers to nicotine stress is associated with the presence of flavonoids, phenolic acids, organic acids, and other substances. Metabolic regulation under nicotine stress primarily involves processes, such as aminoacyl-tRNA biosynthesis, ABC (ATP-binding cassette) transporter activity, glyoxylate and dicarboxylate metabolism and pyrimidine metabolism. Conclusions This report presents the first findings on how nicotine affects the metabolism of chamomile. It also provides a comprehensive understanding of how crops can resist nicotine stress from a metabolic perspective. Graphical Abstract

Abstract Gadolinium (Gd3+)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient radiosensitization efficacy. Little attention has been given to using nanovesicles to improve its efficacy. Herein, Gd-Tex is transformed into building blocks “Gd-Tex-lipids” to self-assemble nanovesicles called Gd-nanotexaphyrins (Gd-NTs), realizing high density packing of Gd-Tex in a single nanovesicle and achieving high Gd-Tex accumulation in tumors. To elucidate the impact of O2 concentration on Gd-Tex radiosensitization, myoglobin (Mb) is loaded into Gd-NTs (Mb@Gd-NTs), resulting in efficient relief of tumor hypoxia and significant enhancement of Gd-Tex radiosensitization, eventually inducing the obvious long-term antitumor immune memory to inhibit tumor recurrence. In addition to Gd3+, the versatile Mb@Gd-NTs can also chelate 177Lu3+ (Mb@177Lu/Gd-NTs), enabling SPECT/MRI dual-modality imaging for accurately monitoring drug delivery in real-time. This “one-for-all” nanoplatform with the capability of chelating various trivalent metal ions exhibits broad clinical application prospects in imaging-guided radiosensitization therapy.

Acting as the most abundant and widely distributed volatile secondary metabolites in plants, terpenoids play crucial roles in diverse physiological regulations and metabolic processes. Terpene synthases play a decisive role in determining the composition and diversity of terpenoids. Though the regulation of terpene synthases has been extensively investigated across various plant species, limited studies have focused on the upstream transcriptional regulation of terpene synthases. In this study, we have identified linalool as the predominant volatile compound that is released gradually from Freesia hybrida flowers throughout flower blooming. In the context of the transcriptome, a typical MYB transcription factor, FhMYB108, was screened based on homologous gene comparison. FhMYB108 is capable of regulating the expression of FhTPS1, and both their expression levels showed gradual increase during flower opening. Moreover, FhMYB108 exerts a stimulatory effect on the transcription of Arabidopsis thaliana AtTPS14, while no significant increase in AtTPS14 expression is observed upon the stabilization of FhMYB108 in A. thaliana. The highly expressed AtMYC2 in A. thaliana could interact with FhMYB108 to suppress the activation of AtTPS14 by FhMYB108. The present study not only elucidates the regulatory mechanism underlying linalool synthesis but also discovers the synergistic effect of MYB and bHLH transcription factors in governing the biosynthesis of volatile terpenoids.

In public-private partnerships (PPPs), governments sometimes may not afford the guarantees in full as initially agreed upon due to limited fiscal budgets. Accordingly, government overcommitment can occur. The degree of government overcommitment fulfillment affects not only the incentives provided by governments but also investors’ willingness to cooperate and efforts. However, until now, this government overcommitment risk has been ignored during negotiations. Moreover, little attention has been paid to the impact of investors’ fairness preference. To this end, this paper constructs an incentive mechanism of government overcommitment based on investors’ fairness preference in the horizontal and vertical dimensions. The results show that the optimal strategies of both sides are usually affected by the degree of government overcommitment fulfillment, investors’ fairness preference and their willingness to cooperate. Contrary to intuition, the optimal incentive of governments and investors’ efforts do not always increase with the decreasing degree of government overcommitment fulfillment, and thus, fairness preferences should be considered. It is not always the case that a higher-level government overcommitment fulfillment is better for themselves. The findings contribute new insights to the incentive mechanism to innovatively work toward creating an effective contract to pay more attention to government overcommitment risk in advance in PPPs.

The evolvement of urbanization has caused artificial light at night (ALAN) to be one of the major pollution sources in major cities, resulting in numerous environmental concerns. In view of the increasing intensity and range of ALAN, this study aims to evaluate the influence of ALAN on the physiology and behavior of the Pacific abalone Haliotis discus hannai, a typical nocturnal marine shellfish. Street lighting at night (SL6, lights on from 18:00 until 00:00; SL12, lights on from 18:00 until 06:00 the next morning) and car lighting (CL, lights were turned once every hour for 30 s and then turned off) were simulated indoors, with the natural light cycle group (lights on from 06:00 to 18:00) treated as the control group (CTR). The significantly higher cumulative distance covered along with the duration of abalone movement was observed in Group SL12 upon comparison with other groups (P

The ongoing course of urbanization has led to excessive use of artificial light at night (ALAN), which has rapidly become an important source of pollution in many cities. The Pacific abalone (Haliotis discus hannai) Larvae were kept under a 12/12 h light/dark photoperiod (DD) in order to determine the effects of ALAN on embryonic development. To simulate the street lighting conditions at night, the artificial light was switched on from 18:00 until midnight (AD) or until 06:00 the next day (ND). Moreover, Groups AD and ND had a considerably greater hatching success rate and metamorphosis rate than Group DD (P

Summary: Background: The impact of previous vaccination on protective immunity, duration, and immune imprinting in the context of BA.5-XBB.1.9.1 reinfection remains unknown. Methods: Based on a 2-year longitudinal cohort from vaccination, BA.5 infection and XBB reinfection, several immune effectors, including neutralizing antibodies (Nabs), antibody-dependent cellular cytotoxicity (ADCC), virus-specific T cell immunity were measured to investigate the impact of previous vaccination on host immunity induced by BA.5 breakthrough infection and BA.5-XBB.1.9.1 reinfection. Findings: In absence of BA.5 Nabs, plasma collected 3 months after receiving three doses of inactivated vaccine (I-I-I) showed high ADCC that protected hACE2-K18 mice from fatality and significantly reduced viral load in the lungs and brain upon BA.5 challenge, compared to plasma collected 12 months after I-I-I. Nabs against XBB.1.9.1 induced by BA.5 breakthrough infection were low at day 14 and decreased to a GMT of 10 at 4 months and 28% (9/32) had GMT ≤4, among whom 67% (6/9) were reinfected with XBB.1.9.1 within 1 month. However, 63% (20/32) were not reinfected with XBB.1.9.1 at 5 months post BA.5 infection. Interestingly, XBB.1.9.1 reinfection increased Nabs against XBB.1.9.1 by 24.5-fold at 14 days post-reinfection, which was much higher than that against BA.5 (7.3-fold) and WT (4.5-fold), indicating an immune imprinting shifting from WT to XBB antigenic side. Interpretation: Overall, I-I-I can provide protection against BA.5 infection and elicit rapid immune response upon BA.5 infection. Furthermore, BA.5 breakthrough infection effectively protects against XBB.1.9.1 lasting more than 5 months, and XBB.1.9.1 reinfection results in immune imprinting shifting from WT antigen induced by previous vaccination to the new XBB.1.9.1 antigen. These findings strongly suggest that future vaccines should target variant strain antigens, replacing prototype strain antigens. Funding: This study was supported by R&D Program of Guangzhou National Laboratory (SRPG23-005), National Key Research and Development Program of China (2022YFC2604104, 2019YFC0810900), S&T Program of Guangzhou Laboratory (SRPG22-006), and National Natural Science Foundation of China (81971485, 82271801, 81970038), Emergency Key Program of Guangzhou Laboratory (EKPG21-30-3), Zhongnanshan Medical Foundation of Guangdong Province (ZNSA-2020013), and State Key Laboratory of Respiratory Disease (J19112006202304).

Abstract Background Changes in cell-type composition of tissues are associated with a wide range of diseases and environmental risk factors and may be causally implicated in disease development and progression. However, these shifts in cell-type fractions are often of a low magnitude, or involve similar cell subtypes, making their reliable identification challenging. DNA methylation profiling in a tissue like blood is a promising approach to discover shifts in cell-type abundance, yet studies have only been performed at a relatively low cellular resolution and in isolation, limiting their power to detect shifts in tissue composition. Methods Here we derive a DNA methylation reference matrix for 12 immune-cell types in human blood and extensively validate it with flow-cytometric count data and in whole-genome bisulfite sequencing data of sorted cells. Using this reference matrix, we perform a directional Stouffer and fixed effects meta-analysis comprising 23,053 blood samples from 22 different cohorts, to comprehensively map associations between the 12 immune-cell fractions and common phenotypes. In a separate cohort of 4386 blood samples, we assess associations between immune-cell fractions and health outcomes. Results Our meta-analysis reveals many associations of cell-type fractions with age, sex, smoking and obesity, many of which we validate with single-cell RNA sequencing. We discover that naïve and regulatory T-cell subsets are higher in women compared to men, while the reverse is true for monocyte, natural killer, basophil, and eosinophil fractions. Decreased natural killer counts associated with smoking, obesity, and stress levels, while an increased count correlates with exercise and sleep. Analysis of health outcomes revealed that increased naïve CD4 + T-cell and N-cell fractions associated with a reduced risk of all-cause mortality independently of all major epidemiological risk factors and baseline co-morbidity. A machine learning predictor built only with immune-cell fractions achieved a C-index value for all-cause mortality of 0.69 (95%CI 0.67–0.72), which increased to 0.83 (0.80–0.86) upon inclusion of epidemiological risk factors and baseline co-morbidity. Conclusions This work contributes an extensively validated high-resolution DNAm reference matrix for blood, which is made freely available, and uses it to generate a comprehensive map of associations between immune-cell fractions and common phenotypes, including health outcomes.

In order to enhance the comprehensive processing quality and production efficiency of seed melons, a seed melon crushing and seed-extraction separator has been developed and designed. Aiming at the issues of high impurity rate and scratch rate of melon seeds in the process of seed–flesh separation, the structure and parameters of the seed–flesh separation device were optimized in this study by simulation analysis and field testing. The simulation model of melon seed, melon flesh, and the seed–flesh separation device based on the discrete element method (DEM) was established, and the simulation parameters were calibrated. Subsequently, the melon seed impurity rate (G1) and the melon seed scratch rate (G2) were used as the evaluation indexes. The single-factor simulation test was carried out on the separation roller speed (A). The spacing between the scraper and the screen (B), the separation roller scraper inclination angle (C), and the influence rules of each factor on the separation effect of the seed–flesh were obtained. Finally, the three-factor and three-level orthogonal test was carried out. Using the method of ANOVA and multi-objective optimization, the optimal working parameters of the device were obtained as A-117.53 r/min, B-5 mm, and C-10°, at which time the optimal evaluation indexes were G1-5.59% and G2-2.85%. The prototype test was carried out with the optimization results. The values of G1 and G2 were measured at 5.71% and 2.91%, respectively, and the relative errors with the simulation values were 2.15% and 2.11%, respectively, which were basically the same between the simulation model and the prototype test. The results indicate that the designed separation roller speed, spacing between the scraper and screen, and separation roller scraper inclination angle can meet the requirements of seed–flesh separation in the seed melon crushing and seed-extraction separator. The results of the DEM study can provide a reference for the optimal design of the seed–flesh separation device.

Wind shear is one of the crucial parameters in wind resource assessment and also serves as a vital parameter and basis for determining wind turbines’ selection and hub height. Existing studies have only focused on typical underlying surface areas, but a relatively limited comprehensive analysis of wind shear characteristics in different complex environments remains. This study analyzes the daily and monthly variations in wind shear index (α) at the station scale based on the observations from 754 wind measurement towers across land surfaces in China. The distribution and empirical values of wind shear in different wind regions and underlying surface types are also investigated. The research findings indicate that the wind shear index derived from fitting the complete annual average wind speeds at multiple height levels of meteorological towers can accurately characterize the stratification state of the atmospheric boundary layer. The variation pattern of solar radiation influences the daily α value in typical regions. In mountainous and desert areas, the monthly variation tends to be higher in autumn and winter and lower in spring and summer. However, its monthly variation shows relatively smaller fluctuations in plain regions. The comprehensive α value over land regions in China is 0.135. The α values for I, II, III, and IV wind fields are 0.111, 0.163, 0.1, and 0.153, respectively. Its values for mountainous, plains, grassland, and desert regions are 0.12, 0.273, 0.123, and 0.104, respectively. By conducting statistical analysis on α values across different wind regions, guidance is provided for extrapolating surface wind speeds to hub-height wind speeds. This serves as a reference for wind energy resource assessment, wind turbine selection, and hub height determination in the atmospheric boundary layer of China.

Abstract Background Rewriting the genomes of living organisms has been a long-standing aim in the biological sciences. The revelation of the CRISPR/Cas9 technology has revolutionized the entire biological field. Since its emergence, this technology has been widely applied to induce gene knockouts, insertions, deletions, and base substitutions. However, the classical version of this system was imperfect for inducing or correcting desired mutations. A subsequent development generated more advanced classes, including cytosine and adenine base editors, which can be used to achieve single nucleotide substitutions. Nevertheless, these advanced systems still suffer from several limitations, such as the inability to edit loci without a suitable PAM sequence and to induce base transversions. On the other hand, the recently emerged prime editors (PEs) can achieve all possible single nucleotide substitutions as well as targeted insertions and deletions, which show promising potential to alter and correct the genomes of various organisms. Of note, the application of PE to edit livestock genomes has not been reported yet. Results In this study, using PE, we successfully generated sheep with two agriculturally significant mutations, including the fecundity-related FecB B p.Q249R and the tail length-related TBXT p.G112W. Additionally, we applied PE to generate porcine blastocysts with a biomedically relevant point mutation (KCNJ5 p.G151R) as a porcine model of human primary aldosteronism. Conclusions Our study demonstrates the potential of the PE system to edit the genomes of large animals for the induction of economically desired mutations and for modeling human diseases. Although prime-edited sheep and porcine blastocysts could be generated, the editing frequencies are still unsatisfactory, highlighting the need for optimizations in the PE system for efficient generation of large animals with customized traits.

Recent research has recognized limestone calcined clay cement (LC3) a promising sustainable cementitious material. While LC3 could be used in a wide range of applications, it is important to explore its feasibility in developing (ultra-)high performance concrete. In this paper we attempt to produce ultrahigh performance LC3 concrete (UHP-LC3). With 20%, 30%, and 40% OPC replaced by coal gangue waste calcined clay and limestone (LC2), the mechanical, hydration, and microstructural properties were extensively studied. The mechanical properties were investigated by compressive and flexural tensile tests. The hydration behavior of UHP-LC3 was evaluated by thermogravimetric analysis (TGA), quantitative X-ray powder diffraction (QXRD) analysis, 29Si nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscope (SEM). Finally, the microstructure of UHP-LC3 was studied by mercury intrusion porosimetry (MIP). Results show that the substitution of LC2 improve the early strength by quickly pozzolanic reaction to form denser hydration products as well as the synergistic interaction between silica fume and limestone/calcined clay in the system. However, the long-term strength would drop as LC3 caused insufficient hydration reaction due to the high water-demand of calcined clay that reduced the amount of free water. Also, there are abundant unreacted calcined clay particles in the hydrated system. Meanwhile, LC3 substitution of OPC seems to improve the polymerization of C-A-S-H gel and densify the pore structure, thus display excellent carbonation resistance. This paper explores new options to prepare more sustainable and cost-effective UHPC.

BackgroundStudies have revealed that there were significant changes in intestinal flora composition in patients with coronavirus disease 2019 (COVID-19) compared to non-COVID-19 patients, regardless of whether they were treated with medication. Therefore, a comprehensive study of the intestinal flora of COVID-19 patients is needed to further understand the mechanisms of COVID-19 development.MethodsIn total, 20 healthy samples and 20 COVID-19 samples were collected in this study. Firstly, alpha diversity and beta diversity were analyzed to assess whether there were difference in species richness and diversity as well as species composition between COVID-19 and control groups. The observed features index, Evenness index, PD index, and Shannon index were utilized to measure alpha diversity. The principal coordinates analysis (PCoA) and non-metric multidimensional scaling (NMDS) were performed to analyzed beta diversity. Linear discriminant analysis Effect Size (LEfSe) was utilized to analyze the variability in the abundance of bacterial taxa from different classification levels. The random forest (RF), Least absolute shrinkage and selection operator (LASSO), and univariate logistic regression were utilized to identify key Amplicon Sequence Variant (ASVs). Finally, the relevant networks of bacterial taxa were created in COVID-19 and control groups, separately.ResultsThere were more species in the control group than in COVID-19 group. The observed features index, Shannon index, and Evenness index in the control groups were markedly higher than in the COVID-19 group. Therefore, there were marked variations in bacterial taxa composition between the COVID-19 and control groups. The nine bacterial taxa were significantly more abundant in the COVID-19 group, such as g-Streptococcus, f-Streptococcaceae, o-Lactobacillales, c-Bacilli and so on. In the control group, 26 bacterial taxa were significantly more abundant, such as c-Clostrjdia, o-Oscillospirales, f-Ruminococcaceae, etc. The 5 key ASVs were obtained through taking the intersection of the characteristic ASVs obtained by the three algorithms, namely ASV6, ASV53, ASV92, ASV96, and ASV105, which had diagnostic value for COVID-19. The relevance network in the control group was more complex compared to the COVID-19 group.ConclusionOur findings provide five key ASVs for diagnosis of COVID-19, providing a scientific reference for further studies of COVID-19.

Pacific abalone (Haliotis discus hannai) are typical nocturnal organisms in the marine benthic ecosystem. However, whether their rhythmic behavior is related to the avoidance of interspecific competition for food resources is unknown. In this study, abalone and sea urchins (Anthocidaris crassispina) with the same feeding habit were placed in the same experimental area, and the effects of food abundance on movement, feeding, spacing between individuals (cohesion), and group polarity (coordination) of H. discus hannai and A. crassispina were studied using infrared video monitoring. The cumulative distance moved, time moved, and cumulative feeding duration of abalone and sea urchins exhibited significant cosine rhythms regardless of food abundance under both monoculture and polyculture. With sufficient food available in polyculture, the cumulative distance moved and time moved by abalone and sea urchins were significantly higher than when food was insufficient. After polyculture with abalone, the cumulative feeding duration of sea urchins under the food insufficient condition was significantly lower than that in the sufficient food group. Under the food sufficient condition, the cohesion of abalone and sea urchins in polyculture did not differ significantly but the coordination of sea urchins was significantly higher compared to that of the insufficient food group. Once the food abundance decreased, the cohesion among individuals in the monoculture sea urchin group decreased; although the group coordination in the abalone group was the lowest at this time, the group coordination of abalone was significantly higher after polyculture with sea urchins. Comparison of the diurnal movement behavior characteristics of abalone and sea urchins revealed that these two species with similar ecological niches coexist through competitive interactions under the abundance and scarcity of food resources. These results provide new insights into how the nocturnal rhythmic behavior of marine organisms occurs, and they also provide important explanatory evidence for the formation and maintenance of marine benthic biodiversity.

Abstract Background Due to the temporal and spatial heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in breast tumors, immunohistochemistry (IHC) cannot accurately reflect the HER2 status in real time, which may cause misguided treatment decisions. HER2-specific imaging can noninvasively determine HER2 status in primary and metastatic tumors. In this study, HER2 expression in breast cancer patients was determined in vivo by SPECT/CT of 99mTc-HP-Ark2, comparing with PET/CT of 18F-FDG lesion by lesion. Methods A novel HER2-targeted peptide probe 99mTc-HP-Ark2 was constructed. Biodistribution and nanoScan SPECT/CT imaging were performed in mice models. The correlation between the quantified tumor uptake and HER2 expression in tumor cells was analyzed. In the pilot clinical study, a total of 34 breast cancer patients (mean age ± SD: 49 ± 10 y) suspected of having breast cancer according to mammography or ultrasonography were recruited at Peking Union Medical College Hospital, and 99mTc-HP-Ark2 SPECT/CT and 18F-FDG PET/CT were carried out with IHC and fluorescence in situ hybridization as validation. Results Small animal SPECT/CT of 99mTc-HP-Ark2 clearly identified tumors with different HER2 expression. The quantified tumor uptake and tumor HER2 expression showed a significant linear correlation (r = 0.932, P

Objects thrown from tall buildings in communities are characterized by their small size, inconspicuous features, and high speed. Existing algorithms for detecting such objects face challenges, including excessive parameters, overly complex models that are difficult to implement, and insufficient detection accuracy. This study proposes a lightweight detection model for objects thrown from tall buildings in communities, named S-YOLOv5, to address these issues. The model is based on the YOLOv5 algorithm, and a lightweight convolutional neural network, Enhanced ShuffleNet (ESNet), is chosen as the backbone network to extract image features. On this basis, the initial stage of the backbone network is enhanced and the simplified attention module (SimAM) attention mechanism is added to utilize the rich position information and contour information in the shallow feature map to improve the detection of small targets. For feature fusion, the sparsely connected Path Aggregation Network (SCPANet) module is designed to use sparsely connected convolution (SCConv) instead of the regular convolution of the Path Aggregation Network (PANet) to fuse features efficiently. In addition, the model uses the normalized Wasserstein distance (NWD) loss function to reduce the sensitivity of positional bias. The accuracy of the model is further improved. Test results from the self-built objects thrown from tall buildings dataset show that S-YOLOv5 can detect objects thrown from tall buildings quickly and accurately, with an accuracy of 90.2% and a detection rate of 34.1 Fps/s. Compared with the original YOLOv5 model, the parameters are reduced by 87.3%, and the accuracy and rate are improved by 0.8% and 63%, respectively.

Analyzing historical and reanalysis datasets for wind energy climatic characteristics offers crucial insights for wind farms and short-term electricity generation forecasting. However, large-scale wind farms in Chinese deserts, the Gobi, and barren areas often lack sufficient wind measurement data, leading to challenges in assessing long-term power generation revenue and introducing uncertainty. This study focuses on the Tengger Desert as the study area, processes the Coupled Model Intercomparison Project Phase 6 (CMIP6) data, and analyzes and compares wind energy’s future characteristics utilizing a developed deep learning (DL) downscaling algorithm. The findings indicate that (1) the Convolutional Neural Network (CNN) downscaling model, with the Weather Research and Forecasting Model (WRF) numerical simulation results as the targets, exhibits spatial distribution consistency with WRF simulation results in the experimental area. (2) Through testing and validation with three practical wind measurements, the annual average wind speed error is below 4%. (3) In the mid-term future (~2050), the average wind speed in the experimental area remains stable with a multi-year average of approximately 7.00 m·s−1. The overall wind speed distribution range is significant, meeting the requirements for wind farm development.

To enhance the utilization of seed-used watermelon peel and mitigate environmental pollution, a hammer-blade seed-used watermelon peel crusher was designed and manufactured, and its structure and working parameters were optimized. Initially, the seed-used watermelon peel crusher and seed-used watermelon peel model were constructed, and the model’s parameters were calibrated. Subsequently, the discrete element method (EDEM2022) was employed to investigate the effects of spindle speed (MSS), the number of hammers (NCB), and feeding volume (FQ) on the pulverizing process. Multivariate nonlinear regression prediction models were developed for the percentage of pulverized particle size less than 8 mm (Psv), pulverizing efficiency (Ge), and power density (Ppd), followed by the analysis of influencing factors and prediction models using ANOVA. The multiobjective optimization of the prediction model utilizing the improved hybrid metacellular genetic algorithm CellDE resulted in solutions of 90.02%, 89.57%, and 8.35 × 10−3 t/(h-kw) for Psv-opt, Ge-opt, and Ppd-opt, respectively. The corresponding optimal interaction values of MSS, NCB, and FQ were determined to be 1500 r/min, 108, and 150 kg/min. Finally, a prototype test was conducted by combining the optimal factor interaction values, yielding statistically calculated values of 96.63%, 92.37%, and 7.76 × 10−3 t/(h-kw) for Psv-pr, Ge-pr, and Ppd-pr, respectively. The results indicate that the optimized values of Psv-opt, Ge-opt, and Ppd-opt models have an error of less than 8% compared to the statistically calculated values of the prototype test and outperform the values of Psv-ori, Ge-ori, and Ppd-ori obtained under the original parameters.

The milestone discovery of GW170817-GRB 170817A-AT 2017gfo has shown that gravitational waves (GWs) could be produced during the merger of a neutron star–neutron star/black hole and that in electromagnetic (EM) waves, a gamma-ray burst (GRB) and a kilonova (KN) are generated in sequence after the merger. Observationally, however, EM properties before the merger phase are still unclear. Here we report a peculiar precursor in a KN-associated long-duration GRB 211211A, providing evidence of the EM before the merger. This precursor lasts ∼0.2 s, and the waiting time between the precursor and the main burst is ∼1 s, comparable to that between GW170817 and GRB 170817A. The spectrum of the precursor could be well fit with a nonthermal cutoff power-law model instead of a blackbody. In particular, a ∼22 Hz quasiperiodic oscillation candidate (∼3 σ ) is detected in the precursor. These temporal and spectral properties indicate that this precursor is probably produced by a catastrophic flare accompanied with magnetoelastic or crustal oscillations of a magnetar in a binary compact merger. The strong magnetic field of the magnetar can also account for the prolonged duration of GRB 211211A. However, it poses a challenge to reconcile the rather short lifetime of a magnetar with the rather long spiraling time of a binary neutron star system only by the GW radiation before the merger.

Embedded memory, which heavily relies on the manufacturing process, has been widely adopted in various industrial applications. As the field of embedded memory continues to evolve, innovative strategies are emerging to enhance performance. Among them, resistive random access memory (RRAM) has gained significant attention due to its numerous advantages over traditional memory devices, including high speed (

Numerous antibiotic resistance genes (ARGs) and virulence factors (VFs) found in animal manure pose significant risks to human health. However, the effects of graphene sodium selenite (GSSe), a novel chemical nano-Selenium, and biological nano-Selenium (BNSSe), a new bioaugmentation nano-Se, on bacterial Se metabolism, chemotaxis, ARGs, and VFs in animal manure remain unknown. In this study, we investigated the effects of GSSe and BNSSe on ARGs and VFs expression in broiler manure using high-throughput sequencing. Results showed that BNSSe reduced Se pressure during anaerobic fermentation by inhibiting bacterial selenocompound metabolism pathways, thereby lowering manure Selenium pollution. Additionally, the expression levels of ARGs and VFs were lower in the BNSSe group compared to the Sodium Selenite and GSSe groups, as BNSSe inhibited bacterial chemotaxis pathways. Co-occurrence network analysis identified ARGs and VFs within the following phyla Bacteroidetes (genera Butyricimonas, Odoribacter, Paraprevotella, and Rikenella), Firmicutes (genera Lactobacillus, Candidatus_Borkfalkia, Merdimonas, Oscillibacter, Intestinimonas, and Megamonas), and Proteobacteria (genera Desulfovibrio). The expression and abundance of ARGs and VFs genes were found to be associated with ARGs-VFs coexistence. Moreover, BNSSe disruption of bacterial selenocompound metabolism and chemotaxis pathways resulted in less frequent transfer of ARGs and VFs. These findings indicate that BNSSe can reduce ARGs and VFs expression in animal manure by suppressing bacterial selenocompound metabolism and chemotaxis pathways.

The aim of this research is to investigate lipid-lowering influence of dietary ginger (Zingier officinales Rocs) polysaccharides (GPS) on hyperlipidemia rats. Rat models with hyperlipidemia was established by high-fat food diet (HFD). Comparing to GP-negative model group, GPS attenuated several effects of HFD feeding, including the levels of blood lipid biochemistry, serum inflammatory markers (tumor necrosis factor TNF-a, interleukin IL-6), antioxidant capacity (superoxide dismutase SOD, glutathione peroxidase GSH-Px, total antioxidant capacity T-AOC, propylene dialdehyde MDA), uric acid and immune index. 16 S rDNA gene sequencing of fecal samples showed that GPS increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes; This changes in microbial community structure can help prevent diet-induced metabolic disease. These results suggest that GPs may act on the gut, changing the structure of the gut microbial community, thereby reducing intestinal and systemic inflammation, thus improved metabolic outcomes.

The studies of polyacrylonitrile (PAN) fiber-reinforced composites primarily focused on Portland cement, and there are few researches related to its effect on the performance of sulfoaluminate cement (SAC). The role of PAN fibers on the mechanical properties and abrasion resistance of SAC-based mortars is studied in this work, and the improvement mechanism of PAN fibers is investigated using scanning electron microscopy (SEM) and X-ray computed tomography (CT). The results demonstrate that the use of PAN fibers significantly enhances the strengths, compressive toughness, and abrasion resistance of the mortars, especially the early performance. The PAN fibers with grooves helped form a strong bond with the matrix. Based on the CT scan results, the fibers effectively inhibit microcrack initiation and restrain crack propagation under loading because they play a positive role in pull-out, crack bridging, and deflection, which is confirmed by SEM observation. This study provides the theoretical support for application of PAN fiber-reinforced sulfoaluminate cement composites in rush repair and construction of pavements.

Abstract The effects of different SARS-CoV-2 vaccinations and variant infection histories on imprinting population immunity and their influence on emerging escape mutants remain unclear. We found that Omicron (BA.1) breakthrough infection, regardless of vaccination with two-dose mRNA vaccines (M-M-o) or two-dose inactivated vaccines (I-I-o), led to higher neutralizing antibody levels against different variants and stronger T-cell responses than Delta breakthrough infection after two-dose inactivated vaccine vaccination (I-I-δ). Furthermore, different vaccination-infection patterns imprinted virus-specific T-cell differentiation; M-M-ο showed higher S/M/N/E-specific CD4+ T cells and less portion of virus-specific CD45RA+CD27–CD8+ T cells by ex vivo assay. Breakthrough infection groups showed higher proliferation and multi-function capacity by in vitro assay than three-dose inactivated vaccine inoculated group (I-I-I). Thus, under wide vaccination coverage, the higher immunogenicity with the Omicron variant may have helped to eliminate the population of Delta variant. Overall, our data contribute to our understanding of immune imprinting in different sub-populations and may guide future vaccination programs.

Purpose To evaluate the efficacy of ferumoxytol, relative to conventional iron supplement formulations, on hemoglobin levels, ferritin level, and adverse event incidence in chronic kidney disease patients. Methods We performed a systematic search of six academic databases (EMBASE, CENTRAL, Scopus, PubMed, Web of sciences, and MEDLINE), adhering to PRISMA guidelines. We performed a meta-analysis on relevant studies to evaluate the overall influence of ferumoxytol, relative to conventional iron supplement formulations, on hemoglobin levels, ferritin level, and treatment related treatment emergent adverse events (TEAEs) incidence in chronic kidney disease patients. Results Seven eligible studies were identified from a total of 1397 studies. These studies contained data on 3315 participants with chronic kidney disease (mean age: 59.2 ± 4.6 years). A meta-analysis revealed that ferumoxytol administration had positive effects on hemoglobin levels (Hedge’s g statistic: 0.51) and ferritin level (0.88), transferrin saturation (0.39). Besides, we also report reduced incidence of treatment related TEAEs (−0.24) for patients consuming ferumoxytol as compared conventional iron supplement formulations. Conclusions This meta-analysis provides preliminary evidence that ferumoxytol use exerts beneficial effects on the overall hematological outcomes in patients with chronic kidney disease. This study also reports improved treatment related safety profile for ferumoxytol when compared with conventional iron formulations. The findings from this study can have direct implications in forming best practice guidelines for managing anemia in patients with chronic kidney disease.

Abstract Background Episiotomy is a surgical solution to relieve perineal stress, resulting in an easily repairable incision, in comparison to the risks of serious vaginal trauma during delivery. The midwife typically adopts such a clinical decision, on experience and subjective judgment. However, the association between perineal stress and episiotomy is poorly characterized. Our aim was to identify a threshold value for perineal stress leading to episiotomy, which eventually may be employed as a clinical tool for assessing whether an episiotomy is required or not. Methods In total, 245 nulliparous women were investigated for perineal stress during non-instrumental vaginal delivery in Ningbo Women & Children’s Hospital. During the second stage of labor, a flexible membrane stress sensor was placed between the fetal head and perineal wall above the anal fissure. Once the entire fetal head pressed against the sensor, real-time perineal stress was measured, and the peak value was recorded. Cases were divided into non-episiotomy group (n = 173) and episiotomy group (n = 72). The correlations between perineal stress and episiotomy was assessed through logistic regression with adjustment for maternal age, estimated birthweight, duration of second stage of labor, maternal body mass index, and presence of analgesia. Midwives were blinded to all stress measurement values. The predictive value of perineal stress on performing episiotomy was evaluated, together with the ideal cut-off perineal stress value for performing episiotomy. A ROC analysis was also performed. Results The episiotomy group had significantly higher levels of perineal stress in comparison to the non-episiotomy group (140.50 ± 16.03 N versus 118.37 ± 19.21 N, p

Summary: The catalytic conversion of lignin into N-containing chemicals is of great significance for the realization of value-added biorefinery concept. In this article, a one-pot strategy was designed for the transformation of lignin β-O-4 model compounds to imidazo[1,2-a]pyridines in yields up to 95% using 2-aminopyridine as a nitrogen source. This transformation involves highly coupled cleavage of C-O bonds, sp3C-H bond oxidative activation, and intramolecular dehydrative coupling reaction to construction of N-heterobicyclic ring. With this protocol, a wide range of functionalized imidazo[1,2-a]pyridines sharing the same structure skeleton as those commercial drug molecules, such as Zolimidine, Alpidem, Saripidem, etc., were synthesized from different lignin β-O-4 model compounds and one β-O-4 polymer, emphasizing the application feasibility of lignin derivatives in N-heterobicyclic pharmaceutical synthesis.

Background: Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by recurring bone fractures. Some OI patients have other clinical manifestations such as growth retardation, dental abnormalities, blue sclera, and hearing loss. The relationship between the phenotype and genotype of OI is indistinct, and there is no cure for OI. Therefore, an appropriate disease model is urgently needed to understand the pathophysiology of OI. Induced pluripotent stem cells (iPSCs) are capable of developing into three germ layers and have the same genetic background as the donor cells they were derived from; thus, they are an appropriate disease model. Methods: Blood samples collected from the proband and her affected children and one unaffected child were used forgenotyping by whole genome sequencing. A patient-specific iPSC line and a healthy donor iPSC line were generated by reprogramming peripheral blood mononuclear cells with episomal plasmids containing seven transcription factors, namely, OCT4, SOX2, NANOG, LIN28, cMYC, KLF4, and SV40LT. Results: The proband and her two affected children were homozygous for a mutation in collagen type I alpha 1 exon 10, c.725G>T, predicting a p.G242V substitution. A patient-specific iPSC line and a healthy donor iPSC line were generated and characterized in terms of their human embryonic stem cell-like morphology, expression of pluripotency markers, and the ability to differentiate into cells of three germ layers. Conclusions: Here, we report the phenotyping and iPSC disease modeling of an OI family. The detailed phenotyping of the OI family and establishment of iPSCs from an OI patient and healthy family member will provide a powerful tool to evaluate the pathophysiology of OI and develop targeted therapies.

Sinocyclocheilus multipunctatus is a second-class nationally protected wild animal in China. As one of the cavefish, S. multipunctatus has strong adaptability to harsh subterranean environments. In this study, we used PacBio SMRT sequencing technology to generate a first representative full-length transcriptome for S. multipunctatus. Sequence clustering analysis obtained 232,126 full-length transcripts. Among all transcripts, 40,487 were annotated in public databases, while 70,300 microsatellites, 2384 transcription factors, and 16,321 long non-coding RNAs were identified. The phylogenetic tree showed that S. multipunctatus shows a closer relationship to Carassius auratus and Cyprinus carpio, phylogenetically diverging from the common ancestor ~14.74 million years ago (Mya). We also found that between 15.6 and 17.5 Mya, S. multipunctatus also experienced an additional whole-genome duplication (WGD) event, which may have promoted the species evolution of S. multipunctatus. Meanwhile, the overall rates of evolutionary of polyploid S. multipunctatus were significantly higher than those of the other cyprinids, and 220 positively selected genes (PSGs) were identified in two sub-genomes of S. multipunctatus. These PSGs are likely to fulfill critical roles in the process of adapting to diverse cave environments. This study has the potential to facilitate future investigations into the genomic characteristics of S. multipunctatus and provide valuable insights into revealing the evolutionary history of polyploid S. multipunctatus.

In this study, we aim to minimize light loss and achieve high power conversion efficiencies (PCE) in perovskite solar cells (PSCs) by employing a spectral conversion film component with antireflection properties. In our scheme, NaYF4:Tm, Yb, and Gd luminescent nanorod/silica nanosphere-based thin films are applied on CH3NH3PbI3 PSCs to improve the device efficiency. The film was fabricated by spin coating an aged silica sol containing NaYF4:Tm, Yb, and Gd luminescent nanorods. The size and the spectral conversion properties of the NaYF4:Tm, Yb, and Gd luminescent nanorods were controlled by tuning the Gd3+ ion concentration. The microstructure and the transmittance properties of the thin film were controlled by changing the concentration of NaYF4:Tm, Yb, and Gd luminescent nanorod in silica sol. The thin films have excellent spectral conversion properties while exhibiting a maximum transmittance. The photovoltaic performance of PSCs with NaYF4:Tm, Yb, and Gd luminescent nanorod/silica nanosphere-based thin films was systematically investigated. The light transmittance was optimized to 95.1% on a cleaned glass substrate, which resulted in an average increase of about 3.0% across the broadband range of 400–800 nm. The optimized films widen the spectrum of light absorbed by conventional PSC cells and reduce reflections across a broad range, enhancing the photovoltaic performance of PSCs. As a result, the PCE of the PSC increased from 14.51% for the reference device without a thin film to 15.67% for the PSC device with an optimized thin film. This study presents a comprehensive solution to the problem of Fresnel reflection and spectral response mismatch of the PSCs, which provides new ideas for the light management of PSCs.

Abstract Background Chromosome aberrations of 10p monosomy and 10q trisomy resulting from parental pericentric inversion 10 are extremely rare, and to date, very few reports have been published on the matter. Case Presentation A 30-year-old pregnant woman with recurrent pregnancy loss is enrolled in this research. In this pregnancy, spontaneous abortion occurred in the first trimester of her pregnancy. Chromosomal microarray analysis of the abortion tissue showed a partial 10p monosomy (arr[GRCh37] 10p15.3p11.21(100,047_34,848,853) × 1) and a duplication of 10q (arr[GRCh37] 10q26.13q26.3(126,093,990_135,426,386) × 3). Further parental karyotype analysis indicated that the chromosomal abnormalities in the fetus was resulted from paternal pericenric inversion inv(10)(p11.21q26.13). This study presents the first case of a large deletion of 10p combined with 10q trisomy, resulting in pregnancy loss. Of these two manifestations, the large deletion of chromosome 10p may be the primary reason for spontaneous abortion in this subject. Conclusions This study presents the first case of partial 10p monosomy associated with 10q trisomy in Chinese population. It provides more information on the chromosome aberration of 10p monosomy and 10q trisomy and further strengthens the application value of microarray in the molecular etiological diagnosis of recurrent spontaneous abortion.

Abstract Background CRISPR/Cas9-based genome-editing systems have been used to efficiently engineer livestock species with precise genetic alterations intended for biomedical and agricultural applications. Previously, we have successfully generated gene-edited sheep and goats via one-cell-stage embryonic microinjection of a Cas9 mRNA and single-guide RNAs (sgRNAs) mixture. However, most gene-edited animals produced using this approach were heterozygotes. Additionally, non-homozygous gene-editing outcomes may not fully generate the desired phenotype in an efficient manner. Results We report the optimization of a Cas9 mRNA-sgRNA delivery system to efficiently generate homozygous myostatin (MSTN) knockout sheep for improved growth and meat production. Firstly, an sgRNA selection software (sgRNAcas9) was used to preliminarily screen for highly efficient sgRNAs. Ten sgRNAs targeting the MSTN gene were selected and validated in vitro using sheep fibroblast cells. Four out of ten sgRNAs (two in exon 1 and two in exon 2) showed a targeting efficiency > 50%. To determine the optimal CRISPR/Cas9 microinjection concentration, four levels of Cas9 mRNA and three levels of sgRNAs in mixtures were injected into sheep embryos. Microinjection of 100 ng/μL Cas9 mRNA and 200 ng/μL sgRNAs resulted in the most improved targeting efficiency. Additionally, using both the highly efficient sgRNAs and the optimal microinjection concentration, MSTN-knockout sheep were generated with approximately 50% targeting efficiency, reaching a homozygous knockout efficiency of 25%. Growth rate and meat quality of MSTN-edited lambs were also investigated. MSTN-knockout lambs exhibited increased body weight and average daily gain. Moreover, pH, drip loss, intramuscular fat, crude protein, and shear force of gluteal muscles of MSTN-knockout lambs did not show changes compared to the wild-type lambs. Conclusions This study highlights the importance of in vitro evaluation for the optimization of sgRNAs and microinjection dosage of gene editing reagents. This approach enabled efficient engineering of homozygous knockout sheep. Additionally, this study confirms that MSTN-knockout lambs does not negatively impact meat quality, thus supporting the adoption of gene editing as tool to improve productivity of farm animals.

Abstract: To further promote the theoretical research that digital finance effectively supports the high-quality development of the real economy, this paper reviews the current situation of domestic and international research on the connotation of digital finance, the connotation of high-quality development of the real economy, and the influence mechanism of digital finance on high-quality economic development. At present, the research on the connotation of digital finance and the connotation of high-quality development of the real economy at home and abroad has been relatively mature. Domestic and foreign research on the influence mechanism of digital finance on high-quality economic development mainly includes direct influence mechanism featuring capital allocation effect and inclusive effect, and indirect influence mechanism featuring innovative development, coordinated development, green development, open development, shared development, and industrial structure transformation and upgrading as channels. Future research directions include: deepening the research on the indirect influence mechanism of digital finance on the high-quality economic development; deepening the research on the influence mechanism of digital finance on the high-quality development of the real economy.

Abstract Background Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X‐linked dominant, lethal male disorder caused by mutations to the NSDHL (NAD(P)H steroid dehydrogenase‐like protein) gene. It primarily exhibits strictly unilateral congenital hemidysplasia with ichthyosiform erythroderma and ipsilateral limb defects in female individuals. Methods A Chinese couple suffering from recurrent spontaneous abortion in male fetuses was enrolled in this study. Chromosomal microarray analysis and whole‐exome sequencing were performed for genetic etiological diagnosis. Results A 33‐year‐old pregnant woman with recurrent spontaneous abortion was experiencing her third pregnancy with a male embryo. In this pregnancy, a miscarriage occurred at a gestational age of 10+6 weeks with no copy number variants. However, a novel mutation c.790‐6C>T in the NSDHL gene was observed in the fetus through whole‐exome sequencing (WES). Parental verification indicated that the NSDHL gene variant was inherited from the mother. Additionally, the variant in the NSDHL gene was absent in her subsequent pregnancy with a female fetus. Conclusion In this study, we detected c.790‐6C>T, a novel variant in the NSDHL gene that results in recurrent miscarriage in males. Our study may broaden the scope of research on the NSDHL gene in CHILD syndrome and strengthens the application value of WES for the genetic etiological identification of recurrent miscarriage.

IntroductionIntegrin αvβ6, which is upregulated in malignancies and remains absent or weak in normal tissue, is a promising target in molecular imaging therapeutics. In vivo imaging of integrin αvβ6 could therefore be valuable for early tumor detection and intraoperative guidance.MethodsIn this study, integrin αvβ6-targeting probe G2-SFLAP3 was labeled with near-infrared (NIR) dye Cy5.5 or radioisotope 68Ga. The resulting probes were evaluated in integrin αvβ6-positive A549 and αvβ6-negative H1703 xenograft mice models.ResultsThe cellar uptake of G2-SFLAP3-Cy5.5 was consistent with the expression of integrin αvβ6. Both subcutaneous and brain metastatic A549 tumors could be clearly visualized by NIR fluorescent imaging of G2-SFLAP3-Cy5.5. A549 tumors demonstrated the highest G2-SFLAP3-Cy5.5 accumulation at 4h post-injection (p.i.) and remain detectable at 84h p.i. The fluorescent signal of G2-SFLAP3-Cy5.5 was significantly reduced in H1703 and A549-blocking groups. Consistently, small-animal PET imaging showed tumor-specific accumulation of 68Ga-DOTA-G2-SFLAP3.DiscussionG2-SFLAP3 represents a promising agent for noninvasive imaging of non-small cell lung cancer (NSCLC) and brain metastases.

Background Although immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT) therapy have achieved impressive clinical outcomes, majority of patients do not respond to immunotherapy. Tumor-infiltrating T cells, a critical factor to immunotherapy, is dynamically changing. Therefore, a reliable real-time in vivo imaging system for tumor-infiltrating T cells, but not immunohistochemical analyses, will be more valuable to predict response and guide immunotherapy. In this study, we developed a new SPECT/CT imaging probe 99mTc-sum IL-2 targeting the IL-2Rβ/IL-2Rγ (CD122/CD132) receptor on tumor-infiltrating T cells, and evaluated its application in predicting the immune response to anti-PD-L1 (αPD-L1) therapy as well as tracking infused T cells in ACT therapy.Methods The binding affinity of the super mutated IL-2 (sum IL-2) in various T cell subtypes was measured. Sum IL-2 was subsequently labeled with 99mTc through Sortase-A mediated site-specific transpeptidation. SPECT/CT imaging and biodistribution studies of 99mTc-sum IL-2 were performed in a MC38 mouse model. Wild type IL-2 (IL-2) was used as control in the above studies. Finally, we evaluated 99mTc-sum IL-2 SPECT/CT for the detection of tumor-infiltrating T cells in the context of αPD-L1 immunotherapy and ACT therapy.Results Sum IL-2 preferentially bound to CD8+ T cells, especially activated CD8+ T cells, while IL-2 showed biased binding to Treg cells. As a result, 99mTc-sum IL-2 could detect tumor-infiltrating T cells. In the MC38 tumor model, SPECT/CT imaging showed the increased tumor uptake of 99mTc-sum IL-2 after αPD-L1 treatment, suggesting that the treatment significantly increased tumor-infiltrating T cells, resulting in a correspondingly significant curative effect. In addition, 99mTc-sum IL-2 SPECT/CT could also track the infiltration of antigen-specific cytotoxic CD8+ T cells during ACT therapy.Conclusion 99mTc-sum IL-2 has great clinical potential for non-invasive and specific SPECT/CT imaging of tumor-infiltrating T cells as well as for timely prediction and evaluation of the therapeutic efficacy of ICB and ACT therapy.

Background:Helicobacter pylori (Hp) persistent infection is an important pathogenic factor for a series of chronic gastric diseases from chronic gastritis to gastric cancer. Genetic and epigenetic abnormalities of microRNAs may play a vital role in the pathological evolution of gastric mucosa in Helicobacter pylori-related gastric diseases (HPGD). This study aimed to investigate the relationship between miR-146a, miR-196a2, miR-149, miR-499 and miR-27a gene single nucleotide polymorphisms (SNPs) and their expressions with pathological changes in gastric mucosa, and to further analyze the interactions between SNPs and Hp.Methods: Subjects in this study included patients diagnosed with HPGD and healthy controls. MiR-146a rs2910164, miR-196a2 rs11614913, miR-149 rs2292832, miR-499 rs3746444 and miR-27a rs895819 were genotyped by direct sequencing. Fluorescence quantitative PCR was used to detect microRNA expressions. Gene-gene and gene-environment interactions were evaluated by multifactor dimensionality reduction (MDR) method.Results: we found that frequency distribution of miR-196a2 rs11614913 CT genotype in gastric precancerous lesion (GPL) group and gastric cancer (GC) group was significantly higher than normal control (NOR) group [adjusted OR = 6.16, 95%CI (1.46–26.03); adjusted OR = 11.83, 95%CI (1.65–84.72), respectively]. CT genotype and C allele of miR-27a rs895819 were associated with increased risk of GC [adjusted OR = 10.14, 95%CI (2.25–45.77); adjusted OR = 3.71, 95%CI(1.46–9.44), respectively]. The MDR analysis results showed that the interaction between miR-196a2 rs11614913 and Hp was associated with the risk of GPL (p = 0.004). Meanwhile, the expression level of miR-196a2 in GC group was significantly higher than NOR, chronic inflammation (CI) and early precancerous lesion (EPL) groups among Hp-positive subjects. And expressions of miR-499 and miR-27a in GC group were both higher than EPL group. Also, miR-27a expression in GC group was higher than CI and gastric atrophy (GA) groups.Conclusion: miR-196a2 rs11614913 and miR-27a rs895819 may affect the genetic susceptibility to GPL or GC. MiR-196a2 rs11614913 and Hp have a synergistic effect in the occurrence and development of GPL. The up-regulation of miR-499, miR-196a2 and miR-27a expression caused by Hp infection may be an important mechanism of gastric carcinogenesis.