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Blasting is a process in which the chemical energy of explosives is rapidly released, causing strong impact on the rock mass and achieving efficient rock fragmentation. The blasting stress wave and blasting gas generated by explosive detonation are the main driving forces for rock fragmentation. The high peak value and short duration of blasting stress wave are generally referred to as “dynamic action”, the low peak value and long duration of blasting gas are generally referred to as “quasi-static action”. The coupling mechanism between the work done by explosive detonation and the energy consumption of rock fragmentation, as well as the fine control principle of explosive energy release and blast crack propagation, are two key scientific problems that need to be solved in the fundamental theories of rock blasting. The study of “dynamic−static relationship” is one of the important ways to solve key scientific problems. Because of the complexity of the blasting process, traditional blasting design often relies on empirical formulas and field tests, posing problems such as low efficiency, high cost, and uncontrollable safety risk. Traditional designs often only focus on the final crushing effect but ignore the fine control of the blasting process. However, the study of dynamic–static relations has introduced a new approach to solution. This article uses a literature review analysis method to conduct a topic search and analysis of journal papers published in CNKI (China national knowledge infrastructure) and WOS (Science citation index-expanded database) in 2000–2023. The study of the dynamic–static relationship in rock blasting is divided into three different stages: Stages I (before 2006), Ⅱ (2007–2015), and Ⅲ (2016–present). Stage I focuses on the dynamic action of blasting stress waves, revealing the propagation mechanism of blasting stress waves and providing a scientific basis for related engineering applications. Stage Ⅱ studies the crack propagation behavior under the action of blasting stress waves; many studies researched the interaction mechanism between blasting stress waves and cracks and the change in the dynamic stress field at the crack tip, helping relevant researchers to understand the crack propagation and rock fracture process under the action of blasting stress waves. Under a national strategy, Stage Ⅲ has a clear application scenario, and the effect of blasting gas has become the focus of this stage. Through the combination of experiments and numerical simulations, the mechanism of the effect of blasting gas on rock fragmentation, energy transfer, and crack propagation during blasting is deeply discussed. These studies reveal the behavioral characteristics of blasting gas under different conditions and provide theoretical support for practical engineering applications. In addition, authors and research institutions with important contributions to the study of dynamic–static relationships are identified. Keywords and their cooccurrence relationships are revealed, highlighting the focus and trends of the research. Through a systematic review of existing research, combined with the research work and achievements of the author team, the research direction of the dynamic–static relationship in the new era has been clarified, including the distribution and efficient utilization of dynamic–static energy between the blasting stress wave and blasting gas, numerical simulation algorithms considering the real physical processes of rock blasting fracture, and quantitative control of the dynamic–static rock breaking effect of blasting stress waves and blasting gas. The in-depth study of the dynamic–static relationship will promote blasting engineering, from experience-led to theoretical guidance and from extensive to fine.

Rock blasting technology is crucial for national economic development, particularly resource extraction and infrastructure construction. This paper explores the constitutive relationships in rock blasting, proposing three evolutionary stages: constitutive relationships 1.0, 2.0, and 3.0. These stages focus on contradictory relationships, energy balance, and minimum action theory, respectively. Constitutive relationship 1.0 centers on the interaction between rock and explosive impact loads, emphasizing the offense–defense dynamic. It analyzes the dynamic mechanical response of rock materials under explosive and impact loads, highlighting the conflict and balance between the explosive force and the rock resistance. This stage provides fundamental insights into the behavior of rock materials under high-stress conditions. Constitutive relationship 2.0 approaches the problem from an energy perspective. It treats rocks with significant anisotropy, joints, fractures, bedding, and cavities as complex structural materials. This stage studies the dynamic equilibrium between load input energy and the energy required to destroy the material. By understanding the relationship between structural strength, input energy, dissipated energy, and releasable strain energy, researchers can better predict the response of complex rock structures to explosive loads and improve blasting efficiency. Constitutive relationship 3.0 examines the propagation laws of stress waves under explosive loads and their relationship with medium damage effects. This stage focuses on optimizing energy propagation paths based on the minimum action theory, aiming to maximize the effectiveness of the explosive force while minimizing unwanted damage to the surrounding rock mass. These theories not only reveal the mechanical behavior of rocks under different load conditions but also provide a theoretical basis for optimizing blasting design and improving blasting outcomes. In addition to these theoretical advancements, the integration of artificial intelligence and big data technologies offers a new approach to managing and predicting rock material performance. This paper proposes the concept of rock material engineering genes, which involves establishing a rock gene library to systematically manage the physical and mechanical parameters of rocks. By constructing performance prediction models using advanced data analytics and machine learning algorithms, this approach enhances the accuracy of predicting how different rock types will respond to various engineering applications. Such a comprehensive database has significant implications for resource extraction, geological disaster prevention, and infrastructure construction. The rock material gene library is expected to play an increasingly important role in mineral resource development, geological disaster prevention, and infrastructure construction, thereby promoting the development and application of engineering technology. Its integration with traditional blasting techniques can lead to more efficient and safer methods of rock blasting, ultimately contributing to the advancement of engineering practices and economic development of regions dependent on these technologies. This holistic approach underscores the importance of continued research and technological innovation in rock blasting and material science.

Abstract Telomerase reverse transcriptase (Tert) has been found to have a protective effect on telomeric DNA, but whether it could improve the repair of reactive oxygen species (ROS)-induced DNA damage and promote myocardial regenerative repair after myocardial infarction (MI) by protecting telomeric DNA is unclear. The immunofluorescence staining with TEL-CY3 and the TeloTAGGG Telomerase PCR ELISA kit were used to show the telomere length and telomerase activity. The heart-specific Tert-deletion homozygotes were generated by using commercial Cre tool mice and flox heterozygous mice for mating. We measured the telomere length and telomerase activity of mouse cardiomyocytes (CMs) at different days of age, and the results showed that they were negatively correlated with age. Overexpressed Tert could enhance telomerase activity and lengthen telomeres, thereby repairing the DNA damage induced by ROS and promoting CM proliferation in vitro. The in vivo results indicated that enhanced Tert could significantly improve cardiac function and prognosis by alleviating CM DNA damage and promoting angiogenesis post-MI. In terms of mechanism, DNA pulldown assay was used to identify that nuclear ribonucleoprotein A2B1 (hnRNPA2B1) could be an upstream regulator of Tert in CMs. Overexpressed Tert could activate the NF-κB signaling pathway in CMs and bind to the VEGF promoter in the endothelium to increase the VEGF level. Further immunoblotting showed that Tert protected DNA from ROS-induced damage by inhibiting ATM phosphorylation and blocking the Chk1/p53/p21 pathway activation. HnRNPA2B1-activated Tert could repair the ROS-induced telomeric DNA damage to induce the cell cycle re-entry in CMs and enhance the interaction between CMs and endothelium, thus achieving cardiac regenerative repair after MI.

Abstract Background Human health is a complex, dynamic concept encompassing a spectrum of states influenced by genetic, environmental, physiological, and psychological factors. Traditional Chinese Medicine categorizes health into nine body constitutional types, each reflecting unique balances or imbalances in vital energies, influencing physical, mental, and emotional states. Advances in machine learning models offer promising avenues for diagnosing conditions like Alzheimer's, dementia, and respiratory diseases by analyzing speech patterns, enabling complementary non-invasive disease diagnosis. The study aims to use speech audio to identify subhealth populations characterized by unbalanced constitution types. Methods Participants, aged 18–45, were selected from the Acoustic Study of Health. Audio recordings were collected using ATR2500X-USB microphones and Praat software. Exclusion criteria included recent illness, dental issues, and specific medical histories. The audio data were preprocessed to Mel-frequency cepstral coefficients (MFCCs) for model training. Three deep learning models—1-Dimensional Convolution Network (Conv1D), 2-Dimensional Convolution Network (Conv2D), and Long Short-Term Memory (LSTM)—were implemented using Python to classify health status. Saliency maps were generated to provide model explainability. Results The study used 1,378 recordings from balanced (healthy) and 1,413 from unbalanced (subhealth) types. The Conv1D model achieved a training accuracy of 91.91% and validation accuracy of 84.19%. The Conv2D model had 96.19% training accuracy and 84.93% validation accuracy. The LSTM model showed 92.79% training accuracy and 87.13% validation accuracy, with early signs of overfitting. AUC scores were 0.92 and 0.94 (Conv1D), 0.99 (Conv2D), and 0.97 (LSTM). All models demonstrated robust performance, with Conv2D excelling in discrimination accuracy. Conclusions The deep learning classification of human speech audio for health status using body constitution types showed promising results with Conv1D, Conv2D, and LSTM models. Analysis of ROC curves, training accuracy, and validation accuracy showed all models robustly distinguished between balanced and unbalanced constitution types. Conv2D excelled with good accuracy, while Conv1D and LSTM also performed well, affirming their reliability. The study integrates constitution theory and deep learning technologies to classify subhealth populations using noninvasive approach, thereby promoting personalized medicine and early intervention strategies.

This study aimed to investigate the effects of maturity on the changes in major lipid metabolites of coffee and their associated pathways. UPLC-ESI-MS/MS was used to compare the lipidomic profiles of coffee beans at five different maturity stages. A total of 516 lipid metabolites across 26 subclasses were identified, with 111 showing significant differences. Glycerolipids (GL) and fatty acyls (FA) were the most abundant, followed by glycerophospholipids (GP), sphingolipids (SP) and prenol lipids (PR). PCA and OPLS-DA analyses demonstrated significant changes in coffee lipids during maturation. Glycerophospholipid metabolism and glycerolipid metabolism were identified as key metabolic pathways, with phosphatidic acid (PA), lysophosphatidic acid (LPA) and diacylglycerol (DG) as key lipid metabolites in these pathways during coffee maturation. Lipids in immature and overripe beans were significantly different from those in mature coffee beans. This study provides a foundational understanding of lipid transformation and flavor profile formation during coffee maturation.

ObjectiveThis study aimed to assess the viability of a multivariate regression model utilizing ultrasound findings and serum markers for predicting thyroid cancer metastasis.MethodsA retrospective analysis of 98 thyroid patients admitted from January 2022 to October 2022 was conducted to categorize them into a metastasis group (n=20) and a non-metastasis group (n=78) based on postoperative pathological results. Both groups underwent ultrasound examination and serum marker testing. Correlative analysis was performed to explore the association between various indicators and thyroid cancer metastasis. A multivariate regression model was developed, and receiver operating characteristic (ROC) curves were used to assess the predictive value of ultrasound findings, serum markers, and their combination for thyroid cancer metastasis.ResultsStatistically significant differences were found in the levels of ultrasound findings and serum markers between the two groups. Nodule boundaries, presence or absence of halos, margins, lobulation, capsular invasion, surface smoothness, nodule aspect ratio, uric acid, total cholesterol, triglyceride, and LDL cholesterol levels were predictors of metastasis in thyroid cancer. The AUC value of 0.950 for the prediction of thyroid cancer metastasis by ultrasound signs combined with serologic indicators was significantly higher than 0.728 and 0.711 predicted by ultrasound signs or serologic indicators alone.ConclusionThe multivariate regression model incorporating ultrasound findings and serum markers enhances the predictive accuracy for thyroid cancer metastasis, offering essential guidance for early prediction and intervention in a clinical setting.

Purpose: To elucidate the etiology of infectious uveitis through the comprehensive analysis of keratic precipitates (KPs) using in vivo confocal microscopy (IVCM). Design: Cross-sectional, observational case series. Methods: This single-center, cross-sectional study was conducted at a tertiary care eye hospital from January 2021 to October 2023. It involved a detailed ophthalmologic evaluation of all subjects and included a total of 46 eyes from 36 subjects who were diagnosed with infectious uveitis. IVCM, specifically utilizing the HRT II Rostock corneal module, was employed to study the biomicroscopic morphology of KPs. The categorization of KPs was based on cell size, morphology, and reflection. Results: Cells of KPs were assessed for size, morphology, and reflection through in vivo confocal microscopy. Patients, ranging in age from 13 to 80 years (median 51 years), exhibited diverse morphologic forms of KPs. Neutrophil-dominated KPs with uniform size were predominantly observed in bacterial and fungal endophthalmitis cases (19/19, 100 %), accompanied by small numbers of mononuclear-macrophages in three eyes (3/19, 15.8 %). Viral uveitis cases displayed a broader array of immune cell types, including characteristic striated or dendritic cells in all eyes (27/27, 100 %). Lymphocytes were commonly present (24/27, 88.9 %), forming clusters in sixteen eyes and dispersed in the corneal endothelium below the midline in eight eyes. Neutrophil infiltration was notable in three cytomegalovirus-infected eyes (3/27, 11.1 %). A marked increase in sub-basal corneal epithelial Langhans cells was associated with viral uveitis. Conclusions: Neutrophil-dominated KPs strongly indicate endogenous bacterial or fungal endophthalmitis, while the presence of dendritic cells and lymphocytes in KPs is suggestive of viral uveitis. In vivo confocal microscopy emerges as a crucial tool for differentiating the etiologic diagnosis of infectious uveitis.

This study attempted to improve commercial Arabica coffee quality by integrating flavor precursors with anaerobic germination. Using raw coffee beans as materials, anaerobic germination was conducted with 5 g/100 g of flavor precursors (sucrose, glucose, fructose). The chemical composition and sensory quality of roasted coffee beans were analyzed. Results showed that adding flavor precursors facilitated the harmonization of water-soluble chemical components and altered aroma characteristics. Specifically, the inclusion of flavor precursors significantly increased the levels of 5-Hydroxymethylfurfural and volatile aldehydes. Principal component analysis (PCA) on chemical composition dataset revealed 48.7% variability. Sensory analysis, employing the Specialty Coffee Association (SCA) cupping protocol, demonstrated that combining flavor precursors with anaerobic germination transformed coffee flavor properties, enhanced quality, and substantially increased sensory scores (p

The action mechanism of blast shock wave and detonation gas in rock blasting remains unclear. This article attempts to reveal the action mechanism of blast shock wave and detonation gas through high-speed schlieren system, overpressure test system and AUTODYN numerical simulation analysis. 5 cartridges under different explosive types and charge structures were designed, and the dynamic action evolution of detonation products can be visualized from schlieren photos. The action change of blast shock wave and detonation gas in the flow field were compared under the said five conditions. The numerical simulation results were compared with the schlieren experiment results, and the detonation wave process in explosives was reversely deduced. The results showed: the blast shock wave initially expand along with the detonation gas, both propagate outwardly around the point of detonation in a spherical shape. During propagation, the blast shock wave is gradually separated from the detonation gas, and the blast shock wave propagates at a higher velocity compared with the detonation gas. In the scenarios of different charge structures, the features for which the blast shock wave is separated from the detonation gas are varied, the time of separation will shorten as the constraining effect of the cartridge shell intensifies. In the scenarios of different explosive types, the wave patterns of shock wave and detonation gas are essentially the same. However, the velocity and pressure change of shock wave and detonation wave may deviate in the course of propagation, due to different physical and mechanical parameters of explosive materials. In the presence of slot, shock wave and detonation gas will first propagate outwardly from the slot, then the flow is carried out in the other direction, and the pressure and speed in the incision direction will increase, the energy along the slot direction is concentrated and the tube wall is first damaged, resulting in the effect of directional damage. In the numerical simulation, the fluctuation pattern and schear experimental results of explosion shock wave and explosion gas are more consistent in morphology.

The quantitative characterization of post-blast rock damage has been a key problem in the field of engineering blasting, and the process of post-blast rock crack initiation, expansion and evolution until penetration is the main cause of rock rupture. In order to study the evolution process of crack expansion and fracture mode within the blasted rock, the industrial CT was used to scan and observe the rock after the blast, a three-dimensional rock fissure model was constructed through image stack vectorization, and statistically the characteristic parameters of the crack structure were analyzed to quantitatively characterize the degree of rock damage and crack expansion. Combined with numerical simulation to analyze the attenuation law of the explosion shock wave pressure, the SEM scanning test was used to study the micro-morphological characteristics of the rock at different locations during the blasting process, and to compare the correlation mechanism between the change of fracture elemental composition and the fracture mode. The results of the study show that using the equivalent sphere method to statistically analyze the fracture structure at different scales within the rock body, the number of microfractures is large and uniformly distributed, and the main fracture is large in volume and has good connectivity. With the increase of the diameter of the fracture equivalent sphere, the fracture surface area and volume exhibit an increase trend. The fracture rate in the three-dimensional reconstruction of the fracture structure can characterize the local crack expansion characteristics of the rock, the fracture rate and three-dimensional fractal dimension of the near zone of the explosion is much larger than that in the far zone of the explosion, indicating that the fracture expansion in the fracture process of the rock evolution is carried out in this stage. Compared with the far zone of the explosion, the peak pressure is high and slow decay rate, making the entire blasting process of the rock microscopic fracture pattern changes, roughly presenting the direction from the fracture along the crystalline fracture to the fracture through the crystalline fracture, brittle fracture to the direction of plastic damage. The changes in non-metallic elements have a significant impact on the transition of each stage of the fracture pattern, the fracture pattern transition region of the non-metallic elements occurring in an obvious decrease in the content. With the weakening of the blasting effect, the rock rupture gradually tends to be disordered and disorganized, and the fracture is not limited to the deconvoluted surface and grain boundaries during rupture.

Abstract This study investigates the impact of different water coupling coefficients on the blasting effect of red sandstone. The analysis is based on the theories of detonation wave and elastic wave, focusing on the variation in wall pressure of the blasting holes. Using DDNP explosive as the explosive load, blasting tests were conducted on red sandstone specimens with four different water coupling coefficients: 1.20, 1.33, 1.50, and 2.00. The study examines the morphologies of the rock specimens after blasting under these different water coupling coefficients. Additionally, the fractal dimensions of the surface cracks resulting from the blasting were calculated to provide a quantitative evaluation of the extent of rock damage. CT scanning and 3D reconstruction were performed on the post-blasting specimens to visually depict the extent of damage and fractures within the rock. Additionally, the volume fractal dimension and damage degree of the post-blasting specimens are calculated. The findings are then combined with numerical simulation to facilitate auxiliary analysis. The results demonstrate that an increase in the water coupling coefficient leads to a reduction in the peak pressure on the hole wall and the crushing zone, enabling more of the explosion energy to be utilized for crack propagation following the explosion. The specimens exhibited distinct failure patterns, resulting in corresponding changes in fractal dimensions. The simulated pore wall pressure–time curve validated the derived theoretical results, whereas the stress cloud map and explosion energy-time curve demonstrated the buffering effect of the water medium. As the water coupling coefficient increases, the buffering effect of the water medium becomes increasingly prominent.

Variable Speed Limit (VSL) is a promising highway traffic management strategy deployed worldwide. Most algorithms deployed operate based on a set of predefined rules which hinders their ability to perform optimally across diverse traffic conditions. Recent studies applying multi-agent reinforcement learning (MARL) techniques to VSL control problems have shown promising results. However, none of the existing MARL frameworks comply with real-world requirements imposed by most traffic agencies across the United States. In this work, we propose MARVEL (Multi-Agent Reinforcement-learning for large-scale Variable spEed Limits), a novel MARL framework for large-scale VSL highway control with real-world deployment capabilities. MARVEL only relies on sensing information available in most real-world settings and learns through a reward structure that incorporates three abstract goals to ensure reasonable behaviors under different traffic conditions. Through parameter sharing among all VSL agents, the proposed framework scales to cover corridors equipped with multiple VSL gantries. The policies are trained in a microscopic traffic simulation environment, focusing on a short freeway stretch with 8 VSL agents spanning 7 miles. For testing, these policies are applied to a more extensive network with 34 VSL agents spanning 17 miles of Interstate 24 (I-24) near Nashville, Tennessee, the United States. MARVEL improves traffic safety by 63.4% compared to the no-control scenario and enhances traffic mobility by 58.6% compared to a state-of-the-practice algorithm that has been deployed on I-24. Finally, we test the response of the policy learned in simulation with real-world data collected from I-24 and illustrate its deployment capability.

Abstract The Jiali-Chayu fault, situated on the eastern side of the eastern Himalayan syntaxis, is the southeastern margin of the large strike-slip fault zone of the Jiali Fault. The study of the distribution and activity within this fault zone is imperative for a comprehensive understanding of the tectonic movement patterns in the southeastern Tibetan Plateau. Previous studies have established that the kinematic characteristic of the Jiali-Chayu fault diverges significantly from that of other segments within the Jiali fault. Nonetheless, the current tectonic characteristics, including the slip sense, slip rate, and geometric deformation of this fault, are still not well resolved, leading to divergent interpretations regarding its contemporary activity intensity. This paper introduced an optimized time-series InSAR method with phase compensation designed for regions characterized by low coherence and exhibiting slow deformation. Using Sentinel-1 SAR data from both ascending and descending orbits spanning the period between 2017 and 2022, we successfully derived deformation rates for the middle part of the Jiali-Chayu fault at a spatial resolution of 150 m. The slip and dip rates of active faults are determined by considering the fault movement rates from two different observation angles, in conjunction with strike angle and the assumed dip angle of the fault. The results show that the deformation rates of the three branches are very different, with F2-1 and F2-2 exhibiting notable activity, while other areas exhibit relatively weaker activity. The strike-slip rates for F2-1 and F2-2 faults range between 3.6 and 5.3 mm/a and 3.05 to 5.13 mm/a, respectively, while their respective dip-slip rates fall within the range of 1.1–2.7 mm/a and 2.99–5.02 mm/a. In accordance with the fault slip directions, we classify the F2-1 fault as a sinistral (left-lateral) strike-slip fault and the F2-2 fault as a dextral (right-lateral) strike-slip fault. This study addresses a gap in remote sensing methods for detecting active fault activity in this region, providing a systematic foundation for identifying weak activity characteristics within the fault zone. Graphical Abstract

Objective: α-Klotho is a potential biological marker of aging with satisfactory clinical applicability. However, its prognostic significance in age-related diseases has largely been undermined. Therefore, we aimed to report the prognostic value of serum α-klotho levels in age-related diseases. Methods: Participants with available serum α-klotho data from the National Health and Nutrition Examination Survey (2007–2016) were included. Their survival status was collected at 7.62 ± 2.99 years after serum α-klotho data was collected, and the endpoint was all-cause and cardiovascular mortality. A Cox regression model was established to examine the association between serum α-klotho levels and all-cause and cardiovascular mortality. Results: The present study included 13,746 U.S. adults with a survey-weighted mean age of 56.19 ± 10.42 years old. Of these, 52.2 % were female and 72.9 % were non-Hispanic whites. The optimal cutoff value of serum α-klotho for predicting all-cause mortality risk in the general population was 603.5 pg/ml. Individuals with low serum α-klotho (

PurposeTo quantify the global impact of vision impairment in individuals aged 65 years and older between 1990 and 2019, segmented by disease, age, and sociodemographic index (SDI).MethodsUsing the Global Burden of Diseases 2019 (GBD 2019) dataset, a retrospective demographic evaluation was undertaken to ascertain the magnitude of vision loss over this period. Metrics evaluated included case numbers, prevalence rates per 100,000 individuals, and shifts in prevalence rates via average annual percentage changes (AAPCs) and years lived with disability (YLDs).ResultsFrom 1990 to 2019, vision impairment rates for individuals aged 65 years and older increased from 40,027.0 (95% UI: 32,232.9-49,945.1) to 40,965.8 (95% UI: 32,911-51,358.3, AAPC: 0.11). YLDs associated with vision loss saw a significant decrease, moving from 1713.5 (95% UI: 1216.2–2339.7) to 1579.1 (95% UI: 1108.3–2168.9, AAPC: −0.12). Gender-based evaluation showed males had lower global prevalence and YLD rates compared to females. Cataracts and near vision impairment were the major factors, raising prevalence by 6.95 and 2.11%, respectively. Cataract prevalence in high-middle SDI regions and near vision deficits in high SDI regions significantly influenced YLDs variation between 1990 and 2019.ConclusionOver the past three decades, there has been a significant decrease in the vision impairment burden in individuals aged 65 and older worldwide. However, disparities continue, based on disease type, regional SDI, and age brackets. Enhancing eye care services, both in scope and quality, is crucial for reducing the global vision impairment burden among the older adults.

The contamination of bone defects is a serious therapeutic problem. The treatment of infected bone defects involves rigorous infection control followed by bone reconstruction. Considering these two processes, the development of biomaterials possessing antibacterial and osteogenic properties offers a promising approach for the treatment of infected bone defects. In this study, a dual-functional, thermosensitive, and injectable hydrogel composed of chitosan (CS), quaternized CS (QCS), and nano-hydroxyapatite (nHA) was designed, and the ratio of CS to QCS in the hydrogel was optimized to enhance the antibacterial efficacy of CS while reducing the cytotoxicity of QCS. In vitro studies demonstrated that the hydrogel with an 85 %:15 % ratio of CS to QCS exhibited excellent biocompatibility and antibacterial properties while also possessing suitable mechanical characteristics and degradability. The incorporation of nHA into the hydrogel enhanced MC3T3-E1 proliferation and osteogenic differentiation. Moreover, this hydrogel demonstrated superior in vivo therapeutic effectiveness in a rabbit model of infected bone defect. In summary, this study provides a promising material design and a comprehensive one-step treatment strategy for infected bone defects.

“Cutting is the key to speed” in rock roadway excavation. With the aim of addressing the challenges related to broken rock disposal, low single-cycle penetration, and high block rate in the conventional straight hole and diagonal hole excavation blasting, the method of medium-deep holein-hole segmented blasting is proposed herein. The mathematical relations for the force and resistance required in the process of rock crushing and ejection in the groove of medium-deep hole-in-hole segmented blasting, as well as that for the expected value range of the key parameters of the cutting groove, were determined. LS-DYNA was used to numerically simulate the process of medium-deep hole-in-hole and ordinary wedge cut blasting. The nature of stress wave propagation during medium-deep hole-in-hole segmental blasting and the stress characteristics of the rock at the bottom of the hole were analyzed. Furthermore, the variation characteristics of the stress wave intensity were compared for different segmental proportions, and the optimal segmental proportions were determined. The results of theoretical analysis and numerical simulation were applied to the excavation site of the rock roadway, and the blasting effect indices, such as singlecycle footage, hole utilization rate, eye mark rate, and block rate, of the medium-deep hole-in-hole segmented blasting and the ordinary wedge blasting schemes were compared. The results showed that rock can be ejected from the cavity when the dynamic force is greater than or equal to the resistance during the rock crushing and ejection process and that the resistance to rock ejection in the medium-deep holeinhole segmented blasting is less than that in ordinary wedge cut blasting, and it is easier to blast into the cavity. Best practices for achieving the complete ejection of broken rocks from the cavity are proposed, and theoretical support for determining the parameters, such as the depth of the hole, is provided. As compared to ordinary wedge cut blasting, producing a large blasting cavity through medium-deep hole-in-hole segmented blasting is easier, which is more favorable for subsequent blasting. The optimal ratio of the hole-in-hole segmented blasting was initially determined to be 0.6. Medium and deep hole-inhole segmented blasting increases the single-cycle footage, improves the utilization rate of the hole, reduces the working time, reduces construction cost, and has excellent economic and socialadvantages.

Six combinations of layered composite rocks were prepared using sandstone, dali rock, and granite. The composite rock specimens underwent a dynamic impact test using the separated Hopkinson pressure rod test system, and the failure patterns of the specimens were recorded using high-speed cameras. The dynamic fracture mode, wave impedance effect, and energy dissipation nature of these composite rock specimens were analyzed, and the relationship between their kinetic energy and fracture energy was explored. The discrete lattice spring model was used to simulate the dynamic fracture process of the composite rock specimens, and the stress wave propagation characteristics and stress and damage evolution nature of the composite specimens were analyzed. The results show that the dynamic fracture characteristics of composite rock materials are strongly influenced by the uppermost and lowermost layer materials. When the dynamic cracking toughness of the material in the lower layer is low, the crack can maintain a high propagation speed and requires a short time from initiation to expansion to the rock cemented surface. The upper layer material has a greater influence on the stress conduction of the composite rock specimen. The overall transmission capacity depends on the upper layer material such that the greater its density, the more conducive it is to wave transmission and the better the stress conduction. The greater the difference in the densities of the lower and upper layer materials, the greater the difference between the stresses at the upper and lower ends of the rock cemented surface. Wave impedance has a significant effect on the propagation behavior of the stress wave. The propagation speed of the stress wave in the composite specimen is influenced by the porosity and density of the material. The larger the wave impedance, the faster the propagation speed of the stress wave, the larger the transmission coefficient, and the higher the energy transmitted. When energy is dissipated, the density, kinetic energy, and fracture energy of the composite rock specimen are influenced by the densities of the materials in the upper and lower layers. If the lower layer material is unchanged, a higher density of the upper layer material results in a smaller density and fracture energy when the energy is dissipated, yielding more kinetic energy when the specimen is completely fractured. When the upper layer material remains unchanged and the density of the lower material is increased, the cutting tip is more likely to crack, and the density and fracture energy are smaller when the energy is dissipated.

Unmanned Aerial Vehicle (UAV) aerial recovery is a challenging task due to the limited maneuverability of both the transport aircraft and the UAV, making it difficult to establish an effective capture connection in the airflow field. In previous studies, we proposed using a Cable-Driven Parallel Robot (CDPR) for active interception and recovery of UAVs. However, during the aerial recovery process, the CDPR is continuously subjected to aerodynamic loads, which significantly affect the stiffness characteristics of the CDPR. This paper conducts a stiffness analysis of a single cable and a CDPR in a flow field environment. Firstly, we derive the stiffness matrix of a single cable based on a model that considers aerodynamic loads. The CDPR is then divided into elements using the finite element method (FEM), and the stiffness matrix for each element is obtained. These element stiffness matrices are assembled to form the stiffness matrix of the CDPR system. Secondly, we analyze the stiffness distribution of a single cable at various equilibrium positions within a flow field environment. Aerodynamic loads were observed to alter the equilibrium position of the cable, thereby impacting its stiffness. The more the cable bends, the greater the reduction in its stiffness. We examine the stiffness distribution characteristics of the CDPR’s end-effector within its workspace and analyze the impact of varying flow velocities and different cable materials on the system’s stiffness. This research offers a methodology for analyzing the stiffness of CDPR systems operating in a flow field environment.

With the increase of the depth of the blast hole, the rock clamping effect at the bottom of the blast hole is enhanced, resulting in low rock breaking efficiency and blast hole utilization. The past continuous charging method can not solve the above problems. On this basis, this paper studies the rock roadway deep hole segmented charging cut blasting technology to improve the cut blasting efficiency. Using the smooth particle hydrodynamics-finite element method (SPH-FEM), a single-hole cut blasting model with different segmented charge structures was established, and the blasting speed of rock particles in the rock, the number of rock blasting and the characteristics of blasting cavity were analyzed in the blasting process under different models. The results show that different charge structures affect the damage range of the rock near the blast hole, and the damage area of the traditional continuous charge structure in the direction of the blast hole is larger than that of the segmented charge structure. In addition, the continuous charge structure makes the energy distribution of the explosive uneven because the explosive is concentrated at the bottom of the blast hole, resulting in poor blasting effect. The segmented charge structure can increase the number of rock fragments and optimize the blasting cavity, and the rock particles accelerate twice in the process of flying. The large or small proportion of the first segment charge obviously causes the unreasonable use of explosive energy and the poor effect of blasting cavity. Under the conditions of blast hole length, rock parameters and explosive performance set in the simulation, when the first stage charge ratio is 0.4, deep-hole rock tunnel excavation and blasting can make full use of explosive energy to achieve better cut blasting effect. The optimal subsection ratio obtained by numerical simulation was applied to the blasting construction of roadway excavation, and the delay initiation of two explosives in the cut hole was realized by using digital electronic detonator. The field test results show that the segmented charging can create good blasting effect and improve the utilization rate of blast holes in deep hole cut blasting.

With the increasing incidence of bone defects in clinical practice, the demand for bone grafts or substitutes has become more urgent. Polydopamine (PDA)-coated bone tissue engineering materials offer a promising alternative in such cases. PDA coating is characterized by a solid coating formed by polymerization of dopamine under alkaline and oxygen-containing conditions, which can provide implants good hydrophilicity through the active functional groups contained in the structure. More importantly, the strong adhesion of the coating can provide an anchor between bone implant materials and drugs to achieve functional modification of the implant surface to enhance bone regeneration. In this review, the different effects of dopamine derivatives and their polymerization in current research were summarized. The mechanisms underlying the effects of PDA in promoting bone regeneration have also discussed in detail, providing a theoretical basis for the clinical application of PDA. Finally, a series of PDA-coated materials for the promotion of bone repair have been summarized and discussed. This review provides cutting-edge design ideas for PDA-based biomaterials and highlights promising treatment strategies for bone defects.

The treatment of bone defects is a difficult problem in orthopedics. The excessive destruction of local bone tissue at defect sites destroys blood supply and renders bone regeneration insufficient, which further leads to delayed union or even nonunion. To solve this problem, in this study, we incorporated icariin into alginate/mineralized collagen (AMC) hydrogel and then placed the drug-loaded hydrogel into the pores of a 3D-printed porous titanium alloy (AMCI/PTi) scaffold to prepare a bioactive scaffold with the dual functions of promoting angiogenesis and bone regeneration. The experimental results showed that the ACMI/PTi scaffold had suitable mechanical properties, sustained drug release function, and excellent biocompatibility. The released icariin and mineralized collagen (MC) synergistically promoted angiogenesis and osteogenic differentiation in vitro. After implantation into a rabbit radius defect, the composite scaffold showed a satisfactory effect in promoting bone repair. Therefore, this composite dual-functional scaffold could meet the requirements of bone defect treatment and provide a promising strategy for the repair of large segmental bone defects in clinic.

[This corrects the article DOI: 10.1371/journal.pgen.1010751.].

Background: Alzheimer’s disease (AD) is a condition that affects the nervous system and that requires considerably more in-depth study. Abnormal Nicotinamide Adenine Dinucleotide (NAD+) metabolism and disulfide levels have been demonstrated in AD. This study investigated novel hub genes for disulfide levels and NAD+ metabolism in relation to the diagnosis and therapy of AD. Methods: Data from the gene expression omnibus (GEO) database were analyzed. Hub genes related to disulfide levels, NAD+ metabolism, and AD were identified from overlapping genes for differentially expressed genes (DEGs), genes in the NAD+ metabolism or disulfide gene sets, and module genes obtained by weighted gene co-expression network analysis (WGCNA). Pathway analysis of these hub genes was performed by Gene Set Enrichment Analysis (GSEA). A diagnostic model for AD was constructed based on the expression level of hub genes in brain samples. CIBERSORT was used to evaluate immune cell infiltration and immune factors correlating with hub gene expression. The DrugBank database was also used to identify drugs that target the hub genes. Results: We identified 3 hub genes related to disulfide levels in AD and 9 related to NAD+ metabolism in AD. Pathway analysis indicated these 12 genes were correlated with AD. Stepwise regression analysis revealed the area under the curve (AUC) for the predictive model based on the expression of these 12 hub genes in brain tissue was 0.935, indicating good diagnostic performance. Additionally, analysis of immune cell infiltration showed the hub genes played an important role in AD immunity. Finally, 33 drugs targeting 10 hub genes were identified using the DrugBank database. Some of these have been clinically approved and may be useful for AD therapy. Conclusion: Hub genes related to disulfide levels and NAD+ metabolism are promising biomarkers for the diagnosis of AD. These genes may contribute to a better understanding of the pathogenesis of AD, as well as to improved drug therapy.

PurposeThe imaging diagnosis of fracture-related infection is often challenging. The aim of this study was to evaluate the value of 18F-FDG PET/CT for the diagnosis of fracture-related infection (FRI) with internal fixation after orthopedic surgery in lower extremities.MethodsA total of 254 consecutive patients who underwent 18F-FDG PET/CT scans with suspected FRI with internal fixation in lower extremities were retrospectively investigated 18F-FDG PET/CT images were semiquantitatively evaluated with multiple metabolic parameters. Additionally, morphological information of the inguinal draining lymph nodes (DLN) with the highest SUV value was also collected and analyzed.ResultsPatients were divided into two groups according to final diagnosis: the infected (N=197) and the non-infected group (N=57). The differences in the inguinal DLN-related parameters, including the long diameter, short diameter, maximum cross-sectional area, maximum standardized uptake value (SUVmax), metabolic volume (MV) 60%, MV70%, MV80%, total lesional glycolysis (TLG) 60%, TLG70%, TLG80%, and the infection suspected area related parameters, including SUVmax, MV25%, MV30%, MV35%, MV40%, MV50%, and TLG70%, between the two groups were statistically significant. We then compared the highest area under the curves (AUCs) among the morphological parameters of DLN, metabolic parameters of DLN, and metabolic parameters of the suspected infection area. The result demonstrated that SUVmax of the inguinal DLN showed the best diagnostic performance with an AUC of 0.939 (P

Bisphosphonates (BPs), the stable analogs of pyrophosphate, are well-known inhibitors of osteoclastogenesis to prevent osteoporotic bone loss and improve implant osseointegration in patients suffering from osteoporosis. Compared to systemic administration, BPs-incorporated coatings enable the direct delivery of BPs to the local area, which will precisely enhance osseointegration and bone repair without the systemic side effects. However, an elaborate and comprehensive review of BP coatings of implants is lacking. Herein, the cellular level (e.g., osteoclasts, osteocytes, osteoblasts, osteoclast precursors, and bone mesenchymal stem cells) and molecular biological regulatory mechanism of BPs in regulating bone homeostasis are overviewed systematically. Moreover, the currently available methods (e.g., chemical reaction, porous carriers, and organic material films) of BP coatings construction are outlined and summarized in detail. As one of the key directions, the latest advances of BP-coated implants to enhance bone repair and osseointegration in basic experiments and clinical trials are presented and critically evaluated. Finally, the challenges and prospects of BP coatings are also purposed, and it will open a new chapter in clinical translation for BP-coated implants.

Abstract Drilling and blasting methods have been used as a common driving technique for shallow-hole driving and blasting in rock roadways. With the advent of digital electronic detonators and the need for increased production efficiency, the traditional blasting design is no longer suitable for deep hole blasting. In this paper, a disperse charge cut blasting method was proposed to address the issues of low excavation depth and high block rate in deep hole undercut blasting. First, a blasting model was used to illustrate the mechanism of the deep hole dispersive charge cut blasting process. Then, continuous charge and dispersed charge blasting models were developed using the smooth particle hydrodynamics-finite element method (SPH-FEM). The cutting parameters were determined theoretically, and the cutting efficiency was introduced to evaluate the cutting effect. The blasting effects of the two charging models were analyzed utilizing the evolution law of rock damage, the number of rock particles thrown, and the cutting efficiency. The results show that using a dispersed charge improves the cutting efficiency by about 20% and the rock breakage for the deep hole cut blasting compared to the traditional continuous charge. In addition, important parameters such as cutting hole spacing, cutting hole depth and upper charge proportion also have a significant impact on the cutting effect. Finally, the deep hole dispersed charge cut blasting technology is combined with the digital electronic detonator through the field engineering practice. It provides a reference for the subsequent deep hole cutting blasting and the use of electronic detonators in rock roadways.

Abstract We investigate the circumstances under which socially responsible investing (SRI) enhances firm long-term financial performance, and therefore provides incentives for firms to self-regulate their environmental performance. Aggregating portfolios across SRI mutual funds, we estimate the effect of SRI investment with environmental screening criteria on firm cost of equity capital. We find that accounting for interactions between firm and non-shareholder stakeholders, and potential agency costs associated with certain environmental activities of the firm, SRI can facilitate the alignment of firms’ environmental and financial goals. We also find that an industry group’s environmental performance and diversity influence the extent to which a firm in that group can benefit from SRI investment.

Abstract Common variants in RET and NRG1 have been associated with Hirschsprung disease (HSCR), a congenital disorder characterised by incomplete innervation of distal gut, in East Asian (EA) populations. However, the allelic effects so far identified do not fully explain its heritability, suggesting the presence of epistasis, where effect of one genetic variant differs depending on other (modifier) variants. Few instances of epistasis have been documented in complex diseases due to modelling complexity and data challenges. We proposed four epistasis models to comprehensively capture epistasis for HSCR between and within RET and NRG1 loci using whole genome sequencing (WGS) data in EA samples. 65 variants within the Topologically Associating Domain (TAD) of RET demonstrated significant epistasis with the lead enhancer variant (RET+3; rs2435357). These epistatic variants formed two linkage disequilibrium (LD) clusters represented by rs2506026 and rs2506028 that differed in minor allele frequency and the best-supported epistatic model. Intriguingly, rs2506028 is in high LD with one cis-regulatory variant (rs2506030) highlighted previously, suggesting that detected epistasis might be mediated through synergistic effects on transcription regulation of RET. Our findings demonstrated the advantages of WGS data for detecting epistasis, and support the presence of interactive effects of regulatory variants in RET for HSCR.

Shape is a primary determinant of consumer preference for many horticultural crops and it is also associated with many aspects of marketing, harvest mechanics, and postharvest handling. Perceptions of quality and preference often map to specific shapes of fruits, tubers, leaves, flowers, roots, and other plant organs. As a result, humans have greatly expanded the palette of shapes available for horticultural crops, in many cases creating a series of market classes where particular shapes predominate. Crop wild relatives possess organs shaped by natural selection, while domesticated species possess organs shaped by human desires. Selection for visually-pleasing shapes in vegetable crops resulted from a number of opportunistic factors, including modification of supernumerary cambia, allelic variation at loci that control fundamental processes such as cell division, cell elongation, transposon-mediated variation, and partitioning of photosynthate. Genes that control cell division patterning may be universal shape regulators in horticultural crops, influencing the form of fruits, tubers, and grains in disparate species. Crop wild relatives are often considered less relevant for modern breeding efforts when it comes to characteristics such as shape, however this view may be unnecessarily limiting. Useful allelic variation in wild species may not have been examined or exploited with respect to shape modifications, and newly emergent information on key genes and proteins may provide additional opportunities to regulate the form and contour of vegetable crops.

Ecosystem carbon flux components, including ecosystem gross primary productivity (GPP), ecosystem respiration (ER), and net ecosystem productivity (NEP), are the most direct indicators of ecosystem production capacity, carbon sequestration, and climate regulation strength. Nevertheless, little is known about how water availability affects the temperature responses of carbon flux components in water-limited ecosystems. Based on a long-term eddy observation dataset of temperate grasslands in northern China, we analyzed the effects of drought on the optimum temperature of carbon flux components ( $T_{{\text{opt}}}^{{\text{flux}}}$ ) in temperate grassland ecosystems and clarified the relative contributions of vegetation and climate factors to $T_{{\text{opt}}}^{{\text{flux}}}$ . We found that the optimum temperatures of carbon flux components were widespread across different grassland types, with a significant lower optimum temperature of NEP ( $T_{{\text{opt}}}^{{\text{NEP}}}$ , 17.32 ± 3.21 °C) than that of GPP ( $T_{{\text{opt}}}^{{\text{GPP}}}$ , 18.67 ± 2.53 °C) and ER ( $T_{{\text{opt}}}^{{\text{ER}}}$ , 19.30 ± 1.94 °C). Drought significantly reduced $T_{{\text{opt}}}^{{\text{NEP}}}$ , but had no significant effects on ${\text{T}}_{{\text{opt}}}^{{\text{GPP}}}\,$ and $T_{{\text{opt}}}^{{\text{ER}}}$ . Obvious shifts of occurrence date of $T_{{\text{opt}}}^{{\text{flux}}}$ were also observed in the years with different precipitation regimes. That is, $T_{{\text{opt}}}^{{\text{GPP}}}$ and $T_{{\text{opt}}}^{{\text{NEP}}}$ occurred significantly earlier than seasonal maximum temperature ( ${T_{{\text{max}}}}$ ) in the dry years, while $T_{{\text{opt}}}^{{\text{flux}}}$ significantly lagged behind the occurrence of ${T_{{\text{max}}}}$ in the wet years. Water availability and vegetation factors co-regulated the spatiotemporal variations of $T_{{\text{opt}}}^{{\text{flux}}}$ . In the dry years, precipitation and soil water content predominated the changes in $T_{{\text{opt}}}^{{\text{GPP}}}$ and $T_{{\text{opt}}}^{{\text{ER}}}$ , whereas vegetation structure (leaf area index) and physiological characteristics played a more important role in the wet years. Our study not only provided the first evidence for the widespread existence of $T_{{\text{opt}}}^{{\text{flux}}}$ of different carbon fluxes, but also addressed the remarkable impacts of drought on $T_{{\text{opt}}}^{{\text{flux}}}$ and their occurrence date in the water-limited grasslands. Therefore, incorporating the unimodality of these observed temperature responses of ecosystem carbon fluxes into land carbon models is necessary for improving the accuracy of carbon sequestration predictions.

A blasting experiment was conducted on iron ore samples by considering multiple coupling charge coefficients. The resulting internal fracture and damage characteristics were quantitatively analyzed via computerized tomography (CT), scanning, and three-dimensional (3D) model reconstruction. The results show that the iron ore primarily displayed radial and circumferential cracks along the blast hole under an explosive load. When the decoupling coefficient was small, the crack surface was dominated by transgranular fractures in the form of intracrystalline fractures. As the uncoupling coefficient increased, the crack surface exhibited transgranular and intergranular coupled fracture modes. Using fractal theory to analyze crack distribution characteristics, as the decoupled coefficient increased, the body fractal dimension tended to decrease, and the degree of damage gradually decreased. The degree of damage reached a turning point when the decoupling charge coefficient was approximately 1.33. A numerical simulation suggested that the explosion energy transmitted to the iron ore and the effective stress decrease sharply when the decoupling coefficient exceeds 1.33. In some optimal uncoupling coefficient range, excessive fragmentation of the ore body is prevented, thereby allowing full use of the explosive energy.

Methyl salicylate is an important inter- and intra-plant signaling molecule, but is deemed undesirable by humans when it accumulates to high levels in ripe fruits. Balancing the tradeoff between consumer satisfaction and overall plant health is challenging as the mechanisms regulating volatile levels have not yet been fully elucidated. In this study, we investigated the accumulation of methyl salicylate in ripe fruits of tomatoes that belong to the red-fruited clade. We determine the genetic diversity and the interaction of four known loci controlling methyl salicylate levels in ripe fruits. In addition to Non-Smoky Glucosyl Transferase 1 (NSGT1), we uncovered extensive genome structural variation (SV) at the Methylesterase (MES) locus. This locus contains four tandemly duplicated Methylesterase genes and genome sequence investigations at the locus identified nine distinct haplotypes. Based on gene expression and results from biparental crosses, functional and non-functional haplotypes for MES were identified. The combination of the non-functional MES haplotype 2 and the non-functional NSGT1 haplotype IV or V in a GWAS panel showed high methyl salicylate levels in ripe fruits, particularly in accessions from Ecuador, demonstrating a strong interaction between these two loci and suggesting an ecological advantage. The genetic variation at the other two known loci, Salicylic Acid Methyl Transferase 1 (SAMT1) and tomato UDP Glycosyl Transferase 5 (SlUGT5), did not explain volatile variation in the red-fruited tomato germplasm, suggesting a minor role in methyl salicylate production in red-fruited tomato. Lastly, we found that most heirloom and modern tomato accessions carried a functional MES and a non-functional NSGT1 haplotype, ensuring acceptable levels of methyl salicylate in fruits. Yet, future selection of the functional NSGT1 allele could potentially improve flavor in the modern germplasm.

Peptide-based hydrogels are widely studied and applied in bone repair because of their good biocompatibility, biodegradability and designability. Peptide-based hydrogels can be endowed with different properties by introducing biologically functional groups into the peptide chain and adjusting the composition of the peptide-based hydrogels. In addition, in combination with growth factors, cells, and other scaffold materials, the peptide-based hydrogels can meet the needs of bone repair under different conditions. Therefore, we first analyzed the expected properties of peptide-based hydrogels in bone repair and methods to obtain these properties. Then, we focused on the applications in bone repair, especially the repair scheme based on peptide-based hydrogels for different types of bone defects. Peptide-based hydrogels can be used alone to fill bone defects, playing a role in bone conduction. The peptide-based hydrogels can also be used as a sustained-release carrier for cells, drugs, and the like, to improve the microenvironment of local bone regeneration and enhance the bone regeneration capacity. In addition, peptide-based hydrogels can provide solutions for repairing large segmental and weight-bearing bone defects by incorporating other scaffold materials. This review will provide the theoretical basis and cutting-edge design strategies for peptide-based hydrogels to promote the repair of bone defects.

The development of interdisciplinary biomedical engineering brings significant breakthroughs to the field of cartilage regeneration. However, cartilage defects are considerably more complicated in clinical conditions, especially when injuries occur at specific sites (e.g., osteochondral tissue, growth plate, and weight-bearing area) or under inflammatory microenvironments (e.g., osteoarthritis and rheumatoid arthritis). Therapeutic implantations, including advanced scaffolds, developed growth factors, and various cells alone or in combination currently used to treat cartilage lesions, address cartilage regeneration under abnormal conditions. This review summarizes the strategies for cartilage regeneration at particular sites and pathological microenvironment regulation and discusses the challenges and opportunities for clinical transformation.

Background: Alzheimer’s disease (AD) occurs in the elderly and pre-elderly, characterized by decline of memory, cognitive dysfunction, impairment of learning capacity, and motor dysfunction. Recently a competitive endogenous RNA (ceRNA) network has been found to be related to AD progression, but there is still little understanding of the ceRNA regulatory network in AD. This study aims to explore the important regulatory mechanisms of ceRNA regulatory networks containing long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in AD. Methods: Data from the gene expression omnibus (GEO) database were used for the analysis. To study enrichment function for the upregulated and downregulated mRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the Metascape database, respectively. Based on the STRING database and Cytoscape software 3.9.1, a protein-protein interaction (PPI) network was constructed. The hub genes in this network were identified utilizing the CytoHubba plugin in Cytoscape. The TargetScan, miRWalk, and miRDB were selected to calculate the regulatory interaction between miRNAs and the hub genes. LncRNAs were predicted using RNA22. Additionally, circRNA prediction was executed using the circBank database. Results: 711 downregulated and 670 upregulated overlapping mRNAs were identified between AD and control samples. 32 downregulated and 340 upregulated miRNAs were obtained from AD samples compared with control samples. 78 upregulated and 205 downregulated circRNAs were screened. 275 upregulated lncRNAs and 209 downregulated lncRNAs were found between AD samples and control samples. The PPI network constructed consists of 1016 nodes and 13,946 edges. Ten hub genes were selected to identify target miRNAs and ceRNAs. On the basis of the ceRNA hypothesis, a circRNA/lncRNA-miRNA-mRNA network was established. It included five lncRNAs (TRHDE-AS1, SNHG10, OIP5-AS, LINC00926 and LINC00662), 26 circRNAs, five miRNAs (hsa-miR-3158-3p, hsa-miR-4435, hsa-let-7d-3p, hsa-miR-330-5p and hsa-miR-3605-3p), and ten mRNAs (RPL11, RPL34, RPL21, RPL22, RPL6, RPL32, RPL24, RPL35, RPL31, and RPL35A). RPL35 and RPL35A were found to be significantly associated with AD pathology in tau and Aβ line AD models by the AlzData database. The study discovered the significance of several lncRNA-miRNA-mRNA axes and circRNA-miRNA-mRNA axes that included RPL35A and RPL35. Conclusions: ceRNAs were found to be important regulators in the development of AD and provide potential biological therapy targets for AD management.

Familial hypercholesterolemia (FH) is a frequently occurring genetic disorder that is linked to early-onset cardiovascular disease. If left untreated, patients with this condition can develop severe cardiovascular complications. Unfortunately, many patients remain undiagnosed, and even when diagnosed, the treatment is often not optimal. Although mutations in the LDLR gene are the primary cause of FH, predicting whether novel variants are pathogenic is not a straightforward task. Understanding the functionality of LDLR variants is crucial in uncovering the genetic basis of FH. Our study utilized CRISPR/Cas9 cytosine base editors in pooled screens to establish a novel approach for functionally assessing tens of thousands of LDLR variants on a large scale. A total of more than 100 single guide RNAs (sgRNAs) targeting LDLR pathogenic mutations were successfully screened with relatively high accuracy. Out of these, 5 sgRNAs were further subjected to functional verification studies, including 1 in the promoter, 1 in the antisense RNA, 1 in the exon, and 2 in the intron. Except for the variant caused by the sgRNA located at intron 16, the functionalities of the other LDLR variants were all downregulated. The high similarity of LDLR intron sequences may lead to some false positives. Overall, these results confirm the reliability of the large-scale screening strategy for functional analysis of LDLR variants, and the screened candidate pathogenic mutations could be used as an auxiliary means of clinical gene detection to prevent FH-induced heart disease.

This study aimed to improve the brewing quality of commercial Arabica coffee through anaerobic germination. Changes in important compounds and cupping scores of germination roasting coffee with different germination degrees were investigated by 1H NMR, HS-SPME-GC-MS and sensory analysis. Statistical analysis of multivariate analysis results indicated that 6 water-soluble chemical components and 8 volatile chemical components have the potential to be markers of germinated roasting coffee. In addition, germination significantly reduced caffeine content and acrylamide formation in roasted coffee. Sensory analysis according to the Specialty Coffee Association (SCA) cupping protocol demonstrated that anaerobic germination modified flavor attributes, improved the quality, and increased sensory scores. Furthermore, anaerobic sprouting increased fruity descriptors, but over-sprouting did not improve overall attributes while producing both fermentative and vegetable descriptors. Therefore, suitable anaerobic germination of green coffee beans can be used as a new strategy to improve the flavor of commercial Arabica coffee.

As a robust antagonist of myostatin (MSTN), follistatin (FST) is an important regulator of skeletal muscle development, and the delivery of FST to muscle tissue represents a potential therapeutic strategy for muscular dystrophies. The N terminus and FSI domain of FST are the functional domains for MSTN binding. Here, we aimed to achieve site-specific integration of FSI-I-I, including the signal peptide, N terminus, and three FSI domains, into the last codon of the porcine MSTN gene using a homology-mediated end joining (HMEJ)-based strategy mediated by CRISPR-Cas9. Based on somatic cell nuclear transfer (SCNT) technology, we successfully obtained FSI-I-I knockin pigs. H&E staining of longissimus dorsi and gastrocnemius cross-sections showed larger myofiber sizes in FSI-I-I knockin pigs than in controls. Moreover, the Smad and Erk pathways were inhibited, whereas the PI3k/Akt pathway was activated in FSI-I-I knockin pigs. In addition, the levels of MyoD, Myf5, and MyoG transcription were upregulated while that of MRF4 was downregulated in FSI-I-I knockin pigs. These results indicate that the FSI-I-I gene mediates skeletal muscle hypertrophy through an MSTN-related signaling pathway and the expression of myogenic regulatory factors. Overall, FSI-I-I knockin pigs with hypertrophic muscle tissue hold great promise as a therapeutic model for human muscular dystrophies.

The treatment of infected bone defects is an intractable problem in orthopedics. It comprises two critical parts, namely that of infection control and bone defect repair. According to these two core tasks during treatment, the ideal approach of simultaneously controlling infection and repairing bone defects is promising treatment strategy. Several engineered biomaterials and drug delivery systems with dual functions of anti-bacterial action and ostogenesis-promotion have been developed and demonstrated excellent therapeutic effects. Compared with the conventional treatment method, the dual-functional composite scaffold can provide one-stage treatment avoiding multiple surgeries, thereby remarkably simplifying the treatment process and reducing the treatment time, overcoming the disadvantages of conventional bone transplantation. In this review, the impaired bone repair ability and its specific mechanisms in the microenvironment of pathogen infection and excessive inflammation were analyzed, providing a theoretical basis for the treatment of infectious bone defects. Furthermore, we discussed the composite dual-functional scaffold composed of a combination of antibacterial and osteogenic material. Finally, a series of advanced drug delivery systems with antibacterial and bone-promoting capabilities were summarized and discussed. This review provides a comprehensive understanding for the microenvironment of infectious bone defects and leading-edge design strategies for the antibacterial and bone-promoting dual-function scaffold, thus providing clinically significant treatment methods for infectious bone defects.

The coronoid process of the ulna, as a key part of the elbow joint, plays an important role in maintaining elbow joint stability. Reconstruction of the coronoid process is necessary in both acute and chronic coronoid defects to restore elbow stability and avoid early joint degeneration. The olecranon tip may be a useful autologous osteochondral graft for reconstructing the same shape of the ulna coronoid process. The purpose of this report was to verify if reconstruction of the coronoid process with the olecranon tip can restore elbow stability and kinematics. Here, we report a 13-year-old boy who had undergone Kirschner-wire fixation for a left supracondylar fracture of the left humerus 9 years previously. After that, the right elbow dislocation and varus deformity gradually appeared. Imaging revealed posterolateral dislocation of the left elbow due to the absence of the coronoid process of the ulna. We reconstructed the ulnar coronoid process by intercepting the ipsilateral olecranon tip. After 22 months of follow-up, the range of motion of the left elbow joint was normal, and the cubitus varus deformity disappeared. The results of this report suggest that olecranon tip autografts are suitable to replace transverse coronoid defects. Given the patient's satisfactory clinical results, this reconstruction technique is safe and effective for the treatment of chronic elbow instability due to coronoid process defects of the ulna.

The large incidence of bone defects in clinical practice increases not only the demand for advanced bone transplantation techniques but also the development of bone substitute materials. A variety of emerging bone tissue engineering materials with osteogenic induction ability are promising strategies for the design of bone substitutes. MicroRNAs (miRNAs) are a class of non-coding RNAs that regulate intracellular protein expression by targeting the non-coding region of mRNA3′-UTR to play an important role in osteogenic differentiation. Several miRNA preparations have been used to promote the osteogenic differentiation of stem cells. Therefore, multiple functional bone tissue engineering materials using miRNA as an osteogenic factor have been developed and confirmed to have critical efficacy in promoting bone repair. In this review, osteogenic intracellular signaling pathways mediated by miRNAs are introduced in detail to provide a clear understanding for future clinical treatment. We summarized the biomaterials loaded with exogenous cells engineered by miRNAs and biomaterials directly carrying miRNAs acting on endogenous stem cells and discussed their advantages and disadvantages, providing a feasible method for promoting bone regeneration. Finally, we summarized the current research deficiencies and future research directions of the miRNA-functionalized scaffold. This review provides a summary of a variety of advanced miRNA delivery system design strategies that enhance bone regeneration.

BackgroundProximal humeral fractures (PHFs) are rare in children. Currently, the recommended surgical methods for severely displaced PHFs are closed reduction and percutaneous fixation using K-wires or intramedullary nailing, which can't provide firm internal fixation, especially for older and high-weight children. This study aimed to introduce a novel surgical approach, pediatric physeal slide-traction plate fixation (PPSP), for Neer–Horwitz grade IV PHFs in children.Case summaryA 9-year-old boy presented with left shoulder pain and swelling due to a car accident. Physical examination revealed a positive shoulder deformity and local tenderness. On physical examination, we palpated bone friction without vascular and nerve damage. Based on imaging findings, we diagnosed Neer-Horwitz grade IV PHF. In view of the patient's condition, we performed PPSP after careful communication with the patient's parents. After 22 months of follow-up, the patient's left shoulder function was satisfactory, and there was no restriction of activities.ConclusionAccording to previous studies, PPSP is only used for femur fractures. To the best of our knowledge, this is the first in the treatment for PHFs. Given the satisfactory outcomes, it is a safe and effective method and may provide a reference to cure analogous patients in the future.

ObjectiveQuantitative hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA in the natural history of chronic HBV infection have not been rationally evaluated. This study aimed to re-characterize quantitative HBsAg and HBV DNA in the natural history phases.MethodsA total of 595 and 651 hepatitis B e antigen (HBeAg)-positive patients and 485 and 705 HBeAg-negative patients were assigned to the early and late cohorts, respectively. Based on the ‘S-shape’ receiver operating characteristic (ROC) curves, the HBeAg-positive sub-cohorts with possibly high HBV replication (PHVR) and possibly low HBV replication (PLVR) and the HBeAg-negative sub-cohorts with possibly high HBsAg expression (PHSE) and possibly low HBsAg expression (PLSE) were designated.ResultsThe areas under the ROC curve (AUCs) of HBsAg and HBV DNA in predicting HBeAg-positive significant hepatitis activity (SHA) in the early cohort, sub-cohort with PHVR, and sub-cohort with PLVR were 0.655 and 0.541, 0.720 and 0.606, and 0.553 and 0.725, respectively; those in the late cohort, sub-cohort with PHVR, and sub-cohort with PLVR were 0.646 and 0.501, 0.798 and 0.622, and 0.603 and 0.674, respectively. The AUCs of HBsAg and HBV DNA in predicting HBeAg-negative SHA in the early cohort, sub-cohort with PHSE, and sub-cohort with PLSE were 0.508 and 0.745, 0.573 and 0.780, and 0.577 and 0.729, respectively; those in the late cohort, sub-cohort with PHSE, and sub-cohort with PLSE were 0.503 and 0.761, 0.560 and 0.814, and 0.544 and 0.722, respectively. The sensitivity and specificity of HBsAg ≤4.602 log10 IU/ml in predicting HBeAg-positive SHA in the early cohort were 82.6% and 45.8%, respectively; those in the late cohort were 87.0% and 44.1%, respectively. The sensitivity and specificity of HBV DNA >3.301 log10 IU/ml in predicting HBeAg-negative SHA in the early cohort were 73.4% and 60.8%, respectively; those in the late cohort were 73.6% and 64.1%, respectively.ConclusionQuantitative HBsAg and HBV DNA are valuable, but their capabilities are divergent in delimiting the natural history phases.

Abstract Background We aimed to formulate a novel predictive nomogram to discriminate liver fibrosis stage in patients with chronic liver disease. Methods Nomograms were established based on the results of multivariate analysis. The predictive accuracy of the nomograms was assessed by ROC analysis and calibration. Decision curve analysis (DCA) was used to determine the clinical benefit of the nomograms. Results INR, platelets, and N-terminal propeptide type III collagen (PIIINP) were independent predictors for advanced liver fibrosis (≥ S3) and cirrhosis (S4) in patients with chronic liver disease in the training cohort. In the training set, the areas under the ROCs (AUROCs) of nomogram S3S4, APRI, FIB-4, and GPR for stage ≥ S3 were 0.83, 0.71, 0.68, and 0.74, respectively; the AUROCs of nomogram S4, APRI, FIB-4, and GPR for stage S4 were 0.88, 0.74, 0.78, and 0.79, respectively. The calibrations showed optimal agreement between the prediction by the established nomograms and actual observation. In the validation set, the AUROCs of nomogram S3S4, APRI, FIB-4, and GPR for stage ≥ S3 were 0.86, 0.79, 0.78, and 0.81, respectively; the AUROCs of nomogram S4, APRI, FIB-4, and GPR for stage S4 were 0.88, 0.77, 0.81, and 0.83, respectively. Furthermore, the decision curve analysis suggested that the nomograms represent better clinical benefits in both independent cohorts than APRI, FIB-4, and GPR. Conclusion The constructed nomograms could be a superior tool for discriminating advanced fibrosis and cirrhosis in chronic liver disease.

The treatment of infected bone defects includes infection control and repair of the bone defect. The development of biomaterials with anti-infection and osteogenic ability provides a promising strategy for the repair of infected bone defects. Owing to its antibacterial properties, chitosan (an emerging natural polymer) has been widely studied in bone tissue engineering. Moreover, it has been shown that chitosan promotes the adhesion and proliferation of osteoblast-related cells, and can serve as an ideal carrier for bone-promoting substances. In this review, the specific molecular mechanisms underlying the antibacterial effects of chitosan and its ability to promote bone repair are discussed. Furthermore, the properties of several kinds of functionalized chitosan are analyzed and compared with those of pure chitosan. The latest research on the combination of chitosan with different types of functionalized materials and biomolecules for the treatment of infected bone defects is also summarized. Finally, the current shortcomings of chitosan-based biomaterials for the treatment of infected bone defects and future research directions are discussed. This review provides a theoretical basis and advanced design strategies for the use of chitosan-based biomaterials in the treatment of infected bone defects.

In pelvic reconstruction surgery, the hemipelvic prosthesis can cause significant changes in stress distribution due to its high stiffness, and its solid structure is not suitable for osseointegration. The purpose of this study was to identify a novel bone mineral density screw channel and design the structure of the prosthesis so as to improve the distribution of stress, promote bone growth, and enhance the biomechanical properties of the prosthesis. The mechanical characteristics of bone mineral density screw and traditional screw were compared by finite element analysis method, and redesigned by topology optimization. The direction of the newly proposed screw channel was the posterolateral entrance of the auricular surface, ending at the contralateral sacral cape. Compared to the original group, the maximum stress of the optimized prosthesis was decreased by 24.39%, the maximum stress of the sacrum in the optimized group was decreased by 27.23%, and the average strain energy density of the sacrum in the optimized group was increased by 8.43%. On the surface of screw and connecting plate, the area with micromotion more than 28 μm is reduced by 12.17%. On the screw surface, the area with micromotion more than 28 μm is reduced by 22.9%. The newly determined screw channel and optimized prosthesis design can effectively improve the biomechanical properties of a prosthesis and the microenvironment of osseointegration. This method can provide a reference for the fixation of prostheses in clinical pelvic reconstruction.

Beijing, as the capital of China, suffers severe subsidence caused by groundwater withdrawal. In this paper, the SBAS-InSAR technique was used to detect surface deformations in the Beijing plain. 47 scenes Envisat ASAR images obtained during June 2003 to August 2010, and 24 Radarsat-2 images obtained during November 2010 to December 2013 were employed to retrieve vertical deformation characteristic over this area. The deformation magnitude, evolution process and spatial distribution of representative targets that occurred during 11 years were retrieved. The vertical surface displacement rates during two periods were validated via leveling observations, which have an RMSE =1.15mm/a, which indicates that the two types of subsidence matched very well. The interferometric results revealed that the subsidence during the two periods show similar special distributions and have an uneven spatial-temporal trend. The scope and deformation rates of funnels continuously increased with from 2003 to 2013. Meanwhile, multiple expressways and urban ring roads spanned the subsidence funnel with sharp deformation rate, and showed different subsidence properties along their paths. Additionally, the spatial and temporal correlation analyses between the deformation measurements and the dynamic variation of groundwater pumping was also performed to explore the response relationship.