Search

Abstract Background The maternal gut microbiome is the direct and important source of early colonization and development of the neonatal gut microbiome. However, differences in unique and shared features between mothers with different physiological phenotypes and their newborns still lack exhaustive investigation. Here, using a cow-to-calf model, a comprehensive investigation was conducted to elucidate the pattern and characterization of microbial transfer from the maternal source to the offspring. Results The microbiota in the rumen and feces of dairy cows were divided into two clusters via enterotype analysis. The cows from the enterotype distinguished by Prevotella in the rumen had better production performance, whereas no difference was observed in the cows classified by feces enterotype. Furthermore, through a pairwise combination of fecal and ruminal enterotypes, we screened a group of dairy cows with excellent phenotypes. The gastrointestinal microbiomes of cows with different phenotypes and their offspring differed significantly. The rumen was a more important microbial source for meconium than feces. Transmission of beneficial bacteria from mother to offspring was observed. Additionally, the meconium inherits advantageous metabolic functions of the rumen. The resistome features of the rumen, feces, and meconium were consistent, and resistome abundance from cows to calves showed an expanding trend. The interaction between antibiotic-resistance genes and mobile genetic elements from the rumen to meconium was the most remarkable. The diversity of core metabolites from cows to calves was stable and not affected by differences in phenotypes. However, the abundance of specific metabolites varied greatly. Conclusions Our study demonstrates the microbial taxa, metabolic function, and resistome characteristics of maternal and neonatal microbiomes, and reveals the potential vertical transmission of the microbiome from a cow-to-calf model. These findings provide new insights into the transgenerational transmission pattern of the microbiome. Video Abstract

Abstract For the polarization multiplexing requirements in all-optical networks, this work presents a compact all-fiber polarization beam splitter (PBS) based on dual-core photonic crystal fiber (PCF) and an elliptical gold layer. Numerical analysis using the finite element method (FEM) demonstrates that the mode modulation effect of the central gold layer effectively reduces the dimensions of the proposed PBS. By determining reasonable structural parameters of the proposed PCF, the coupling length ratio (CLR) between X- and Y-polarized super-modes can approach 2, achieving a minimal device length of 0.122 mm. The PBS exhibits a maximum extinction ratio (ER) of − 65 dB at 1.55 μm, with an operating bandwidth spanning 100 nm (1.5–1.6 μm) and a stable insertion loss (IL) of ~ 1.5 dB at 1.55 μm. Furthermore, the manufacture feasibility and performance verification scheme are also investigated. It is widely anticipated that the designed PBS will play a crucial role in the ongoing development process of miniaturization and integration of photonic devices.

Abstract The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic β cell from STZ-induced apoptosis, promotion of pancreatic β cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM.

Abstract The dominant bacteria in the hindgut of calves play an important role in their growth and health, which could even lead to lifelong consequences. However, the identification of core probiotics in the hindgut and its mechanism regulating host growth remain unclear. Here, a total of 1045 fecal samples were analyzed by 16S rRNA gene sequencing from the 408 Holstein dairy calves at the age of 0, 14, 28, 42, 56, and 70 days to characterize the dynamic changes of core taxa. Moreover, the mechanisms of nutrient metabolism of calf growth regulated by core bacteria were investigated using multi-omics analyses. Finally, fecal microbiota transplantation (FMT) in mice were conducted to illustrate the potential beneficial effects of core bacteria. Four calf enterotypes were identified and enterotypes dominated by Bifidobacterium and Oscillospiraceae_UCG-005 were representative. The frequency of enterotype conversion shifted from variable to stable. The close relationship observed between phenotype and enterotype, revealing a potential pro-growth effect of Bifidobacterium, might be implemented by promoting the use of carbohydrate, activating the synthesis of volatile fatty acids, amino acids and vitamin B6, and inhibiting methane production in the hindgut. The FMT results indicated the beneficial effect of Bifidobacterium on host growth and hindgut development. These results support the notion that the Bifidobacterium-dominated fecal microbiome would be an important driving force for promoting the host growth in the early life. Our findings provide new insights into the potential probiotic mining and application strategies to promote the growth of young animals or improve their growth retardation.

IntroductionDisorders of acid-base balance in the rumen of dairy cows have a significant impact on their health and performance. However, the effect of transient differences in pH on susceptibility to subacute ruminal acidosis (SARA) and lipopolysaccharide (LPS) biosynthesis in dairy cows remains unclear.MethodsIn this study, milk, serum, and rumen fluid samples from 40 Holstein dairy cows (on d 56 postpartum) with different rumen pH (2–4 h after morning feeding) were explored to investigate the difference of susceptibility to SARA and the correlation between microbiome, LPS and inflammation. These cows were categorized into low pH (LPH, pH ≤ 6.0, n = 20) and high pH (HPH, pH ≥ 6.5, n = 20) groups.ResultsThe results showed that LPH group increased the concentrations of total volatile fatty acids, acetate, propionate, butyrate and valerate. However, milk yield and milk compositions were unaffected. Compared to the HPH group, the LPH group increased the concentrations of serum BHBA, NEFA, LPS, HIS, IL-2, IL-6, TNF-α, and MDA, and decreased the concentrations of serum IgA, IgM, IgG, SOD, T-AOC, and mTOR. In addition, the LPH group decreased the copies of Ruminococcus flavefaciens and increased the copies of Fibrobacter succinogenes. Microbial community analysis isupplendicated a significant difference in bacterial composition between the two groups. At the phylum level, Bacteroidota and Firmicutes were enriched in the LPH and HPH groups, respectively. At the genus level, the dominant bacteria in the LPH group were Prevotella. Additionally, the LPH group increased the proportions of Gram-negative phenotypes, potentially pathogenic phenotypes and LPS biosynthesis. The close correlation between two key enzymes for LPS synthesis LpxL and LpxM with rumen pH, inflammatory markers, and microorganisms indicates that low pH may increase the risk of inflammation by facilitating the lysis of Gram-negative bacteria and the release of penta-acylated LPS. Penta-acylated and hexa-acylated LPS may be mainly derived from Prevotella and Succinivibrionaceae_UCG-001, respectively.DiscussionOverall, these results support the notion that transient low pH could reflect the risk of cows suffering from SARA and associated inflammation and is strongly associated with penta-acylated LPS. Our findings provide new insights into ruminant health improvement and disease prevention strategies.

ABSTRACT Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in de novo guanine nucleotide biosynthesis executed by inosine-5´-monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether in vivo inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial. Here, we describe the discovery of extremely potent small molecule GuaB inhibitors (GuaBi) specific to pathogenic bacteria with a low frequency of on-target spontaneous resistance and bactericidal efficacy in vivo against Acinetobacter baumannii mouse models of infection. The spectrum of GuaBi activity includes multidrug-resistant pathogens that are a critical priority of new antibiotic development. Co-crystal structures of A. baumannii, Staphylococcus aureus, and Escherichia coli GuaB proteins bound to inhibitors show comparable binding modes of GuaBi across species and identifies key binding site residues that are predictive of whole-cell activity across both Gram-positive and Gram-negative clades of Bacteria. The clear in vivo efficacy of these small molecule GuaB inhibitors in a model of A. baumannii infection validates GuaB as an essential antibiotic target.IMPORTANCEThe emergence of multidrug-resistant bacteria worldwide has renewed interest in discovering antibiotics with novel mechanism of action. For the first time ever, we demonstrate that pharmacological inhibition of de novo guanine biosynthesis is bactericidal in a mouse model of Acinetobacter baumannii infection. Structural analyses of novel inhibitors explain differences in biochemical and whole-cell activity across bacterial clades and underscore why this discovery may have broad translational impact on treatment of the most recalcitrant bacterial infections.

Summary: The increasing prevalence of antibiotic resistance demands the discovery of antibacterial chemical scaffolds with unique mechanisms of action. Phenotypic screening approaches, such as the use of reporters for bacterial cell stress, offer promise to identify compounds while providing strong hypotheses for follow-on mechanism of action studies. From a collection of ∼1,800 Escherichia coli GFP transcriptional reporter strains, we identified a reporter that is highly induced by cell envelope stress—pPromrcsA-GFP. After characterizing pPromrcsA-GFP induction, we assessed a collection of bioactive small molecules for reporter induction, identifying 24 compounds of interest. Spontaneous suppressors to one compound in particular, MAC-0452936, mapped to the gene encoding the essential prolipoprotein diacylglyceryl transferase, lgt. Lgt inhibition by MAC-0452936 inhibition was confirmed through genetic, phenotypic, and biochemical approaches. The oxime ester, MAC-0452936, represents a useful small molecule inhibitor of Lgt and highlights the potential of using pPromrcsA-GFP as a phenotypic screening tool.

Objective: To evaluate the efficacy of pulmonary rehabilitation in the outcomes of patients with chronic obstructive pulmonary disease–obstructive sleep apnoea overlap syndrome patients who used positive airway pressure. Design: Prospective randomized controlled single- blind trial. Patients: A total of 79 patients with chronic obstructive pulmonary disease–obstructive sleep apnoea overlap syndrome were randomly assigned to either the intervention group (n = 40) or control group (n = 39). Methods: All patients consistently adhered to positive airway pressure therapy every night from enrolment in the study, while intervention group patients received additional moderate-intensity aerobic exercise for 20 weeks. Pre- and post-intervention measurements included the 6-Minute Walk Test, Barthel Index, body mass index, fat mass, free fat mass, forced expiratory volume in 1 s (FEV1), FEV1%predicted, modified Medical Research Council, and polysomnography parameters. Results: After 20 weeks, the intervention group exhibited statistically significant improvements in 6MWD, Barthel Index, body mass index, fat mass, and modified Medical Research Council compared with control group (all p

In order to explore the distribution characteristics of “three zones” of spontaneous combustion in goaf under different ventilation modes, based on the engineering background of “two into one” ventilation mode at 1532 (1) working face of Gubei Mine, and based on airflow control equation, concentration component equation and energy equation, by using the Fluent numerical simulation method, the multi-physical coupling numerical model of coal spontaneous combustion and the real-time dynamic advance model of working face are established, and the distribution characteristics of “three zones” of spontaneous combustion in goaf by the “110 construction method” under three ventilation modes are simulated. The results show that with the continuous advance of the working face, under the conditions of ventilation mode 1 (air intake from the machine side and gob-side entry retaining, return air along the return air lane) and ventilation mode 2 (air intake from the machine side and along the return lane, and return air in gob-side entry retaining), the oxidation spontaneous combustion belt in the goaf is evenly distributed in the side of the belt machine, the middle of the working face and the side of the lane, and the oxygen concentration distribution is not much different. About 50 days after mining, the highest temperature appeared in the deep side of the transportation lane, and the temperature at this position did not increase with the continuous advance of the working face. Under the condition of ventilation mode 3 (air intake in gob-side entry retaining and return air lane, and air return at the side of the machine lane), the oxidation spontaneous combustion belt at the side of the goaf retaining roadway becomes 2-4 times wider, the middle of the working face and the side of the belt conveyor become obviously narrow, the oxygen volume fraction at the side of the belt conveyor in the goaf is lower, the oxygen concentration at the side of the belt conveyor is higher, and the air leakage increases significantly. The high temperature location of goaf mainly appears in the side of the stop line of 1532(1) working face, and the temperature of goaf here is the highest after 50 days of working face. In summary, combined with the actual situation of the site, the width and location of the oxidation spontaneous combustion belt are analyzed, and the ventilation mode 3 is finally determined to be more conducive to preventing the occurrence of coal spontaneous combustion, which provides theoretical guidance for the prevention of coal spontaneous combustion in mines.

Tax risk behavior causes serious loss of fiscal revenue, damages the country’s public infrastructure, and disturbs the market economic order of fair competition. In recent years, tax risk detection, driven by information technology such as data mining and artificial intelligence, has received extensive attention. To promote the high-quality development of tax risk detection methods, this paper provides the first comprehensive overview and summary of existing tax risk detection methods worldwide. More specifically, it first discusses the causes and negative impacts of tax risk behaviors, along with the development of tax risk detection. It then focuses on data-mining-based tax risk detection methods utilized around the world. Based on the different principles employed by the algorithms, existing risk detection methods can be divided into two categories: relationship-based and non-relationship-based. A total of 14 risk detection methods are identified, and each method is thoroughly explored and analyzed. Finally, four major technical bottlenecks of current data-driven tax risk detection methods are analyzed and discussed, including the difficulty of integrating and using fiscal and tax fragmented knowledge, unexplainable risk detection results, the high cost of risk detection algorithms, and the reliance of existing algorithms on labeled information. After investigating these issues, it is concluded that knowledge-guided and data-driven big data knowledge engineering will be the development trend in the field of tax risk in the future; that is, the gradual transition of tax risk detection from informatization to intelligence is the future development direction.

Kinship and pedigree, used for estimating inbreeding, heritability, selection, and gene flow, are useful for breeding and animal conservation. However, as the size of crossbred populations increases, inaccurate generation and parentage assignment in livestock farms increase. Restriction-site-associated DNA sequencing is a cost-effective platform for single nucleotide polymorphism (SNP) discovery and genotyping. Here, we performed a kinship analysis and pedigree reconstruction for Angus and Xiangxi yellow cattle. A total of 975 cattle, including 923 offspring with 24 known sires and 28 known dams, were sampled and subjected to SNP discovery and genotyping. The identified SNP panel included 7,305 SNPs capturing the maximum difference between paternal and maternal genome information, allowing us to distinguish F1 from F2 generations with 90% accuracy. In conclusion, we provided a low-cost and efficient SNP panel for kinship analyses and the improvement of local genetic resources, which are valuable for breed improvement, local resource utilization, and conservation.

Wood wool cement board is made of Portland cement as a cross-linking agent, wood fiber as a fiber reinforcement material, and some additives. The precast WWCB-filled concrete floor slabs are a new type of hollow slab. This structure formed by pouring the bottom layer of concrete, laying the WWCB, then pouring the top layer of concrete, and finally curing. And this type of floor slabs is composed of double-layer reinforcement mesh, including top and bottom reinforcement which connected by triangular contact bars. In order to study the mechanical properties of the precast WWCB-filled concrete slabs themselves, this paper conducted four-point bending loading tests on 9 precast WWCB-filled concrete slabs of different sizes to analyze the effect of penetration type and cavity size on the flexural performance of the slabs. The results of the experimental study show that: the ultimate load-bearing capacity of precast WWCB-filled concrete slabs is higher than 100-mm-thick solid slabs, and their deflection of them is similar to that of ordinary solid slabs, with good plasticity and flexibility; the overall flexural resistance of the precast WWCB-filled concrete slabs is good, the crack distribution is uniform, and the damage pattern is better than that of cast-in-situ slabs.

Abstract CD44, a nonkinase single span transmembrane glycoprotein, is a major cell surface receptor for many other extracellular matrix components as well as classic markers of cancer stem cells and immune cells. Through alternative splicing of CD44 gene, CD44 is divided into two isoforms, the standard isoform of CD44 (CD44s) and the variant isoform of CD44 (CD44v). Different isoforms of CD44 participate in regulating various signaling pathways, modulating cancer proliferation, invasion, metastasis, and drug resistance, with its aberrant expression and dysregulation contributing to tumor initiation and progression. However, CD44s and CD44v play overlapping or contradictory roles in tumor initiation and progression, which is not fully understood. Herein, we discuss the present understanding of the functional and structural roles of CD44 in the pathogenic mechanism of multiple cancers. The regulation functions of CD44 in cancers‐associated signaling pathways is summarized. Moreover, we provide an overview of the anticancer therapeutic strategies that targeting CD44 and preclinical and clinical trials evaluating the pharmacokinetics, efficacy, and drug‐related toxicity about CD44‐targeted therapies. This review provides up‐to‐date information about the roles of CD44 in neoplastic diseases, which may open new perspectives in the field of cancer treatment through targeting CD44.

Invasive alien species Alternanthera philoxeroides was found on Lake Biwa shore for almost two decades and has been causing huge loss for this region. This study aims at investigating three impact factors on reproduction of A. philoxeroides, namely nutrients, stem length, and stem diameter. Utilizing a ternary configuration dispersion method on 120 fragment samples collected from Lake Biwa shore after 10-days cultivation, the result indicates that nutrient salts significantly enhance growth (p < 0.01, Welch’s t-test), highlighting the species Epreference for eutrophic environments. Smaller stem fragments exhibit reduced growth, emphasizing the importance of thorough removal to minimize its persistence. Comparative analysis with Ludwigia grandiflora underscores that the latter exhibited bigger leaves under same experiment condition, and stem diameter significantly influence on its growth (37.7% contribution rate). These findings not only offer valuable references for elimination activities, but also stress the need for appropriate eradication strategies to preserve Lake Biwa’s aquatic ecosystem, contributing valuable insights to invasive species management in ecologically sensitive areas.

With the escalating requirements for maintenance of wind turbines, the deployment of Unmanned Aerial Vehicles (UAVs) for inspection tasks has become increasingly prevalent. However, wind turbine blades, which are thin and long, possess weak texture features that lead to target confusion when tracking specific parts of the dynamic blades. Additionally, wind turbine units, being large dynamic structures, often exceed the camera’s field of view (FOV) and exhibit unique motion characteristics. These factors make the visual tracking of specific components unstable due to the lack of global motion information. In order to address the aforementioned challenges and achieve consistent calibration of key components under the dynamic operating conditions of wind turbines, this study has adopted a strategy of integrating the Squeeze-and-Excitation Network (SEnet) into the backbone network of YOLOv5. Innovatively, two hyperparameters have been introduced into the existing loss function to adjust the weights of samples under conditions of data imbalance, thereby enhancing the performance of the detection model. In the application of the DeepSORT tracking algorithm, Long Short-Term Memory (LSTM) networks have been combined to predict the trajectory of the rotor blade’s central point, and an optimized Kalman filter has been employed to significantly improve the system’s adaptability and precision under various motion conditions. Empirical results from this study underscore the efficacy of the proposed method, demonstrating its capability to accurately differentiate individual blades as well as specific blade segments. Compared to the traditional YOLOv5, the enhanced YOLOv5-SE has demonstrated a 5.3% improvement in the Mean Average Precision (mAP_0.5) evaluation metric. Moreover, the improved DeepSORT algorithm has exhibited high efficiency in maintaining continuous and stable tracking of moving blades, adeptly handling scenarios where rotor blades frequently enter and exit the FOV. This advancement paves the way for the broader application of UAVs in wind turbine inspections, offering the potential for more efficient and accurate maintenance protocols.

Summary: The Escherichia coli outer membrane channel TolC complexes with several inner membrane efflux pumps to export compounds across the cell envelope. All components of these complexes are essential for robust efflux activity, yet E. coli is more sensitive to antimicrobial compounds when tolC is inactivated compared to the inactivation of genes encoding the inner membrane drug efflux pumps. While investigating these susceptibility differences, we identified a distinct class of inhibitors targeting the core-lipopolysaccharide translocase, MsbA. We show that tolC null mutants are sensitized to structurally unrelated MsbA inhibitors and msbA knockdown, highlighting a synthetic-sick interaction. Phenotypic profiling revealed that tolC inactivation induced cell envelope softening and increased outer membrane permeability. Overall, this work identified a chemical probe of MsbA, revealed that tolC is associated with cell envelope mechanics and integrity, and highlighted that these findings should be considered when using tolC null mutants to study efflux deficiency.

Abstract Tumor‐associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research diverse pathways for adjuvant thrombolysis in antitumor therapy. Previously, the phenotypic and functional transformation of monocytes/macrophages is widely reported to be involved in intratribal collagen regulation. This study finds that myeloid deficiency of the oncogene SHP2 sensitizes Ly6Clow monocyte/macrophage differentiation and can alleviate thrombus organization by increasing thrombolytic Matrix metalloproteinase (MMP) 2/9 activities. Moreover, pharmacologic inhibition by SHP099, examined in mouse lung metastatic tumor models, reduces tumor and thrombi burden in tumor metastatic lung tissues. Furthermore, SHP099 increases intrathrombus Ly6Clow monocyte/macrophage infiltration and exhibits thrombolytic function at high concentrations. To improve the thrombolytic effect of SHP099, NanoSHP099 is constructed to achieve the specific delivery of SHP099. NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor‐suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6Clow monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.

Summary: Background: Due to the rarity of pelvic haemophilic pseudotumour (PHPT) and demanding surgical technique for PHPT excision, no study reports the mid-term follow-up outcomes of surgical treatment of PHPT in a relatively large cohort. PHPT with varying degrees of bony pelvic involvement and infection status necessitates different operative procedures, yet there is currently no classification system for PHPT based on surgical practice. Methods: The study was conducted between June 25, 2004 and July 18, 2023, in Peking Union Medical College Hospital and Nanfang Hospital in China. We performed a retrospective analysis involving 21 patients with 24 PHPTs with a mean follow-up period of 7.1 years. The demographic information, PHPT characteristics, surgical data, and perioperative complications were analysed. Findings: 21 consecutive male patients with 24 PHPTs (21 primary PHPTs and three recurrent PHPTs) that underwent surgical treatment were involved in the study. A classification system including four subtypes was introduced as (I) PHPT confined to soft tissue; (II) PHPT involving bony pelvic without pelvic discontinuity; (III) PHPT causing pelvic discontinuity; (IV) Infectious PHPT. Of the 24 PHPTs, 11 (45.8%) were identified as Type I, five (20.8%) as Type II, three (12.5%) as Type III, and five (20.8%) as Type IV. At the time of surgery, the patients had a mean age of 37.0 ± 9.5 years (Range, 24–52 years). The mean maximum diameter of PHPTs upon surgery was 17.0 ± 7.7 cm (Range, 4.3–40.0 cm). The mean surgical duration was 192 ± 77 min (Range, 60–330 min) and the median intraoperative blood loss was 400 mL (IQR, 225–950 mL, Range, 100–3000 mL). One patient (4.8%) underwent intraoperative cardiopulmonary arrest and expired the following week. Four PHPTs (16.7%) presented postoperative wound infections and poor wound healing. During the follow-up period, five PHPTs (20.8%) experienced pseudotumour recurrence. Interpretation: Our findings suggest that surgical treatment for PHPTs is feasible and relatively safe. Symptomatic and progressive PHPTs should undergo surgical intervention as early as possible to minimise the surgical risks. Intraoperative use of abundant gelatin sponges in PHPT excision draws attention to severe embolism complications. Funding: There are no sources of funding for this manuscript.

Shape recognition plays a significant role in the field of robot perception. In view of the low efficiency and few types of shape recognition of the fiber tactile sensor applied to flexible skin, a convolutional-neural-network-based FBG tactile sensing array shape recognition method was proposed. Firstly, a sensing array was fabricated using flexible resin and 3D printing technology. Secondly, a shape recognition system based on the tactile sensing array was constructed to collect shape data. Finally, shape classification recognition was performed using convolutional neural network, random forest, support vector machine, and k-nearest neighbor. The results indicate that the tactile sensing array exhibits good sensitivity and perception capability. The shape recognition accuracy of convolutional neural network is 96.58%, which is 6.11%, 9.44%, and 12.01% higher than that of random forest, k-nearest neighbor, and support vector machine. Its F1 is 96.95%, which is 6.3%, 8.73%, and 11.94% higher than random forest, k-nearest neighbor, and support vector machine. The research of FBG shape sensing array based on convolutional neural network provides an experimental basis for shape perception of flexible tactile sensing.

This is an essay in the field of metallurgical engineering. The ion-type rare earth ore in Ganzhou was treated as the research object. Continuous stirring leaching and column leaching were used to study the leaching of rare earth and impurity elements in ore samples. The test results provide a reference for the green and efficient mining of ion-type rare earth mineral resources. The test results show that the rare earth leaching rate is about 80% in the continuous stirring leaching process. The TREO/Al in the secondary leaching solution increases significantly, while the TREO/Ca decreases significantly and the TREO/Mg decreases slightly. With the increase of ore depth, the pH value of leachate gradually increased, TREO/Al increased to 15.52, and TREO/Ca decreased to 0.64. The leaching rate of rare earths all reached more than 96%, but with the increase of depth, the proportion of light rare earth increased from 49.43% to 53.28%, and the proportion of heavy rare earth gradually decreased from 35.91% to 32.18%. The continuous stirring leaching and column leaching tests both show that with the increase of the depth of the ore sample, the leaching rate of rare earth does not decrease significantly, and the leaching of rare earth in low-grade ore seams is still feasible.

Abstract Lung cancer has been the leading cause of cancer-related deaths worldwide for decades. Despite the increasing understanding of the underlying disease mechanisms, the prognosis still remains poor for many patients. Novel adjuvant therapies have emerged as a promising treatment method to augment conventional methods and boost the therapeutic effects of primary therapies. Adjuvant therapy based on nanomedicine has gained considerable interest for supporting and enhancing traditional therapies, such as chemotherapy, immunotherapy, and radiotherapy, due to the tunable physicochemical features and ease of synthetic design of nanomaterials. In addition, nanomedicine can provide protective effects against other therapies by reducing adverse side effects through precise disease targeting. Therefore, nanomedicine-based adjuvant therapies have been extensively employed in a wide range of preclinical and clinical cancer treatments to overcome the drawbacks of conventional therapies. In this review, we mainly discuss the recent advances in adjuvant nanomedicine for lung cancer treatment and highlight their functions in improving the therapeutic outcome of other therapies, which may inspire new ideas for advanced lung cancer therapies and stimulate research efforts around this topic. Graphical Abstract

Introduction Total knee arthroplasty (TKA) is a common surgical intervention to treat joint diseases. However, TKA is associated with significant blood loss. Tranexamic acid (TXA) has been used to reduce perioperative bleeding and postoperative blood transfusion. This study aims to explore the effectiveness and safety of intraosseous regional administration (IORA) of TXA in TKA and compare differences in perioperative blood loss between IORA of TXA, intravenous infusion of TXA, and combined IORA and intravenous infusion of TXA.Methods and analysis This randomised controlled trial will enrol 105 patients with osteoarthritis who meet the inclusion criteria for unilateral TKA. Patients were randomly divided into three groups using the random number table method. Group A received 1.0 g of TXA via IORA, group B received 1.0 g of TXA via intravenous infusion 15 min prior to the tourniquet release, and group C received both IORA of 1.0 g of TXA and intravenous infusion of 1.0 g of TXA. The primary outcome measure is perioperative total blood loss. Secondary outcomes include bleeding events, venous thromboembolism events, inflammation reactions, other complications and knee function assessments.Ethics and dissemination This study has been approved by the Ethics Committee of Peking Union Medical College Hospital and registered in the Chinese Clinical Trial Registry. Informed consent will be obtained from all the patients before enrolment. The trial will be conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The results of this study will be disseminated through peer-reviewed publications, conference presentations and social media platforms. The findings will provide valuable insights into the use of IORA of TXA in TKA and may lead to the development of new strategies for perioperative blood management in joint replacement surgery.Trial registration number The Ethics Committee of Peking Union Medical College Hospital (approval number: K2371); Chinese Clinical Trial Registry (trial registration number: ChiCTR2200066293).

Modern-day optical systems are evolving towards miniaturization and integration, leading to higher performance demands for polarizing beam splitters (PBSs). A simple-structure and high-performance PBS based on dual-core photonic crystal fiber (DC-PCF) with As2S3 layer is proposed. The finite element method (FEM) and classical coupled-mode theory (CMT) are utilized to investigate the performance of this PBS. Simulation results demonstrate that the proposed PBS can achieve a minimum length of 2.65 mm, a minimum extinction ratio of −64 dB, an operating bandwidth of 420 nm, and a minimum insertion loss of 0.03 dB when the optimal parameters include cladding hole diameter of 1.0 μm, central hole diameter of 2.0 μm, lattice spacing of 2.0 μm, and As2S3 ring layer thickness of 50 nm. Moreover, it also possesses a high birefringence of 3.58 × 10−3 and a negative dispersion of −30 ps/km/nm at 1.55 μm. It is believed that the proposed PBS holds great potential to become a critical device in optical multiplexing technologies.

Superchargers have become a focus of much research into new-energy vehicles, for which the cooling of high-current cable cores is a key problem that needs to be solved. To estimate influences of different core structures of liquid-cooled cables on the fluid flow and heat transfer characteristics in circular pipes, nine helical cable core structures with insertion of smooth pipes were designed taking dimethyl silicone oil as the coolant. The fluid flow and heat transfer in the pipes were studied through computational fluid dynamics (CFD) numerical simulation at different inlet velocities (0.2–2.0 m/s), and the models were verified by building an experimental platform. Numerical calculation results show that under conditions of the same Re and pitch of cable cores, the average surface temperature of three-core cables is lower than those of single-core and double-core cables. Moreover, the mean flow velocity v in pipes, heat transfer performance Nu, resistance factor f, evaluation factor for comprehensive heat transfer performance (PEC), and field synergy number Fc all increase with the decrease in the pitch of cable cores. This finding indicates that the heat transfer effect is gradually enhanced. The research implies that when the pitch p is 22.4 mm (cable C6), the velocity field is the most synergetic with the temperature field and the comprehensive heat transfer performance is optimal. This research provides an excellent cooling scheme for cable cores in superchargers under a high current load.

Esophageal squamous cell carcinoma (ESCC) consistently ranks as one of the most challenging variants of squamous cell carcinomas, primarily due to the lack of effective early detection strategies. We herein aimed to elucidate the underlying mechanisms and biological role associated with A-kinase anchoring protein 12 (AKAP12) in the context of ESCC. Bioinformatic analysis had revealed significantly lower expression level of AKAP12 in ESCC tissue samples than in their non-cancerous counterparts. To gain deeper insights into the potential role of AKAP12 in the progression of ESCC, we conducted a single-gene set enrichment analysis of AKAP12 on ESCC datasets. Our findings suggested that AKAP12 exhibits functions inhibiting cell cycle progression, tumor proliferation, and epithelial-mesenchymal transition. To further validate our findings, we subjected ESCC cell lines to AKAP12 overexpression using CRISPR/Cas9-SAM. In vitro analyses demonstrated that increased expression of AKAP12 significantly reduced cell proliferation, migration, and cell cycle progression. Simultaneously, genes associated with this biological role undergo corresponding regulatory shifts. These observations provided valuable insights into the biological role played by AKAP12 in ESCC progression. In summary, AKAP12 shows promise as a new potential biomarker for early ESCC diagnosis, offering potential advantages for subsequent therapeutic intervention and disease management.

AbstractObjective: To verify that the TiO2 nanofilm dip-coated by sol-gel can reduce titanium alloy implants (TAI)’s heat production after microwave diathermy (MD).Methods: The effect of 40 W and 60 W MD on the titanium alloy substrate coated with TiO2 nanofilm (Experimental Group) and the titanium alloy substrate without film (Control Group) were analyzed in vitro and in vivo. Changes in the skeletal muscle around the implant were evaluated in ex vivo by histology.Results: After 20 min of MD, in vitro the temperature rise of the titanium substrate was less in the Experimental Group than in the Control Group (40 W: 1.4 °C vs. 2.6 °C, p

Abstract Background Tumor angiogenesis, immunosuppression, and progression are all closely correlated with the tumor microenvironment (TME). Immune evasion is supported by both M2 phenotype tumor-associated macrophages (TAMs) and vascular aberrations in the TME. TME reprogramming is a promising therapeutic approach for treating tumors. Anti-angiogenesis has the power to control the polarization of macrophages, prevent progression, and increase drug penetration. Additionally, polyamine blocking therapy can increase CD8+ T cell infiltration and decrease immunosuppressive cells. These results led to developing a potential therapeutic regimen that targets TAMs and angiogenesis to reprogram the osteosarcoma TME. Results For the targeted biomimetic co-delivery of regorafenib and alpha-difluoromethylornithine via the mannose receptor, which is overexpressed in both TAMs and osteosarcoma cells, mannosylated poly(lactide-co-glycolide)-polyethylene glycol nanoparticles (Man-NPs) were synthesized. The superior physiological properties and intratumoral accumulation of the Man-NPs efficiently promoted TAMs polarization and inhibited angiogenesis. Macrophage repolarization further activated immune cells, which contributed to remodeling the TME. Conclusion Overall, these findings suggested that using Man-NPs as an immunotherapeutic approach to treat osteosarcoma may be promising. Graphical Abstract

Oxidative stress damage in periparturient cows decreases both production and their health; supplementation with complex additives during the periparturient period has been used as an important strategy to enhance the antioxidant status and production of dairy cows. The periparturient cows not only risk a negative energy balance due to reduced dry matter intake but also represent a sensitive period for oxidative stress. Therefore, we have developed an immunomodulatory and nutritional regulation combined additive (INC) that hopefully can improve the immune status and production of cows during the periparturient period and their offspring health and growth by improving their antioxidant stress status. The INC comprised a diverse array of additives, including water-soluble and fat-soluble vitamins, Selenomethionine, and active dry Saccharomyces cerevisiae. Forty-five multiparous Holstein cows were randomly assigned to three treatments: CON (no INC supplementation, n = 15), INC30 (30 g/d INC supplementation, n = 15), and INC60 (60 g/d INC supplementation, n = 15) based on last lactation milk yield, body condition score, and parity. Newborn calves were administered 4 L of maternal colostrum originating from the corresponding treatment and categorized based on the treatment received by their respective dams. The INC not only served to maintain the antioxidative stress system of dairy cows during the periparturient period but also showed a tendency to improve the immune response (lower tumor necrosis factor and interleukin-6) during the perinatal period. A linear decrease in concentrations of alkaline phosphatase postpartum and β-hydroxybutyrate was observed with INC supplementation. Milk fat yield, milk protein yield, and energy-corrected milk yield were also increased linearly with increasing additive supplementation. Calves in the INC30 group exhibited greater wither height and chest girth but no significant effect on average daily gain or body weight. The diarrhea frequency was linearly decreased with the incremental level of INC. Results indicate that supplementation with INC in peripartum dairy cows could be a major strategy to improve immune response, decrease inflammation, maintain antioxidant stress status in transition dairy cows, and have merit in their calves. In conclusion, this study underlines the benefits of INC supplementation during the transition period, as it improved anti-inflammatory capacity, could positively impact antioxidative stress capacity, and eventually enhanced the production performance of dairy cows and the health and growth of calves.

In order to solve the problem of flexible sliding tactile composite sensing in the actual grasp of intelligent robot fingers, this paper proposes a research on a convex fiber grating tactile sliding sensor based on mechanical fingers. Based on the sensing principle of fiber Bragg grating, 3D printing technology was used to encapsulate the FBG sensor array with elastic 50 A resin, a double-layer “hemispherical cuboid” distributed sensing unit was designed, and the FBG slippery tactile sensor was actually pasted on the surface of the mechanical finger for static and dynamic experiments. The experimental results show that the slippery tactile sensor designed in this paper has a good linear relationship with temperature and strain. The temperature sensitivities of the polymer-packaged FBGs are KT1 = 13.04 pm/°C and KT2 = 12.91 pm/°C, and they have a pressure sensitivity of 40.4 pm/N and 31.2 pm/N, respectively. The FBG sliding tactile sensor not only realizes the identification of the sliding signal generation point and the end point but also completes the classification and identification of sandpaper, cardboard, and polypropylene plastic, and it has a high degree of fit with the robot finger, which has certain application value for the intelligent robot sliding tactile signal perception.

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel instigator for mitochondrial dysfunction, and plays an important role in the pathogenesis of cardiovascular diseases. However, the role and mechanism of DNA-PKcs in angiotensin II (Ang II)-induced vascular remodeling remains obscure. Methods: Rat aortic smooth muscle cells (SMC) and VSMC-specific DNA-PKcs knockout (DNA-PKcsΔVSMC) mice were employed to examine the role of DNA-PKcs in vascular remodeling and the underlying mechanisms. Blood pressure of mice was monitored using the tail-cuff and telemetry methods. The role of DNA-PKcs in vascular function was evaluated using vascular relaxation assessment. Results: In the tunica media of remodeled mouse thoracic aortas, and renal arteries from hypertensive patients, elevated DNA-PKcs expression was observed along with its cytoplasmic translocation from nucleus, suggesting a role for DNA-PKcs in vascular remodeling. We then infused wild-type (DNA-PKcsfl/fl) and DNA-PKcsΔVSMC mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcsΔVSMC mice displayed attenuated vascular remodeling through inhibition of dedifferentiation of VSMCs. Moreover, deletion of DNA-PKcs in VSMCs alleviated Ang II-induced vasodilation dysfunction and hypertension. Mechanistic investigations denoted that Ang II-evoked rises in cytoplasmic DNA-PKcs interacted with dynamin-related protein 1 (Drp1) at its TQ motif to phosphorylate Drp1S616, subsequently promoting mitochondrial fragmentation and dysfunction, as well as reactive oxygen species (ROS) production. Treatment of irbesartan, an Ang II type 1 receptor (AT1R) blocker, downregulated DNA-PKcs expression in VSMCs and aortic tissues following Ang II administration. Conclusion: Our data revealed that cytoplasmic DNA-PKcs in VSMCs accelerated Ang II-induced vascular remodeling by interacting with Drp1 at its TQ motif and phosphorylating Drp1S616 to provoke mitochondrial fragmentation. Maneuvers targeting DNA-PKcs might be a valuable therapeutic option for the treatment of vascular remodeling and hypertension.

Abstract Background Sanfu herbal patch (SHP) is widely used in the prevention and treatment of bronchial asthma in China, but its efficacy and mechanism of action are not completely clear. This trial aims to determine the efficacy of SHP and the underlying mechanism. Methods/design We will conduct a multi-centre parallel randomised controlled trial consisting of 72 participants with bronchial asthma recruited and randomly allocated at a ratio of 1:1 into two groups. The patients in one group will receive three courses of SHP treatment, and the patients in the other group will receive placebo treatment, with 24 weeks of follow-up evaluation for both groups. The primary outcome, i.e. forced expiratory volume in the first second (FEV1), which refers to the change in FEV1 from the beginning of the baseline to the end of 3 treatment sessions (TSs), will be assessed and compared via Student’s t test or the Mann–Whitney U test. Other outcomes will include questionnaire surveys and laboratory indicators. Detailed and complete statistical analyses in a double-blinded fashion will be provided for evaluating this trial. Discussion The data we obtain will be examined based on the above statistical analysis, which will help to reduce the risk of external reporting bias and data-driven results. Trial registration Chinese Clinical Trial Registry ( http://www.chictr.org.cn ), ChiCTR1900024616. Registered on 19 July 2019.

Abstract Background Stent implantation-induced neointima formation is a dominant culprit in coronary artery disease treatment failure after percutaneous coronary intervention. Ferroptosis, an iron-dependent regulated cell death, has been associated with various cardiovascular diseases. However, the effect of ferroptosis on neointima formation remains unclear. Methods The mouse common right carotid arteries were ligated for 16 or 30 days, and ligated tissues were collected for further analyses. Primary rat vascular smooth muscle cells (VSMCs) were isolated from the media of aortas of Sprague-Dawley (SD) rats and used for in vitro cell culture experiments. Results Ferroptosis was positively associated with neointima formation. In vivo, RAS-selective lethal 3 (RSL3), a ferroptosis activator, aggravated carotid artery ligation-induced neointima formation and promoted VSMC phenotypic conversion. In contrast, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), showed the opposite effects in mice. In vitro, RSL3 promoted rat VSMC phenotypic switching from a contractile to a synthetic phenotype, evidenced by increased contractile markers (smooth muscle myosin heavy chain and calponin 1), and decreased synthetic marker osteopontin. The induction of ferroptosis by RSL3 was confirmed by the increased expression level of ferroptosis-associated gene prostaglandin-endoperoxide synthase 2 (Ptgs2). The effect of RSL3 on rat VSMC phenotypic switching was abolished by Fer-1. Moreover, N-acetyl-l-cysteine (NAC), the reactive oxygen species inhibitor, counteracted the effect of RSL3 on the phenotypic conversion of rat VSMCs. Conclusions Ferroptosis induces VSMC phenotypic switching and accelerates ligation-induced neointimal hyperplasia in mice. Our findings suggest inhibition of ferroptosis as an attractive strategy for limiting vascular restenosis.

Measurement(s) highway vehicle routing Technology Type(s) GPS location tracking Sample Characteristic - Location Sonoma County, California, USA

Abstract Bone diseases including bone defects, bone infections, osteoarthritis, and bone tumors seriously affect life quality of the patient and bring serious economic burdens to social health management, for which the current clinical treatments bear dissatisfactory therapeutic effects. Biomaterial‐based strategies have been widely applied in the treatment of orthopedic diseases but are still plagued by deficient bioreactivity. With the development of nanotechnology, layered double hydroxides (LDHs) with adjustable metal ion composition and alterable interlayer structure possessing charming physicochemical characteristics, versatile bioactive properties, and excellent drug loading and delivery capabilities arise widespread attention and have achieved considerable achievements for bone disease treatment in the last decade. However, to the authors' best knowledge, no review has comprehensively summarized the advances of LDHs in treating bone disease so far. Herein, the advantages of LDHs for orthopedic disorders treatment are outlined and the corresponding state‐of‐the‐art achievements are summarized for the first time. The potential of LDHs‐based nanocomposites for extended therapeutics for bone diseases is highlighted and perspectives for LDHs‐based scaffold design are proposed for facilitated clinical translation.

Abstract The design and fabrication of flexible, porous, conductive electrodes with customizable functions become the prime challenge in the development of new‐generation wearable electronics, especially for rechargeable batteries. Here, the NiCo bialloy particulate catalyst‐loaded self‐supporting carbon foam framework (NiCo@SCF) as a flexible electrode has been fabricated through one facile adsorption‐pyrolysis method using a commercial melamine foam. Compared with the electrode with Pt/C and Ir/C benchmark catalysts, the NiCo@SCF electrode exhibited superior bifunctional electrocatalytic performance in alkaline media with a half‐wave potential of 0.906 V for oxygen reduction reaction, an overpotential of 286 mV at j = 10 mA cm−2 for oxygen evolution reaction, and stable bifunctional performance with a small degradation after 20,000 voltammetric cycles. The as‐assembled aqueous zinc–air battery (ZAB) with NiCo@SCF as a self‐supporting air cathode demonstrated a high peak power density of 178.6 mW cm−2 at a current density of 10 mA cm−2 and a stable voltage gap of 0.94 V over a 540 h charge−discharge operation. Remarkably, the as‐assembled flexible solid‐state ZAB with self‐supporting NiCo@SCF as the air cathode presented an engaging peak power density of 80.1 mW cm−2 and excellent durability of 95 h undisrupted operation, showing promise for the design of wearable ZAB. The demonstrated electrode fabrication approach exemplifies a facile, large‐scale avenue toward functional electrodes, potentially extendable to other wearable electronics for broader applications.

Wildfires significantly change boreal forest ecosystem carbon balance through both direct combustion and post-fire carbon dynamics. Affected vegetation influences soil thermal regime and carbon cycling by impacting the surface energy balance of boreal forests. This study uses a process-based biogeochemistry model to quantify carbon budget of North American boreal forests during 1986–2020 based on satellite-derived burn severity data. During the study period, burn severity generally increases. Fires remove ecosystem carbon of 2.4 Pg C and reduce net ecosystem production (NEP) from 32.6 to 0.8 Tg C yr ^−1 , making the forest ecosystems lose 3.5 Pg C, shifting a carbon sink to a source. The canopy’s cooling effect leads to lower soil temperature and lower net primary production due to lower nitrogen mineralization and uptake. Post-fire NEP decreases from 1.6 to 0.8 Tg C yr ^−1 . This reduction accounts for 50% of the simulated NEP when the effects of fire-affected canopy are not considered. Our study highlights the importance of wildfires and their induced-canopy changes in soil thermal and ecosystem carbon dynamics of boreal forests.

Traditional methods for determining the chemical composition of cattle feces are uneconomical. In contrast, near-infrared reflectance spectroscopy (NIRS) has emerged as a successful technique for assessing chemical compositions. Therefore, in this study, the feasibility of NIRS in terms of predicting fecal chemical composition was explored. Cattle fecal samples were subjected to chemical analysis using conventional wet chemistry techniques and a NIRS spectrometer. The resulting fecal spectra were used to construct predictive equations to estimate the chemical composition of the feces in both cows and calves. The coefficients of determination for calibration (RSQ) were employed to evaluate the calibration of the predictive equations. Calibration results for cows (dry matter [DM], RSQ = 0.98; crude protein [CP], RSQ = 0.93; ether extract [EE], RSQ = 0.91; neutral detergent fiber [NDF], RSQ = 0.82; acid detergent fiber [ADF], RSQ = 0.89; ash, RSQ = 0.84) and calves (DM, RSQ = 0.92; CP, RSQ = 0.89; EE, RSQ = 0.77; NDF, RSQ = 0.76; ADF, RSQ = 0.92; ash, RSQ = 0.97) demonstrated that NIRS is a cost-effective and efficient alternative for assessing the chemical composition of dairy cattle feces. This provides a new method for rapidly predicting fecal chemical content in cows and calves.

Abstract Background Extensive muscle atrophy is a common occurrence in orthopaedics patients who are bedridden or immobilized. The incidence is higher in intensive care unit (ICU) inpatients. There is still controversy about how to use neuromuscular electrical stimulation (NMES) in ICU patients. We aim to compare the effectiveness and safety of NMES to prevent muscle atrophy in intensive care unit (ICU) patients without nerve injury. Methods ICU patients without central and peripheral nerve injury were randomized into experimental group I (Exp I: active and passive activity training (APAT) + NMES treatment on the gastrocnemius and tibialis anterior muscle), experimental group II (Exp II: APAT + NMES treatment on gastrocnemius alone), and control group (Ctl: APAT alone). Changes in the strength of gastrocnemius, the ankle range of motion, and the muscle cross-section area of the lower leg were evaluated before and after the intervention. Also, changes in prothrombin time, lactic acid, and C-reactive protein were monitored during the treatment. Results The gastrocnemius muscle strength, ankle joint range of motion, and cross-sectional muscle area of the lower leg in the three groups showed a downward trend, indicating that the overall trend of muscle atrophy in ICU patients was irreversible. The decrease in gastrocnemius muscle strength in Exp I and Exp II was smaller than that in the control group (P 0.05). Conclusion In addition to early exercise training, NMES should be applied to prevent muscle atrophy for patients without nerve injury in ICU. Also, simultaneous NMES treatment on agonist/antagonist muscle can enhance the effect of preventing muscle atrophy. Trial registration This study was prospectively registered in China Clinical Trial Registry ( www.chictr.org.cn ) on 16/05/2020 as ChiCTR2000032950.

Abstract Osteonecrosis of the femoral head (ONFH) is a devastating and complicated disease with an unclear etiology. Femoral head‐preserving surgeries have been devoted to delaying and hindering the collapse of the femoral head since their introduction in the last century. However, the isolated femoral head‐preserving surgeries cannot prevent the natural progression of ONFH, and the combination of autogenous or allogeneic bone grafting often leads to many undesired complications. To tackle this dilemma, bone tissue engineering has been widely developed to compensate for the deficiencies of these surgeries. During the last decades, great progress has been made in ingenious bone tissue engineering for ONFH treatment. Herein, we comprehensively summarize the state‐of‐the‐art progress made in bone tissue engineering for ONFH treatment. The definition, classification, etiology, diagnosis, and current treatments of ONFH are first described. Then, the recent progress in the development of various bone‐repairing biomaterials, including bioceramics, natural polymers, synthetic polymers, and metals, for treating ONFH is presented. Thereafter, regenerative therapies for ONFH treatment are also discussed. Finally, we give some personal insights on the current challenges of these therapeutic strategies in the clinic and the future development of bone tissue engineering for ONFH treatment.

Upon migrating into the tissues, hematopoietic stem cell (HSC)-derived monocytes differentiate into macrophages, playing a crucial role in determining innate immune responses towards external pathogens and internal stimuli. However, the regulatory mechanisms underlying monocyte-to-macrophage differentiation remain largely unexplored. Here we divulge a previously uncharacterized but essential role for an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), in monocyte-to-macrophage maturation. FLRT2 is almost undetectable in human monocytic cell lines, human peripheral blood mononuclear cells (PBMCs), and mouse primary monocytes but significantly increases in fully differentiated macrophages. Myeloid-specific deletion of FLRT2 (Flrt2ΔMyel) contributes to decreased peritoneal monocyte-to-macrophage generation in mice in vivo, accompanied by impaired macrophage functions. Gain- and loss-of-function studies support the promoting effect of FLRT2 on THP-1 cell and human PBMC differentiation into macrophages. Mechanistically, FLRT2 directly interacts with Unc-5 netrin receptor B (UNC5B) via its extracellular domain (ECD) and activates Akt/mTOR signaling. In vivo administration of mTOR agonist MYH1485 reverses the impaired phenotypes observed in Flrt2ΔMyel mice. Together, these results identify FLRT2 as a novel pivotal endogenous regulator of monocyte differentiation into macrophages. Targeting the FLRT2/UNC5B-Akt/mTOR axis may provide potential therapeutic strategies directly relevant to human diseases associated with aberrant monocyte/macrophage differentiation.

Synpolydactyly (SPD) is caused by mutations in the transcription factor gene HOXD13. Such mutations include polyalanine expansion (PAE), but further study is required for the phenotypic spectrum characteristics of HOXD13 PAE. We investigated four unrelated Chinese families with significant limb malformations. Three PAEs were found in the HOXD13 polyalanine coding region: c.172_192dup (p.Ala58_Ala64dup) in Family 1, c.169_192dup (p.Ala57_Ala64dup) in Family 2, and c.183_210dup (p.Ala62_Ala70dup) in Family 3 and Family 4. Interestingly, we identified a new manifestation of preaxial polydactyly in both hands in a pediatric patient with an expansion of seven alanines, a phenotype not previously noted in SPD patients. Comparing with the wild-type cells and mutant cells with polyalanine contractions (PACs), the HOXD13 protein with a PAE of nine-alanine or more was difficult to enter the nucleus, and easy to form inclusion bodies in the cytoplasm, and with the increase of PAE, the more inclusion bodies were formed. This study not only expanded the phenotypic spectrum of SPD, but also enriched our understanding of its pathogenic mechanisms.

Abstract Backgrounds Mismatch between knee surface and prosthesis components is related to postoperative complications. Morphological differences between ethnicity and gender may affect prosthesis coverage. The purpose of this study is to describe morphological characters of resected knee surface (distal femur, proximal tibia) in the Chinese population, analyze the influence of gender and other demographical factors, and validate the effect of ethnic difference by calculating the coverage of Western-designed knee prostheses on Chinese knee surface. Methods Intraoperative anthropometries were performed during total knee arthroplasty performed by one single team. After screening out severe deformities and bone defects, data were separated via prosthesis system. Multiple linear regression and partial correlation analysis of morphological parameters on age, gender, height, weight were used to find out independent factors influencing morphology. Based on the 5 mm-tolerance in the prosthesis, simulation on scatter plots was brought out to calculate the prosthesis coverage to the resected bone surface. Results A total of 865 cases of total knee arthroplasty were involved in this study. Though gender differences were found in all knee morphological parameters regardless of the type of prosthesis, significant association was only found between gender and mediolateral width of femoral surface after adjusting demographical factors (p

Abstract Background Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced endoscopic procedure and requires deep sedation. Deep sedation with dexmedetomidine for the respiratory drive preserved has become popular in recent years. However, the use of dexmedetomidine in elderly patients is controversial because its adverse events are more common. The objective of this study was to investigate the effectiveness of a single loading dose of dexmedetomidine combined with propofol for deep sedation of ERCP in elderly patients. Methods In this prospective randomized trial, 49 elderly patients undergoing ERCP were randomly allocated to the dexmedetomidine (DEX) or propofol (PRO) groups. The single loading dose of dexmedetomidine was set at 0.5 μg/kg at the start of anesthesia induction and loading for 10 min. The primary outcome was the cumulative dose of propofol. Secondary outcomes included time to awake, the frequency of airway interventions, and hemodynamics. Results The intraoperative cumulative dose of propofol was lower in the DEX group (111.0 ± 12.6 μg/kg/min) than the PRO group (143.7 ± 23.4 μg/kg/min) (P

A new 3D mesoscale computational approach to simulate the mechanical behavior of soil–rock mixtures (SRMs) with the consideration of the grain-crushing process is proposed in this study. The proposed approach adopts a random SRM mesostructure generation algorithm to create a random SRM structure. Based on the generated mesostructure, the whole simulation area is divided into discrete cubic numbers, and the mesostructure is transformed into a material distribution matrix as an input for the computational approach. The computational approach is achieved by the coupling calculation of Matlab and COMSOL. Theimulations are presented alongside experimental data to validate the efficiency of the proposed approach. The simulation results indicate that the proposed computational approach can accurately capture the mechanical behavior of SRMs under loadings. This method helps to predict the physical properties of SRMs and has promising applications in engineering.

Abstract Background Osteoarthritis (OA) is widely recognized as the most common chronic joint disease accompanied by progressive cartilage and subchondral bone damage. Toddalolactone (TOD), a natural compound extracted from Toddalia asiatica (L.) Lam., has been widely used in the treatment of stroke, rheumatoid arthritis, and oedema. Nevertheless, what TOD acts as in the pathogenesis and progression of OA hasn’t been reported. In this investigation, we have aimed to determine how TOD affects OA in vitro and in vivo. Methods LPS (10 µg/ml) and IL-1β (10 ng/ml) were employed to induce chondrocyte inflammation or RANKL to induce osteoclast differentiation in bone marrow derived macrophages (BMMs). The effects of TOD on chondrocyte inflammation and osteoclast differentiation were evaluated. Anterior cruciate ligament transection (ACLT) was performed to develop an OA animal model and study the effects of TOD. Results We found that TOD inhibited the expression of inflammatory and catabolic mediators (IL-6, IL-8, TNF-α, MMP2, MMP9, and MMP13) in inflammatory chondrocytes in vitro. Furthermore, TOD was proven to inhibit RANKL-induced-osteoclastogenesis and inhibit the expression of osteoclast marker genes. Our data also confirmed that TOD suppressed the destruction of articular cartilage and osteoclastogenesis via inhibiting the activation of NF-κB and MAPK signalling pathways. In the ACLT mouse model, we found that TOD attenuated cartilage erosion and inhibited bone resorption. Conclusions These results showed that TOD can be adopted as a potential therapeutic agent for OA.

Abstract Background N6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression. Methods The expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD. Results The results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc−, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues. Conclusions These findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.

BackgroundWith the aging of the population, the prevalence and incidence of stroke in China are increasing every year. China advocates the establishment of a three-level medical service system for stroke rehabilitation, but it lacks uniform information management among all levels of medical institutions.ObjectiveTo achieve unified management of stroke patient rehabilitation in multilevel hospitals in the region through informatization construction.MethodsThe need for informatization of three-level stroke rehabilitation management was analyzed. Then, network connections were established, and a common rehabilitation information management system (RIMS) was developed for all levels of hospitals to enable daily stroke rehabilitation management, inter-hospitals referral, and remote video consultation. Finally, the impact on the efficiency of daily rehabilitation work, the functioning and satisfaction of stroke patients were investigated after implementing the three-level rehabilitation network.ResultsOne year after implementation, 338 two-way referrals and 56 remote consultations were completed using RIMS. The stroke RIMS improved the efficiency of doctors’ orders, reduced therapists’ time to write medical documents, simplified statistical analysis of data and made referrals and remote consultations more convenient compared to the traditional model. The curative effect of stroke patients managed by RIMS is better than that of traditional management. Patient satisfaction with rehabilitation services in the region has increased.ConclusionThe three-level stroke rehabilitation informatization has enabled the unified management of stroke rehabilitation in multilevel hospitals in the region. The developed RIMS improved the efficiency of daily work, improved the clinical outcomes of stroke patients, and increased patient satisfaction.

The void phenomenon behind the tunnel lining has become the main cause of tunnel disease, easily triggering tunnel lining structure damage, shedding, water seepage, and other diseases that seriously threaten the normal operation of the tunnel. The void area behind the lining seriously reduces the seismic capacity of the tunnel. In this paper, the mechanical parameters of the surrounding rock are calculated by optimizing the inversion of the improved system identification sensitivity analysis method, and the numerical model of the tunnel’s dynamic response is optimized using the improved inversion results to study the repair effect and seismic capacity of the Longmenshan tunnel using polymer grouting to repair the void area behind the lining under the action of a seismic load. The results show that the displacement and stress at the top of the tunnel secondary lining void area are significantly reduced and close to normal after the repair of polymer grouting; however, the stress and displacement at the top of the secondary lining are significantly different under the action of seismic waves at the same peak at different site conditions, which indicates that the dynamic response of this tunnel model has obvious sensitivity to the seismic wave spectrum.