Search

Abstract Imbalanced datasets, where the minority class is underrepresented, pose significant challenges for node classification in graph learning. Traditional methods often address this issue through synthetic oversampling techniques for the minority class, which can complicate the training process. To address these challenges, we introduce a novel training paradigm for node classification on imbalanced graphs, based on mixed entropy minimization (ME). Our proposed method, GraphME, offers a ‘free imbalance defense’ against class imbalance without requiring additional steps to improve classification performance. ME aims to achieve the same goal as cross-entropy-maximizing the model’s probability for the correct classes-while effectively reducing the impact of incorrect class probabilities through a “guidance” term that ensures a balanced trade-off. We validate the effectiveness of our approach through experiments on multiple datasets, where GraphME consistently outperforms the traditional cross-entropy objective, demonstrating enhanced robustness. Moreover, our method can be seamlessly integrated with various adversarial training techniques, leading to substantial improvements in robustness. Notably, GraphME enhances classification accuracy without compromising efficiency, a significant improvement over existing methods. The GraphME code is available at: https://github.com/12chen20/GraphME .

Abstract The orbital Hall effect in light materials has attracted considerable attention for developing orbitronic devices. Here we investigate the orbital torque efficiency and demonstrate the switching of the perpendicularly magnetized materials through the orbital Hall material, i.e., Zr. The orbital torque efficiency of approximately 0.78 is achieved in the Zr orbital Hall material with the perpendicularly magnetized [Co/Pt]3 sample, which significantly surpasses that of the perpendicularly magnetized CoFeB/Gd/CoFeB sample (approximately 0.04). Such a notable difference is attributed to the different spin-orbit correlation strength between the [Co/Pt]3 sample and the CoFeB/Gd/CoFeB sample, confirmed through theoretical calculations. Furthermore, the full magnetization switching of the [Co/Pt]3 samples with a switching current density of approximately 2.6×106 A/cm2 has been realized through Zr, which even outperforms that of the W spin Hall material. Our finding provides a guideline to understand orbital torque efficiency and paves the way for developing energy-efficient orbitronic devices.

In individuals afflicted with hemophilia, characterized by a deficiency of coagulation factor VIII (FVIII), the occurrence of spontaneous recurrent intra-articular hemorrhage precipitates the emergence of hemophilic arthropathy (HA). Although clotting factor replacement therapy reduces joint bleeding clinically, clotting factors need to be injected frequently due to the rapid diffusion of the drug. Hence, a novel drug delivery approach may be developed to improve the drug therapy. Platelet-derived extracellular vesicles (PEVs) are known to possess anti-inflammatory and hemostatic properties and could be used as a potential HA therapy. In this study, we constructed a PEV-LS@FVIII nanotherapeutic system by combining thioketal (TK), liposomes (LS), and FVIII to form the LS@FVIII complexes, and then hybridizing PEV with LS@FVIII. Our results demonstrated that PEV-LS@FVIII could efficiently facilitate FVIII delivery and specifically target the injured knee joint. Both in vitro and in vivo studies showed a reduction in the M1 phenotype of macrophages and an enhancement of the M2 phenotype, compared to FVIII free control. Furthermore, PEV-LS@FVIII appeared to alleviate HA-induced cartilage damage. In conclusion, our findings demonstrate that PEV-LS@FVIII could delay the progression of HA by targeting bleeding joints, modulating macrophage polarization to suppress inflammation, and mitigating cartilage damage.

The Earth’s electron radiation belts typically exhibit a two-belt structure. However, observations from the Van Allen Probes revealed the existence of a three-belt structure. This structure consists of an inner belt, a slot region, a remnant belt, a “second slot,” and a new outer belt (or the “third belt”). The formation of the structure involves both the partial loss of the original outer belts and the formation of the third belts. These processes are likely associated with radial diffusion induced by ultra-low-frequency (ULF) waves. In this study, we mainly analyzed electron flux data from medium Earth orbit (MEO) navigation satellites M17–M19 to supplement the observational evidence for the sub-relativistic electron (~100–500 keV) three-belt structure. Evidence of substorm injections and ULF waves during the three-belt event was identified, suggesting they played significant roles in the formation and evolution of the third belt. Substorm injections may introduce new electron populations to the third belt, whereas ULF waves may influence the evolution of the third belt through radial diffusion. Toward the end of the three-belt event, the compression of the magnetosphere by shocks may lead to the dropout of the third belt because of the magnetopause shadowing effect and outward radial diffusion, ultimately disrupting the three-belt structure. This study provides more evidence for the presence of a sub-relativistic electron three-belt structure and offers an analysis of the evolutionary mechanisms of the third belt, which may contribute to a comprehensive understanding of the electron three-belt structure in the radiation belts.

(–)-α-Bisabolol is a plant-derived sesquiterpene derived from Eremanthus erythropappus, which can be used as a raw material in cosmetics and has anti-inflammatory function. In this study, we designed six mutation sites of the (–)-α-bisabolol synthase BOS using the plmDCA algorithm. Among these, the F324Y mutation demonstrated exceptional performance, increasing the product yield by 73 %. We constructed a de novo (–)-α-bisabolol biosynthesis pathways through systematic synthetic biology strategies, including the enzyme design of BOS, selection of different linkers in fusion expression, and optimization of the mevalonate pathway, weakening the branching metabolic flow and multi-copy strategies, the yield of (–)-α-bisabolol was significantly increased, which was nearly 35-fold higher than that of the original strain (2.03 mg/L). The engineered strain was capable of producing 69.7 mg/L in shake flasks. To the best of our knowledge, this is the first report on the biosynthesis of (–)-α-bisabolol in Komagataella phaffii, implying this is a robust cell factory for sustainable production of other terpenoids.

Abstract Background Acinetobacter baumannii (A. baumannii) is a common opportunistic pathogen in hospitals that causes nosocomial infection. In order to understand the phenotypic and genotypic characteristics of A. baumannii isolates, we sequenced and analyzed 62 A. baumannii isolates from a hospital in Gansu province. Results Non-repeated 62 A. baumannii isolates were collected from August 2015 to November 2021. Most isolates (56/62) were resistant to multiple drugs. All the 62 A. baumannii isolates were resistant to aztreonam and contained bla ADC-25 gene which exists only on chromosome contigs. The 62 isolates in this study were not clustered in a single clade, but were dispersed among multiple clades in the common genome. Seven sequence types were identified by Multilocus sequence type (MLST) analysis and most isolates (52/62) belonged to ST2. The plasmids were grouped into 11 clusters by MOB-suite. Conclusions This study furthers the understanding of A. baumannii antimicrobial-resistant genotypes, and may aid in prevention and control nosocomial infection caused by drug-resistant A. baumannii.

Abstract Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D) culture model, closely mimics tissues or organs in vivo. Insulin-secreting islet organoid, derived from stem cells induced in vitro with 3D structures, has emerged as a potential alternative for islet transplantation and as a possible disease model that mirrors the human body’s in vivo environment, eliminating species difference. This technology has gained considerable attention for its potential in diabetes treatment. Despite advances, the process of stem cell differentiation into islet organoid and its cultivation demonstrates deficiencies, prompting ongoing efforts to develop more efficient differentiation protocols and 3D biomimetic materials. At present, the constructed islet organoid exhibit limitations in their composition, structure, and functionality when compared to natural islets. Consequently, further research is imperative to achieve a multi-tissue system composition and improved insulin secretion functionality in islet organoid, while addressing transplantation-related safety concerns, such as tumorigenicity, immune rejection, infection, and thrombosis. This review delves into the methodologies and strategies for constructing the islet organoid, its application in diabetes treatment, and the pivotal scientific challenges within organoid research, offering fresh perspectives for a deeper understanding of diabetes pathogenesis and the development of therapeutic interventions.

Abstract The Omicron subvariants BQ.1.1, XBB.1.5, and XBB.1.16 of SARS-CoV-2 are known for their adeptness at evading immune responses. Here, we isolate a neutralizing antibody, 7F3, with the capacity to neutralize all tested SARS-CoV-2 variants, including BQ.1.1, XBB.1.5, and XBB.1.16. 7F3 targets the receptor-binding motif (RBM) region and exhibits broad binding to a panel of 37 RBD mutant proteins. We develop the IgG-like bispecific antibody G7-Fc using 7F3 and the cross-neutralizing antibody GW01. G7-Fc demonstrates robust neutralizing activity against all 28 tested SARS-CoV-2 variants and sarbecoviruses, providing potent prophylaxis and therapeutic efficacy against XBB.1 infection in both K18-ACE and BALB/c female mice. Cryo-EM structure analysis of the G7-Fc in complex with the Omicron XBB spike (S) trimer reveals a trimer-dimer conformation, with G7-Fc synergistically targeting two distinct RBD epitopes and blocking ACE2 binding. Comparative analysis of 7F3 and LY-CoV1404 epitopes highlights a distinct and highly conserved epitope in the RBM region bound by 7F3, facilitating neutralization of the immune-evasive Omicron variant XBB.1.16. G7-Fc holds promise as a potential prophylactic countermeasure against SARS-CoV-2, particularly against circulating and emerging variants.

IntroductionIn the face of global challenges, higher education is regarded as an important force to promote the achievement of the 2030 Sustainable Development Goals (SDGs). Existing research has focused on articulating and analyzing the impact of value shaping for sustainable growth in higher education, although articulation and systematic analysis of higher education policy remain lacking.MethodsBased on the policy tool perspective, this paper constructed a three-dimensional analysis framework by using content analysis and the PMC index model to undertake a thorough analysis of higher education policies published at the central level in China from 2009 to 2024.ResultsThis study found that current higher education policies had multiple impacts on the formation of sustainable development values: (1) In the four dimensions of sustainable development proposed by the United Nations, China's higher education policy had shown clear guiding ideology and action direction; (2) In shaping sustainable values, China's higher education policies showed clear progress in three key dimensions; (3) The value and innovation of this study in shaping the values of sustainable development in higher education policies were primarily expressed in the following aspects.DiscussionThis paper suggested a way for optimizing the design of China's higher education policies, providing empirical data and theoretical support for China's higher education policies to better promote the ideals of sustainable development.

BackgroundSubstantial studies reveal that tertiary lymphoid structure (TLS) correlate with prognosis and immunotherapy response in various types of cancers. However, the predictive value of TLS, the specific immune cell subtype within TLS and their anti-tumor mechanisms remain unclear.MethodsBased on 23 TLS-related genes (TLSRGs), we utilized bioinformatics methods to construct a scoring system, named TLSscore. By integrating RNA and single-cell sequencing data, we assessed the utility of TLSscore in head and neck squamous cell carcinoma (HNSCC). Flow cytometric sorting was used to isolate specific T cells subtypes, in vivo and in vitro experiments were conducted to demonstrate its anti-tumor effects.ResultsThe TLSscore model was constructed and specific TLSscore-genes were found to consistently align with the spatial location of TLS. TLSscore has proven to be a robust predictive model for predicting survival prognosis, immune cell infiltration, somatic mutation and immunotherapy response. Notably, a specific PD1+CXCL13+CD8+T cell subtype was identified within TLS. Both in vivo and in vitro experiments demonstrated that PD1+CXCL13+CD8+T cell might represent a functional cell subtype exerting anti-tumor effects during the process of immune surveillance.ConclusionsOur study presents a predictive model for TLS, which can evaluate its presence and predicts survival prognosis and immunotherapy response in HNSSC patients. Additionally, we identify a specific subtype of T cells that might elucidate the mechanism of TLS function in anti-tumor activities. This T cell subtype holds the potential to be a prognostic marker and a target for adoptive cell therapy (ACT) in the future.

Mitotic anaphase onset is a key cellular process tightly regulated by multiple kinases. The involvement of mitogen-activated protein kinases (MAPKs) in this process has been established in Xenopus egg extracts. However, the detailed regulatory cascade remains elusive, and it is also unknown whether the MAPK-dependent mitotic regulation is evolutionarily conserved in the single-cell eukaryotic organisms such as fission yeast (Schizosaccharomyces pombe). Here, we show that two MAPKs in S. pombe indeed act in concert to restrain anaphase-promoting complex/cyclosome (APC/C) activity upon activation of the spindle assembly checkpoint (SAC). One MAPK, Pmk1, binds to and phosphorylates Slp1Cdc20, the co-activator of APC/C. Phosphorylation of Slp1Cdc20 by Pmk1, but not by Cdk1, promotes its subsequent ubiquitylation and degradation. Intriguingly, Pmk1-mediated phosphorylation event is also required to sustain SAC under environmental stress. Thus, our study establishes a new underlying molecular mechanism of negative regulation of APC/C by MAPK upon stress stimuli, and provides a previously unappreciated framework for regulation of anaphase entry in eukaryotic cells.

Objectives With the emergence of new COVID-19 variants (Omicron BA.5.2.48 and B.7.14), predicting the mortality of infected patients has become increasingly challenging due to the continuous mutation of the virus. Existing models have shown poor performance and limited clinical utility. This study aims to identify the independent risk factors and develop practical predictive models for mortality among patients infected with new COVID-19 variants.Design A retrospective study.Setting and participants We extracted data from 1029 COVID-19 patients in the respiratory disease wards of a general hospital in China between 22 December 2022 and 15 February 2023.Outcome measures Mortality within 15 days after hospital discharge.Results A total of 987 cases with new COVID-19 variants (Omicron BA.5.2.48 and B.7.14) were eventually included, among them, 153 (15.5%) died. Non-invasive ventilation, intubation, myoglobin, international normalised ratio, age, number of diagnoses, respiratory rate, pulse, neutrophil count and albumin were the most important predictors of mortality among new COVID-19 variants. The area under the curve of logistic regression (LR), decision tree (DT) and Extreme Gradient Boosting (XGBoost) models were 0.959, 0.883 and 0.993, respectively. The diagnostic accuracy was 0.926 for LR, 0.918 for DT and 0.977 for XGBoost. XGBoost model had the highest sensitivity (0.908) and specificity (0.989).Conclusion Our study developed and validated three practical models for predicting mortality in patients with new COVID-19 variants. All models performed well, and XGBoost was the best-performing model.

The traditional stir-fry process before pressing is crucial to manufacture Hainan camellia oil. To assess the effects of the stir-fry process on Hainan camellia oil, six samples across different stir-fry stages were analyzed. The stir-fry process modified odors, volatile metabolite profiles, and human health-promoting functions of Hainan camellia oil. Totally, 350 volatile metabolites were detected, and heterocyclic compounds were revealed as the main contributors of strong aroma. Potential indicators for monitoring the stir-fry degree were established. Eight key aroma volatile metabolites were identified, including three new ones (1-octen-3-one, 2,3-butanedione, and vanillin). Lipids degradation and the Millard reaction are probably the main pathways for aroma generation. Over-stir-fry treatment diminished the contents of some important volatile metabolites but increased the risk of arising burnt odor. Our work offered insights into the effects of the stir-fry process and over-stir-fry treatment on Hainan camellia oil, which is meaningful for improving the hot-pressing technique.

Abstract Natural photosynthesis enzymes utilize energies of several photons for challenging oxidation of water, whereas artificial photo‐catalysis typically involves only single‐photon excitation. Herein, a multiphoton excitation strategy is reported that combines parallel photo‐excitations with a photoinduced electron transfer process for the activation of C(sp3)─H bonds, including methane. The metal–organic framework Fe3‐MOF is designed to consolidate 4,4′,4″‐nitrilotrisbenzoic units for the photoactivation of dioxygen and trinuclear iron clusters as the HAT precursor for photoactivating alkanes. Under visible light irradiation, the dyes and iron clusters absorbed parallel photons simultaneously to reach their excited states, respectively, generating 1O2 via energy transfer and chlorine radical via ligand‐to‐metal charge transfer. The further excitation of organic dyes leads to the reduction of 1O2 into O2•− through a photoinduced electron transfer, guaranteeing an extra multiphoton oxygen activation manner. The chlorine radical abstracts a hydrogen atom from alkanes, generating the carbon radical for further oxidation transformation. Accordingly, the total oxidation conversion of alkane utilizing three photoexcitation processes combines the energies of more than two photons. This new platform synergistically combines a consecutive excited photoredox organic dye and a HAT catalyst to combine the energies of more than two photons, providing a promising multiphoton catalysis strategy under energy saving, and high efficiency.

Abstract Background Patients in spine surgery often have emotional disorders which is caused by multi-factors. Therefore, a multidisciplinary and multimodal intervention program is required to improve emotional disorders during the perioperative period. However, related studies were rare. This study aimed to confirm that the multidisciplinary-based psychological management leading by nurses was effective in treating emotional disorders and show the assignments of the members of the multidisciplinary team with the orientations of nurses. Design A retrospective, comparative study. Method This study was a retrospective cohort research and compared the results between the intervention group and control group using the Huaxi Emotional Distress Index (HEI) which was used to evaluate emotional disorders. The intervention group consisted of patients who underwent surgery between January 2018 and December 2020 after psychological management was implemented. The control group consisted of patients with regular care who underwent surgery between January 2015 and December 2017. To improve comparability between the two groups, baseline data from the recruited patients were analyzed using propensity-score-matching (PSM) based on age, sex, marital status, education, and disease region. Results A total of 539 (11.5%) people developed emotional disorders, of which 319 (6.8%), 151 (3.2%) and 69 (1.5%) had mild, moderate mood and severe emotional disorders, respectively. 2107 pairs of patients were matched after PSM. Scores of HEI in the intervention group were heightened compared with those in the control group (P

Abstract Traditional Chinese medicinal books have noted that sea bass (Lateolabrax maculatus) may effectively manage inflammation‐linked conditions. The folk use of sea bass during pregnancy as nutritional care is also popular in China. However, scientific verification of health benefits of sea bass remains a lack of report. Our previous studies have proven that sea bass has therapeutic benefits for ulcerative colitis (UC). However, a further investigation on the interacted mechanism among sea bass, UC, and gut microbiota has still not been fully explored and clarified. Hence, gut microbiota as the crucial mechanism of UC was evaluated. Gut ecosystem was analyzed by 16sRNA sequencing. The potential microbial biomarker was found through LEfSe analysis. Flow cytometry was then further applied to verify the identified biomarker. Results revealed that sea bass could effectively recover the abundance of UC‐mediated microbiota. LEfSe analysis found that Christensenellaceae could be identified as the potential biomarker for sea bass‐mediated gut microbiota in UC. Further in vitro study conjointly confirmed that the identified bioactive constituent of sea bass could significantly promote the growth of Christensenella minuta. Sufficient results derived that sea bass could ameliorate UC through gut microbiota modulation. C. minuta was identified as the promising microbial biomarker for the mechanism of sea bass in treating intestinal inflammation. It provided further elucidation on the pharmacological mechanism of sea bass in alleviating UC through gut microbiota modulation. It is a crucial driving force for the progress of scientific research on the dietary therapy of sea bass.

Introduction Patients with hemophilia (PWH) constantly suffer hemarthrosis, which leads to deformity of the hip joint. Therefore, PWH who are going to receive total hip arthroplasty (THA) should be exclusively treated before the surgery with careful measurement of their proximal femur. Hence, we conducted a retrospective study to explore the anatomical parameters of and differences in the proximal femur in hemophilic patients who underwent THA. Methods The retrospective study comprised data of adult patients who received total hip arthroplasty from 2020 to 2022 in the research center. Patients having a diagnosis of hemophilic arthritis and received THA were included in experimental group, and patients with hip arthritis or femoral head necrosis were taken as control group. Parameters including femoral offset, neck‐shaft angle (NSA), medullary cavity of 20 mm above mid‐lesser trochanter level (T+20), mid‐lesser trochanter level (T), and 20 mm blow it (T−20), and canal flare index (CFI), femoral cortical index (FCI) were measured on X‐ray and CT images with PACS by two independent doctors. Data was analyzed by SPSS 20. Kolmogorov–Smirnov test was used to test data normality. Student's t‐test was performed between PWH and control group. p

BackgroundThere is a growing interest in the use of complementary therapies for the prevention of disease and the maintenance of health. Furthermore, complementary therapies that incorporate exercise are becoming increasingly prevalent among the older adult, and thus may represent a crucial strategy for the primary and secondary prevention of cardiovascular disease (CVD). Exercise therapy, as a means to prevent and treat cardiovascular diseases, has been gradually applied in clinical practice. It has the advantages of reducing mortality, improving clinical symptoms, restoring physical function and improving quality of life. In recent years, traditional Chinese sports such as Ba Duan Jin and Qigong have developed rapidly. Therefore, a comprehensive systematic review is required to examine interventions involving Ba Duan Jin exercise in healthy adults or those at increased risk of CVD in order to determine the effectiveness of Ba Duan Jin exercise for the primary prevention of CVD.ObjectiveTo investigate the effect of Ba Duan Jin exercise intervention for the primary prevention of cardiovascular diseases.MethodsEight databases were systematically searched from inception to July, 2024 for randomized controlled trials (RCTs) to evaluated the impact of Ba Duan Jin exercise intervention on cardiovascular diseases. The search terms were “Cardiovascular diseases” “Ba Duan Jin” and “Randomized controlled.” The Cochrane risk assessment tool was used to evaluate the study quality, and the meta-analysis was performed using Rev. Man 5.4 software.ResultsSeventeen completed trials were conducted with 1,755 participants who were randomly assigned and met the inclusion criteria. All 17 studies were conducted in China. The meta-analysis indicates that Ba Duan Jin exercise therapy can provide long-term benefits (20–30 years) by reducing all-cause mortality (RR = 0.55, 95% CI: 0.44–0.68, p

The squeeze film damper (SFD) is a damping device that has been widely used in rotating machines. The SFD can effectively suppress rotor vibration and reduce transmitted forces. However, it would cause complex motions of the rotor system under specific operating conditions. This paper investigates the support structure of a high-pressure stage simulated rotor in an aircraft engine. A dynamic model of the SFD considering the effects of inertia and cavitation is established to investigate the influence of structural parameters on the stiffness and damping coefficient of the damper. Subsequently, a finite element model of the Jeffcott rotor–SFD system is developed to explore the effects of the structure parameters of the SFD on the critical speed, mode shapes, and other dynamic characteristics of the Jeffcott rotor–SFD system. Experimental tests are conducted to validate and refine the numerical calculations regarding the dynamic characteristics of the rotor–damper system. The results indicate that there is consistency between numerical simulations and experimental results. Within a certain range, enlarging the width of the damper can significantly increase the magnitude of the pressure distribution of the oil film. However, when the pressure amplitude increases to the saturation vapor pressure of the lubricating oil, the cavitation effect begins to manifest. As the width of the damper increases, both the stiffness coefficient and damping coefficient of the SFD are enhanced. Consequently, the vibration reduction effectiveness of the SFD is significantly improved.

Abstract Purpose Previous studies have shown that DNA methyltransferase 3b (Dnmt3b) is the only Dnmt responsive to fracture repair and Dnmt3b ablation in Prx1-positive stem cells and chondrocyte cells both delayed fracture repair. Our study aims to explore the influence of Dnmt3b ablation in Gli1-positive stem cells in fracture healing mice and the underlying mechanism. Methods We generated Gli1-CreERT2; Dnmt3bflox/flox (Dnmt3b Gli1ER ) mice to operated tibia fracture. Fracture callus tissues of Dnmt3b Gli1ER mice and control mice were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and TUNEL assay. Results The cartilaginous callus significantly decrease in ablation of Dnmt3b in Gli1-positive stem cells during fracture repair. The chondrogenic and osteogenic indicators (Sox9 and Runx2) in the fracture healing tissues in Dnmt3b Gli1ER mice much less than control mice. Dnmt3b Gli1ER mice led to delayed bone callus remodeling and decreased biomechanical properties of the newly formed bone during fracture repair. Both the expressions of Caspase-3 and Caspase-8 were upregulated in Dnmt3b Gli1ER mice as well as the expressions of BCL-2. Conclusions Our study provides an evidence that Dnmt3b ablation Gli1-positive stem cells can affect fracture healing and lead to poor fracture healing by regulating apoptosis to decrease chondrocyte hypertrophic maturation.

Abstract Poor efficiency of dietary fibre utilization not only limits global pork production profit margin but also adversely affects utilization of various dietary nutrients. Poor efficiency of dietary nutrient utilization further leads to excessive excretion of swine manure nutrients and results in environmental impacts of emission of major greenhouse gases (GHG), odor, nitrate leaching and surface-water eutrophication. Emission of the major GHG from intensive pork production contributes to global warming and deteriorates heat stress to pigs in tropical and sub-tropical swine production. Exogenous fibre enzymes of various microbial cellulases, hemicellulases and pectinases have been well studied and used in swine production as the non-nutritive gut modifier feed enzyme additives in the past over two decades. These research efforts have aimed to improve growth performance, nutrient utilization, intestinal fermentation as well as gut physiology, microbiome and health via complementing the porcine gut symbiotic microbial fibrolytic activities towards dietary fibre degradation. The widely reported exogenous fibre enzymes include the singular use of respective cellulases, hemicellulases and pectinases as well as their multienzyme cocktails. The currently applied exogenous fibre enzymes are largely limited by their inconsistent in vivo efficacy likely due to their less defined enzyme stability and limited biochemical property. More recently characterized monomodular, multifunctional and processive endoglucanases have the potential to be more efficaciously used as the next-generation designer fibre biocatalysts. These newly emerging multifunctional and processive endoglucanases have the potential to unleash dietary fibre sugar constituents as metabolic fuels and prebiotics, to optimize gut microbiome, to maintain gut permeability and to enhance performance in pigs under a challenged environment as well as to parallelly unlock biomass to manufacture biofuels and biomaterials.

Objective Existing studies have conflicting results about the predictors of forgotten joints in patients with total knee arthroplasty (TKA), and the relationship between psychosocial factors and forgotten knees is unknown. The purpose of this study was to confirm predictors for the forgotten joint in TKA patients. Methods This was an observational, prospective longitudinal study. A total of 205 patients who underwent TKA and a 6‐month follow‐up were included between August 2020 and September 2021. Demographic characteristics, clinical characteristics, and psychosocial variables were collected before TKA surgery (T0). The forgotten joint score (FJS) was taken before TKA surgery (T0) and at 1 month (T1), 3 months (T3), and 6 months (T6) after TKA surgery. The psychosocial variables were also completed at T6. Bivariate and multivariable linear regressions (LR) were performed to screen the predictors associated with FJS (T6). Results Patients who underwent TKA in our study had a mean FJS of 20.3 ± 12.2 before surgery, 15.9 ± 10.3 at 1 month, 28.7 ± 12.6 at 3 months, and 40.3 ± 12.5 at 6 months. The predictors were sex, combined musculoskeletal disorders (MSD), operation time, FJS (T3), range of motion (ROM) (T6), pain score (T6), Groningen orthopaedic social support scale (GO‐SSS) score (T6), and the generalized anxiety disorder scale (GAD) score (T6). The data satisfied the assumptions of multivariable linear regressions. The multiple R2of LR was 0.71, and the adjusted R2 was 0.70. The F‐statistic of the LR model was 59.5 (p

Urethane surfactants (REQ) were synthesized with octadecanol ethoxylate (AEO) and isocyanate methacrylate (IEM). Subsequently, reactive-carbamate-surfactant-modified nanomicrospheres (PER) were prepared via two-phase aqueous dispersion polymerization using acrylamide (AM), 2-acrylamido-2-methylpropanesulfonic acid (AMPS) and ethylene glycol dimethacrylate (EGDMA). The microstructures and properties of the nanomicrospheres were characterized and examined via infrared spectroscopy, nano-laser particle size analysis, scanning electron microscopy, and in-house simulated exfoliation experiments. The results showed that the synthesized PER nanomicrospheres had a uniform particle size distribution, with an average size of 336 nm. The thermal decomposition temperature of the nanomicrospheres was 278 °C, and the nanomicrospheres had good thermal stability. At the same time, the nanomicrospheres maintained good swelling properties at mineralization < 10,000 mg/L and temperature < 90 °C. Under the condition of certain permeability, the blocking rate and drag coefficient gradually increased with increasing polymer microsphere concentration. Furthermore, at certain polymer microsphere concentrations, the blocking rate and drag coefficient gradually decreased with increasing core permeability. The experimental results indicate that nanomicrospheres used in the artificial core simulation drive have a better ability to drive oil recovery. Compared with AM microspheres (without REQ modification), nanomicrospheres exert a more considerable effect on recovery improvement. Compared with the water drive stage, the final recovery rate after the drive increases by 23.53%. This improvement is attributed to the unique structural design of the nanorods, which can form a thin film at the oil–water–rock interface and promote oil emulsification and stripping. In conclusion, PER nanomicrospheres can effectively control the fluid dynamics within the reservoir, reduce the loss of oil and gas resources, and improve the economic benefits of oil and gas fields, giving them a good application prospect.

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of Tnxb in F8-/- mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss. Tnxb knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following Tnxb knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.

Competence development is essential for bacterial transformation since it enables bacteria to take up free DNA from the surrounding environment. The regulation of teichoic acid biosynthesis is tightly controlled during pneumococcal competence; however, the mechanism governing this regulation and its impact on transformation remains poorly understood. We demonstrated that a defect in lipoteichoic acid ligase (TacL)-mediated lipoteichoic acids (LTAs) biosynthesis was associated with impaired pneumococcal transformation. Using a fragment of tacL regulatory probe as bait in a DNA pulldown assay, we successfully identified several regulatory proteins, including ComE. Electrophoretic mobility shift assays revealed that phosphomimetic ComE, but not wild-type ComE, exhibited specific binding to the probe. DNase I footprinting assays revealed the specific binding sequences encompassing around 30 base pairs located 31 base pairs upstream from the start codon of tacL. Expression of tacL was found to be upregulated in the ΔcomE strain, and the addition of exogenous competence-stimulating peptide repressed the tacL transcription in the wild-type strain but not the ΔcomE mutant, indicating that ComE exerted a negative regulatory effect on the transcription of tacL. Mutation in the JH2 region of tacL upstream regulatory sequence led to increased LTAs abundance and displayed higher transformation efficiency. Collectively, our work identified the regulatory mechanisms that control LTAs biosynthesis during competence and thereby unveiled a repression mechanism underlying pneumococcal transformation.

Abstract Background The emergence of proprotein convertase subtilisin/kexin type 9 inhibitors offered dyslipidemia patients an alternative to statins for lipid‐lowering treatment. Understanding patient and physician preferences for lipid‐lowering drugs may promote shared decision‐making and improve treatment outcomes. Methods This study utilized an online discrete choice experiment (DCE) to assess the relative importance (RI) of six attributes related to lipid‐lowering drugs, including frequency of administration, mode of administration, reduction of low‐density lipoprotein cholesterol (LDL‐C) level, risk of myopathy, risk of liver damage, and out‐of‐pocket monthly cost. Respondents were recruited from dyslipidemia patients and cardiovascular physicians in China. A mixed logit model and latent class analysis were employed to estimate the preference coefficient, marginal willingness to pay (mWTP), and RI of attributes. Ethical approval has been obtained for this study. Results A total of 708 patients and 507 physicians participated in the survey. Patients prioritized the ‘risk of liver damage’ (RI = 23.6%) with ‘mode of administration’ (RI = 19.2%) and ‘frequency of administration’ (RI = 18.8%) following closely. Contrarily, physicians prioritized the ‘reduction of LDL‐C level’ (RI = 33.5%), followed by ‘risk of liver damage’ (RI = 26.0%) and ‘risk of myopathy’ (RI = 16.1%). Patients placed a higher value on ‘frequency of administration’ (p

Background: Bufei Huoxue capsule (BFHX) is widely used for the clinical treatment of chronic obstructive pulmonary disease (COPD) in China.Objectives: The aim of this study is to explore the effects on COPD and the underlying mechanism of BFHX.The process and methods: In this study, we established a COPD mouse model through cigarette smoke (CS) exposure in combination with lipopolysaccharide (LPS) intratracheal instillation. Subsequently, BFHX was orally administrated to COPD mice, and their pulmonary function, lung pathology, and lung inflammation, including bronchoalveolar lavage fluid (BALF) cell count and classification and cytokines, were analyzed. In addition, the anti-oxidative stress ability of BFHX was detected by Western blotting, and the bacterial diversity, abundance, and fecal microbiome were examined using 16S rRNA sequencing technology.Outcome: BFHX was shown to improve pulmonary function, suppress lung inflammation, decrease emphysema, and increase anti-oxidative stress, whereas 16S rRNA sequencing indicated that BFHX can dynamically regulate the diversity, composition, and distribution of the intestinal flora microbiome and regulate the lysine degradation and phenylalanine metabolism of COPD mice. These results highlight another treatment option for COPD and provide insights into the mechanism of BFHX.

BackgroundThe use of multidisciplinary treatment programs in out-of-hospital healthcare is a new area of research. Little is known about the benefits of this method in the management of discharged patients undergoing cervical spondylosis surgery.ObjectiveThis study aimed to explore the effect of a contracted-based, multidisciplinary follow-up plan in patients after cervical spondylosis surgery.MethodsThis non-blinded non-randomized controlled study was conducted with 88 patients (44 in the intervention group, 44 in the control group). The clinical outcomes, including Neck Disability Index (NDI), pain score (VAS), Self-Efficacy for Managing Chronic Disease 6-item Scale (SECD-6), and 12-Item Short-Form Health Survey (SF-12) score were assessed at the time of discharge, 24–72 h, 1 month, and 3 months post-discharge. The complications, patient satisfaction, and economic indicators were assessed at the final follow-up (3 months).ResultsPatients who received contracted follow-up showed greater improvement in neck dysfunction at 24–72 h, 1 month, and 3 months after discharge compared to those who received routine follow-up (p

Lentiviral vectors (LVs) have been widely used as a tool for gene therapies. However, tissue-selective transduction after systemic delivery remains a challenge. Inducible degrader of low-density lipoprotein receptor is an attractive target for treating hypercholesterolemia. Here, a liver-targeted LV, CS8-LV-shIDOL, is developed by incorporating a hepatocyte-targeted peptide derived from circumsporozoite protein (CSP) into the lentivirus envelope for liver-targeted delivery of IDOL-shRNA (short hairpin RNA) to alleviate hypercholesterolemia. Tail-vein injection of CS8-LV-shIDOL results in extremely high accumulation in liver and nearly undetectable levels in other organs in mice. In addition, it shows superior therapeutic efficacy in lowering serum low-density lipoprotein cholesterol (LDL-C) and reducing atherosclerotic lesions over unmodified LV-shIDOL in hyperlipidemic mice. Mechanically, the envelope-engineered CS8-LV-shIDOL can enter liver cells via low-density lipoprotein receptor-related protein (LRP). Thus, this study provides a novel approach for liver-targeted delivery of IDOL-shRNA to treat hypercholesterolemia by using an envelope-engineered LV, and this delivery system has great potential for liver-targeted transgene therapy.

Background: The progression and metastasis of tumors are typically accompanied by angiogenesis. Crucially, vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a significant role in tumor-associated angiogenesis. In this study, the aim was to investigate the antitumor effect of combining bevacizumab (Bev) with anlotinib (An) on colorectal cancer (CRC). Methods: The CCK-8 assay, EdU assay, and Annexin V staining were conducted to evaluate the proliferation and apoptosis of CRC cells in vitro. The migration capability of CRC cells and HUVECs was assessed using the Transwell assay. Additionally, the tube formation capability of HUVECs was investigated. Furthermore, the antitumor and antiangiogenic effects were evaluated in the BALB/c mice model using immunohistochemistry, TUNEL staining, and 18F-FDG PET/CT imaging. Finally, we analyzed the inhibitory effect of Bev and/or An on related signaling effectors through western blotting. Results: The in vivo CRC mice model revealed that the combination of Bev + An significantly suppressed tumor formation and angiogenesis. Bev + An inhibited tumor glucose metabolism and increased the median survival period in tumor-bearing mice. Mechanistically, the expressions of VEGF, VEGFR2, PDGFR, and FGFR, as well as the phosphorylation levels of AKT, were inhibited after Bev+An treatment. In conclusion, the dual vertical targeting of VEGF and VEGFR in the CRC mice model strongly inhibited tumor growth and angiogenesis, with the suppression of the AKT signaling pathway playing a partial role.

In this study, label-free proteomic technology was applied to analyze and compare the whey proteomes of porcine colostrum and mature milk. In total, 2993 and 2906 whey proteins were detected in porcine colostrum and mature milk, respectively. A total of 2745 common proteins were identified in the two milk samples, and 280 proteins were found to be significantly differentially expressed whey proteins in porcine milk. Gene Ontology analysis demonstrated that the differentially expressed whey proteins were primarily enriched in lipid homeostasis, oxidoreductase activity, and the collagen trimer. Kyoto Encyclopedia of Genes and Genomes analysis suggested that the phagosome and endocytosis were the crucial pathways. This study provides systematic and in-depth insight into the compositions and functional properties of whey proteins in porcine milk during different periods of lactation, which may be beneficial for the development of porcine whey proteins in the future.

Abstract Bile duct tumor thrombosis (BDTT) is a complication mostly observed in patients with advanced hepatocellular carcinoma (HCC), causing jaundice and associated with poor clinical outcome. However, its underlying molecular mechanism is unclear. Here, we develop spontaneous preclinical HCC animal models with BDTT to identify the role of BMI1 expressing tumor initiating cells (BMI1high TICs) in inducing BDTT. BMI1 overexpression transforms liver progenitor cells into BMI1high TICs, which possess strong tumorigenicity and increased trans-intrahepatic biliary epithelial migration ability by secreting lysosomal cathepsin B (CTSB). Orthotopic liver implantation of BMI1high TICs into mice generates tumors and triggers CTSB mediated bile duct invasion to form tumor thrombus, while CTSB inhibitor treatment prohibits BDTT and extends mouse survival. Clinically, the elevated serum CTSB level determines BDTT incidence in HCC patients. Mechanistically, BMI1 epigenetically up-regulates CTSB secretion in TICs by repressing miR-218-1-3p expression. These findings identify a potential diagnostic and therapeutic target for HCC patients with BDTT.

Abstract Conventional chemotherapy targets malignant cells without evaluating counter protection from the tumor microenvironment that often causes treatment failure. Herein, we establish chemoresistant fibroblasts (rCAFs) as regulators of neoadjuvant chemotherapeutic (NACT) response in head and neck squamous cell carcinoma (HNSCC). Clinically, high expression of CAF-related gene signature correlates with worse prognosis and chemotherapeutic response in multiple cancers, while the population of CAFs in the residual tumors of chemoresistant HNSCC patients remains unchanged after NACT treatment, compared to chemosensitive patients. Using a murine cancer model or patient-derived organoid, and primary CAFs isolated from chemo-sensitive (sCAFs) or -resistant patients, we show that rCAFs, but not sCAFs, are resistant to chemotherapy-induced apoptosis while reducing HNSCC cell chemosensitivity via paracrine signals. Combined multi-omics and biochemical analyses indicate an elevated PI3K/AKT/p65 driven cell survival and cytokine production in rCAFs, while rCAF-secreted TGFα promotes cancer cell chemoresistance by activating EGFR/Src/STAT3 survival signaling axis. Treatment with anti-EGFR cetuximab restores the chemosensitivity of tumors derived from co-injection of cancer cells and rCAFs in vivo, while the serum level of TGFα determines NACT response in HNSCC patients. Overall, our findings uncover a novel insight whereby the crosstalk between tumor cell and rCAF determines chemotherapeutic response and prognosis in cancer patients.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is characterised by limited responses to chemoimmunotherapy attributed to highly desmoplastic tumor microenvironment. Disrupting the tumor-stromal cell crosstalk is considered as an improved PDAC treatment strategy, whereas little progress has been made due to poor understanding of its underlying mechanism. Here, we examined the cellular role of melanoma associated antigen A isoforms (MAGEA) in regulating tumor-stromal crosstalk mediated chemoresistance. Methods We used clinical samples to explore the correlation between MAGEA expression and patient prognosis in multiple cancers. We utilized cancer cell lines, patient derived organoids and orthotopic PDAC model to examine the function of MAGEA in chemoresistance. We performed biochemical, proteome profiler array and transcriptional analysis to uncover a mechanism that governs tumor-stromal crosstalk. We developed a multi-MAGEA antigen targeted DNA vaccine and tested its effect on PDAC tumor growth. Results We establish MAGEA as a regulator of the tumor-stromal crosstalk in PDAC. We provide strong clinical evidence indicating that high MAGEA expression, including MAGEA2, MAGEA3 and MAGEA10, correlates with worse chemotherapeutic response and poor prognosis in multiple cancers, while their expression is up-regulated in chemoresistant PDAC patient derived organoids and cancer cell lines. Mechanistically, MAGEA2 prohibits gemcitabine-induced JNK-c-Jun-p53 mediated cancer cell apoptosis, while gemcitabine stimulated pancreatic stellate cells secretes GDF15 to further enhance the gemcitabine resistance of MAGEA2 expressing cells by activating GFRAL-RET mediated Akt and ERK1/2 dependent survival pathway. Strikingly, immunization with a DNA vaccine that targeting multiple MAGEA antigens, including MAGEA2, MAGEA3 and MAGEA10, elicits robust immune responses against the growth of gemcitabine resistant tumors. Conclusions These findings suggest that targeting MAGEA-mediated paracrine regulation of chemoresistance by immunotherapy can be an improved pancreatic cancer treatment strategy.

Donkey milk has a variety of physiological functions, including antibacterial and anti-inflammatory. Donkey whey proteins (DWPs), as the main functional component in donkey milk, its inhibitory effect on colitis is still unclear. In this study, the inhibitory effect and potential mechanism of DWPs on dextran sulfate sodium (DSS)-induced colitis were investigated. Firstly, the DWPs and bovine milk whey proteins (BWPs) were characterized using proteomics. Then, we administered DWPs and BWPs to mice with colitis via oral gavage. The results of immunohistochemistry and flow cytometry indicated that DWPs increased T regulatory cell accumulation and increased the abundance of the cluster of differentiation 205+ (CD205+) macrophages compared to those with BWPs and in model groups. In addition, DWPs exhibited a more remarkable ability to inhibit pro-inflammatory proteins (S100A8, TRAF6, and NF-κB) expression and inflammatory secretion than BWPs. In addition, DWPs significantly decreased NF-κB and CD86 levels more than BWPs or the negative control in both LPS-stimulated human peripheral blood mononuclear cells or cell lines. These findings indicate that DWPs comprise a promising anti-colitis functional food, and this work has established a foundation for future research on these compounds.

Glucocorticoid-induced osteonecrosis of the femoral head (GONFH) is a common refractory joint disease characterized by bone damage and the collapse of femoral head structure. However, the exact pathological mechanisms of GONFH remain unknown. Here, we observed abnormal osteogenesis and adipogenesis associated with decreased β-catenin in the necrotic femoral head of GONFH patients. In vivo and in vitro studies further revealed that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation of bone marrow mesenchymal cells (BMSCs) by inhibiting β-catenin signaling in glucocorticoid-induced GONFH rats. Col2+ lineage largely contributes to BMSCs and was found an osteogenic commitment in the femoral head through 9 mo of lineage trace. Specific deletion of β-catenin gene (Ctnnb1) in Col2+ cells shifted their commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice. Overall, we uncover that β-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of GONFH and identify an ideal genetic-modified mouse model of GONFH.

Nowadays, in view of the increasingly serious problems of electromagnetic interference (EMI) and radiation pollution, smart EMI shielding materials with tunable shielding effectiveness (SE), especially “On/Off” switchable capability, are highly desirable. Herein, Co‐based amorphous wires (AWs) with excellent soft magnetic and mechanical properties are regularly arranged on a 3D‐printed mold as tunable EMI shielding composites. The EMI SE can be easily tuned in the range of ≈0.6–24.7 dB by way of rotation, which has been confirmed to be an effective way to achieve free tuning of EMI SE by simulation. In addition, by compositing AWs with reduced graphene oxide and constructing a double‐layer structure with a gap of 1/4 wavelength in the X‐band, a much wider SE tuning range of ≈1.0–57.7 dB is further realized. The representative “On/Off” switchable shielding capability that can switch between EM transmission and effective shielding, together with the wide SE tuning range larger than 50 dB, shows the great potential of Co‐based AW composites in smart EMI shielding applications.

Background. Local infiltration analgesia (LIA) provides postoperative analgesia for total knee arthroplasty (TKA). The purpose of this study was to evaluate the analgesic effect of a cocktail of ropivacaine, morphine, and Diprospan for TKA. Methods. A total of 100 patients from September 2018 to February 2019 were randomized into 2 groups. Group A (control group, 50 patients) received LIA of ropivacaine alone (80 ml, 0.25% ropivacaine). Group B (LIA group, 50 patients) received an LIA cocktail of ropivacaine, morphine, and Diprospan (80 ml, 0.25% ropivacaine, 0.125 mg/ml morphine, and 62.5 μg/ml compound betamethasone). The primary outcomes were the levels of inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6), pain visual analog scale (VAS) scores, opioid consumption, range of motion (ROM), functional tests, and sleeping quality. The secondary outcomes were adverse events, satisfaction rates, HSS scores, and SF-12 scores. The longest follow-up was 2 years. Results. The two groups showed no differences in terms of characteristics (P > 0.05). Group B had lower resting VAS pain scores (1.54 ± 0.60, 95% CI = 1.37 to 1.70 vs. 2.00 ± 0.63, 95% CI = 2.05 to 2.34) and active VAS pain scores (2.64 ± 0.62, 95% CI = 2.46 to 2.81 vs. 3.16 ± 0.75, 95% CI = 2.95 to 3.36) within 48 h postoperatively than Group A (P

Unprogrammed macrophage polarization, especially prolonged activation of proinflammatory macrophages, is associated with delayed wound healing in diabetic objectives. Macrophage-derived exosomes cargo a variety of microRNAs (miRNAs), participating in different stages in wound healing. Here, exosomes were isolated from naive bone marrow–derived macrophages (BMDMs) (M0-Exos), interferon-γ plus lipopolysaccharide-polarized BMDMs (M1-Exos), and interleukin-4-polarized BMDMs (M2-Exos). M1-Exos impaired migration and tube formation in human umbilical vein endothelial cells (HUVECs) compared to M0-Exos, whereas M2-Exos exhibited the opposite effects. High-throughput sequencing was performed to decipher the miRNA expression profiles in M0-Exos, M1-Exos, and M2-Exos. A total of 63 miRNAs were identified to be differentially expressed in exosomes derived from polarized BMDMs. Among them, miRNA-155-5p is highly expressed in M1-Exos, which interrupted angiogenesis in HUVECs. Furthermore, miRNA-155-5p directly binds to the 3′ UTR of growth differentiation factor 6 (GDF6) mRNA to suppress its protein expression. Lastly, local administration of a temperature-sensitive hydrogel Pluronic F-127 loading miRNA-155-5p antagomiR promoted angiogenesis and accelerated wound healing in diabetic db/db mice via enhancing GDF6. In summary, this study deciphered the miRNA expression profiles in exosomes from polarized macrophages. M2-like macrophage-derived exosomes and miRNA-155-5p inhibitors could be promising therapeutics against diabetic foot ulcers.

Summary: Although numerous susceptibility loci are nominated for nicotine dependence (ND), no report showed any association of ARVCF with ND. Through genome-wide sequencing analysis, we first identified genetic variants associated nominally with ND and then replicated them in an independent sample. Of the six replicated variants, rs148582811 in ARVCF located in the enhancer-associated marker peak is attractive. The effective-median-based Mendelian randomization analysis indicated that ARVCF is a causal gene for ND. RNA-seq analysis detected decreased ARVCF expression in smokers compared to nonsmokers. Luciferase reporter assays indicated that rs148582811 and its located DNA fragment allele-specifically regulated ARVCF expression. Immunoprecipitation analysis revealed that transcription factor X-ray repair cross-complementing protein 5 (XRCC5) bound to the DNA fragment containing rs148582811 and allele-specifically regulated ARVCF expression at the mRNA and protein levels. With the Arvcf knockout mouse model, we showed that Arvcf deletion not only impairs hippocampus-dependent learning and memory, but also alleviated nicotine-induced memory deficits.

Drug resistance is one of the major causes of cancer treatment failures. In recent years, to combat the issue of drug resistance, a large volume of strategies has been established along the development of biomedical nanomaterials. Compared with traditional nanocarrier-based drug delivery strategies, in situ supramolecular self-assembly has emerged as a promising strategy to overcome drug resistance. This review first introduced the concept of in situ supramolecular self-assembly. The second part illustrated the mechanisms of constructing in situ supramolecular self-assembly as a multi-step process. The third part elucidated the role of in situ supramolecular self-assembly to reverse drug resistance, which included three categories: active self-assembly materials, drug-carrier self-assembly materials and drug-coupled self-assembly materials. At last, we summarized the current development of in situ supramolecular self-assembly for the reversal of drug resistance and the remaining concerns to be addressed.

Abstract Background Intraoperative cell salvage (ICS) is an important component of blood management in patients undergoing orthopedic surgery. However, the role of ICS is less well defined in total hip arthroplasty (THA) with subtrochanteric shortening osteotomy (SSO) which is a common surgical technique to manage high hip dislocation. This study aimed to determine the effect of ICS during THA with SSO and to identify factors associated with the ability to salvage sufficient collection for reinfusion in patients with high hip dislocation. Methods We identified 178 patients who underwent THA with SSO for high hip dislocation between November 2010 and April 2021. The consecutive cohort was analyzed by logistic regression to determine the effect of ICS on postoperative allogeneic blood transfusion (ABT) and to explore the associations between patient demographics, clinical and radiographic characteristics, preoperative laboratory examination, and surgical variables with the ability to generate adequate blood salvage to reinfuse. Results In the consecutive cohort of 178 patients, cell salvage was reinfused in 107 patients (60.1%) and postoperative allogeneic red blood cell (RBC) transfusion within 3 days of implantation was administrated in 40 patients (22.5%). In multivariate analysis, the reinfusion of ICS (OR (95%CI) 0.17 (0.07–0.47)), center of rotation (COR) height ≥ 60 mm (OR (95%CI) 3.30 (1.21–9.01)), the length of SSO ≥ 30 mm (OR (95%CI) 2.75 (1.05–7.22)) and the use of drainage (OR (95%CI) 2.28 (1.04–5.03)) were identified as independent factors of postoperative allogeneic RBC transfusion. In addition, the following variables were identified as independent factors associated with the ability to generate sufficient blood salvage volume for reinfusion: COR height ≥ 60 mm (OR (95%CI) 3.47 (1.58–7.61)), limb-length discrepancy (LLD) ≥ 25 mm (OR (95%CI) 2.55 (1.15–5.65)) and length of SSO ≥ 30 mm (OR (95%CI) 2.75 (1.33–5.69)). Conclusions ICS was efficacious in reducing the exposure rate of postoperative RBC transfusion for high hip dislocation during THA with SSO. In addition, patients with greater COR height, larger LLD, and longer length of SSO were predisposed to generate sufficient collection for reinfusion in THA with SSO.

High-voltage switchgear is a key control and protection unit in power systems. The reliable operation of the operating mechanism is essential for the reliable opening and closing of the switchgear. This is a vital guarantee for the safety and stability of the power systems. The spring operating mechanism is a commonly used actuator for circuit breakers at 12–252 kV. However, a reliability estimation method that is convenient, practical and accurate is still lacking. The aim of this paper is to explore a reliability estimation method based on a stress–strength interference reliability theory and a fatigue life theory. The changing rules of the reliability of the main axis, and the closing pawl and opening pawl in the spring operating mechanism during operations, are achieved. The accuracy of the calculated reliability based on theories of stress–strength interference and fatigue life is verified by adopting a test data statistical reliability model based on Weibull distribution. The results show that the reliability estimation method based on stress–strength interference and fatigue life theories has a high degree of confidence. The maximum tolerance is 0.024. The study would help in providing a useful reference for the optimization and durability estimation of a spring operating mechanism and its key components in high-voltage circuit breakers.

Poor palatal wound healing after cleft palate repair could lead to unfavorable prognosis such as oronasal fistula (ONF), which might affect the patient’s velopharyngeal function as well as their quality of life. Thus, restoring poor palatal wound healing for avoiding the occurrence of ONF should be considered the key to postoperative care after cleft palate repair. This review provided current insights in the preclinical study of poor palatal wound healing after cleft palate repair. This review comprehensively introduced the animal model establishment for palatal wound healing and related ONF, including the models by mice, rats, piglets, and dogs, and then demonstrated the aspects for investigating poor palatal wound healing and related treatments, including possible signaling pathways that could be involved in the formation of poor palatal wound healing, the related microbiota changes because of the deformity of palatal structure, and the studies for potential therapeutic strategies for palatal wound healing and ONF. The purpose of this review was to show the state of the art in preclinical studies about palatal wound healing after cleft palate repair and to show the promising aspects for better management of palatal wound healing.

BackgroundThe optimal local treatment for HCC with tumor diameter ≥ 5 cm is not well established. This research evaluated the effectiveness of external beam radiation therapy (EBRT) versus transcatheter arterial chemoembolization (TACE) for HCC with tumor diameter ≥ 5 cm.MethodsA total of 1210 HCC patients were enrolled in this study, including 302 and 908 patients that received EBRT and TACE, respectively. Propensity score matching (PSM) was used to identify patient pairs with similar baseline characteristics. Overall survival (OS) was the primary study endpoint.ResultsWe identified 428 patients using 1:1 PSM for survival comparison. Compared with the TACE group, the EBRT group had a significantly longer median OS (mOS) before (14.9 vs. 12.3 months, p = 0.0085) and after (16.8 vs. 11.4 months, p = 0.0026) matching. In the subgroup analysis, compared with the TACE group, the EBRT group had a significantly longer mOS for HCC with tumor diameters of 5-7 cm (34.1 vs. 14.3 months, p = 0.04) and 7-10 cm (34.4 vs. 10 months, p = 0.00065), whereas for HCC with tumor diameters ≥ 10 cm, no significant difference in mOS was observed (11.2 vs. 11.2 months, p = 0.83). In addition, the multivariable Cox analysis showed that Child-A, alkaline phosphatase < 125 U/L, and EBRT were independent prognostic indicators for longer survival.ConclusionEBRT is more effective than TACE as the primary local treatment for HCC with tumor diameter ≥ 5 cm, especially for HCC with tumor diameter of 5-10 cm.

Objective During total knee arthroplasty, femur and tibia parts are regularly replaced, while resurfacing the patellar or not is an ongoing discussion. To compare revision rate, anterior knee pain rate, patient‐reported outcome measures, complication, radiographic, and clinical outcomes after patellar resurfacing versus non‐resurfacing in total knee arthroplasty. Methods PubMed, Medline, EMBASE, CENTRAL, and CINAHL databases were searched on 25 April 2021 to enroll randomized controlled trials that compared patellar resurfacing versus non‐resurfacing. We used the grading of recommendations assessment, development and evaluation (GRADE) framework to assess the certainty of evidence. Our primary outcome was revision rate and secondary outcomes was anterior knee pain rate. Outcomes were pooled using the random‐effect model and presented as risk ratio (RR), or mean difference (MD), with 95% confidence interval (CI). Results Fifty studies (5586 knees) were included. Significant reductions in patellar revision rate (RR 0.41, 95% CI [0.19, 0.88]; P = 0.02; I2 = 24.20%) and non‐patellar revision rate (RR 0.64, 95% CI [0.55, 0.75]; P

LegendreNet is a novel graph neural network (GNNs) model that addresses stability issues present in traditional GNN models such as ChebNet, while also more effectively capturing higher-order dependencies within graphical data. Compared to traditional GNNs models such as GCN, LegendreNet is better equipped to handle large-scale graphical data, demonstrating superior performance on such datasets. Furthermore, Legendre polynomials, which are a set of completely orthogonal polynomials, are capable of approximating any function to arbitrary precision within a bounded interval. As such, when applied to graph neural networks, Legendre polynomials provide a more precise and stable means of fitting spectral filters to graphical data. This enables LegendreNet to more accurately capture graphical features when dealing with complex graphical data, and to exhibit greater robustness in adversarial attack scenarios. Compared to traditional GNNs methods, LegendreNet offers improved modeling and generalization capabilities, making it a more effective solution across various graphical data applications. Our experiments have demonstrated that our model outperforms state-of-the-art methods on large-scale graphical datasets. The code for LegendreNet is available at https://github.com/12chen20/LegendreNet.

In the process of designing and adjusting the solar simulator, the side lobe effect and aberration of the optical integrator affect the irradiation uniformity, an integrating sphere is proposed to replace the optical integrator for uniform light and the compound parabolic reflector for beam shaping. First, based on the equal illuminance theorem and the radiation transfer theory, the calculation formula of the energy transmission efficiency of the porous integrating sphere is derived; Then, the light hole illuminance interference factor is introduced, and the effects of the aperture size of the integrating sphere, the radius of the integrating sphere, and the size and position of the baffle on the energy transmission efficiency and irradiation uniformity are analyzed. Finally, an integrating sphere uniform light system with high energy transmission efficiency and uniformity is designed and simulated with LightTools software. The simulation results show that: the average difference of irradiation uniformity and the range difference of irradiation uniformity are closest to 1 in the area where the ratio of the opening size and radius of the integrating sphere is 36%–40%, and the light is evenly distributed; When the baffle position is 0.8 times of integrating sphere radius away from the light entrance hole, irradiation non-uniformity at the outlet hole is 1.99%, which is the best position of the baffle; In the effective irradiation surface of Φ1032 mm, the irradiation non-uniformity is 1.98%, and the maximum irradiance is 0.62 solar constants, the spot simulation with high irradiation uniformity on large irradiation surface is realized.

Objectives To evaluate the combination of the infiltration between the popliteal artery and the posterior capsule of the knee (iPACK) block and single adductor canal block (SACB) versus SACB for motor‐sparing knee analgesia effects after total knee arthroplasty (TKA). Methods PubMed, Ovid, Cochrane Library, and other databases were searched from the inception to January 2021. Randomized controlled trials (RCTs) comparing patients receiving iPACK plus SACB with patients receiving SACB after TKA were included. The included studies were assessed by two reviewers according to the Cochrane risk of bias criteria. Meta‐analysis was performed with STATA 13.0 software, the risk ratios (RR) and mean differences (MD) were used to compare dichotomous and continuous variables. The primary outcome was ambulation pain and secondary outcomes were rest pain, opioid consumption, function ability, clinical outcomes, and complications. Results Seven RCTs (304 knees in iPACK + SACB group; 305 knees in SACB group) were included. The follow‐up periods ranged from 2 days to 3 months. Pooled data indicated lower pain scores at ambulation (p