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Abstract Anion exchanger 3 (AE3) is pivotal in regulating intracellular pH across excitable tissues, yet its structural intricacies and functional dynamics remain underexplored compared to other anion exchangers. This study unveils the structural insights into human AE3, including the cryo-electron microscopy structures for AE3 transmembrane domains (TMD) and a chimera combining AE3 N-terminal domain (NTD) with AE2 TMD (hAE3NTD2TMD). Our analyzes reveal a substrate binding site, an NTD-TMD interlock mechanism, and a preference for an outward-facing conformation. Unlike AE2, which has more robust acid-loading capabilities, AE3’s structure, including a less stable inward-facing conformation due to missing key NTD-TMD interactions, contributes to its moderated pH-modulating activity and increased sensitivity to the inhibitor DIDS. These structural differences underline AE3’s distinct functional roles in specific tissues and underscore the complex interplay between structural dynamics and functional specificity within the anion exchanger family, enhancing our understanding of the physiological and pathological roles of the anion exchanger family.

Abstract Background Late-onset Pompe disease (LOPD) is mainly characterized by progressive limb-girdle muscle weakness and respiratory impairment, whereas stroke and cerebrovascular abnormalities have been insufficiently studied in LOPD. This study aimed to evaluate the frequency and pattern of intracranial artery and brain parenchyma abnormalities in LOPD patients. Results Neuroimaging data from 30 Chinese adult LOPD patients were collected from our center. Seven patients (7/30) had acute cerebral infarction or hemorrhage. Brain magnetic resonance angiography (MRA) or computed tomography angiography (CTA) revealed artery abnormalities in 23 patients (23/30). Dilative arteriopathy was found in 19 patients (19/30), with vertebrobasilar dolichoectasia found in 17 patients and dilatation of the anterior circulation arteries found in 8 patients. The maximum diameter of the basilar artery was correlated with disease duration (p

Abstract Brain disease diagnosis using multiple imaging modalities has shown superior performance compared to using single modality, yet multi-modal data is not easily available in clinical routine due to cost or radiation risk. Here we propose a synthesis-empowered uncertainty-aware classification framework for brain disease diagnosis. To synthesize disease-relevant features effectively, a two-stage framework is proposed including multi-modal feature representation learning and representation transfer based on hierarchical similarity matching. Besides, the synthesized and acquired modality features are integrated based on evidential learning, which provides diagnosis decision and also diagnosis uncertainty. Our framework is extensively evaluated on five datasets containing 3758 subjects for three brain diseases including Alzheimer’s disease (AD), subcortical vascular mild cognitive impairment (MCI), and O[6]-methylguanine-DNA methyltransferase promoter methylation status for glioblastoma, achieving 0.950 and 0.806 in area under the ROC curve on ADNI dataset for discriminating AD patients from normal controls and progressive MCI from static MCI, respectively. Our framework not only achieves quasi-multimodal performance although using single-modal input, but also provides reliable diagnosis uncertainty.

Abstract IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis.

Abstract The critical value of rock failure is determined by irreversible deformation (inelastic deformation, damage, and other internal dissipation) processes and external conditions before rock failure. Nevertheless, a thorough explanation of the mechanism causing cracks in rock material has not yet been provided. The strain energy theory is applied in this work to assess the initiation of rock cracks and investigate the relationship between energy digestion and rock strength. Firstly, the uniaxial compression test was conducted on sandstone samples under quasi-static loading conditions and the results of energy evolution, non-linear cumulative digestion, and stored ultimate energy were obtained. Then, a novel algorithm for assessing the initiation of rock cracks has been put forth. The concept of energy digestion index (EDI), which is the ratio of digested energy over the external loading energy, has been developed to characterize the energy absorption capacity of rock material. The result shows a relationship between the maximum growth rate of energy digestion and the increasing rate of variable elasticity modulus and crack initiation. The mechanical characteristics and peak strength of the rock material are negatively correlated with the EDI. By monitoring the digested energy status, an evaluation of the residual strength is introduced based on the relationships, which will initiate further research into in-situ monitoring and failure prediction.

Abstract Natural antimicrobial peptides (AMPs) and enzymes (AMEs) are promising non-antibiotic candidates against antimicrobial resistance but suffer from low efficiency and poor stability. Here, we develop peptide nanozymes which mimic the mode of action of AMPs and AMEs through de novo design and peptide assembly. Through modelling a minimal building block of IHIHICI is proposed by combining critical amino acids in AMPs and AMEs and hydrophobic isoleucine to conduct assembly. Experimental validations reveal that IHIHICI assemble into helical β-sheet nanotubes with acetate modulation and perform phospholipase C-like and peroxidase-like activities with Ni coordination, demonstrating high thermostability and resistance to enzymatic degradation. The assembled nanotubes demonstrate cascade antifungal actions including outer mannan docking, wall disruption, lipid peroxidation and subsequent ferroptotic death, synergistically killing >90% Candida albicans within 10 min on disinfection pad. These findings demonstrate an effective de novo design strategy for developing materials with multi-antimicrobial mode of actions.

Objective: To explore the application value and morphological characteristics of CT angiography (CTA) in the risk assessment of intracranial aneurysm rupture. Method: We included 82 patients with intracranial aneurysms from the Third Affiliated Hospital of Bengbu Medical College from October 2018 to October 2021. All study participants underwent CTA and digital subtraction angiography (DSA) examinations using Siemens 64 row 128 slice spiral CT and Siemens DSA machines. Statistical analyses were conducted on the condition of tumor rupture. The morphological characteristics of different tumor rupture cases, and the factors influencing intracranial aneurysm rupture were analyzed. Result: The rupture rate of 82 carotid artery patients in this group was 74.39% (61/82), and the non-rupture rate of the tumor was 25.61% (21/82). The number of sub-capsules (60.66%), area ratio, Size ration (SR), Aspect ratio (AR) and length of the ruptured aneurysm were greater than that of the unruptured aneurysm. The ruptured and unruptured aneurysms did not differ significantly in the incidence of single aneurysm (91.80%) and the distribution of aneurysms. Logistic regression analysis confirmed that area ratio, SR, AR, and tumor length were important risk factors for intracranial aneurysm rupture. Conclusion: CTA examination can clarify the morphological characteristics of intracranial aneurysms and evaluate the risk of tumor rupture.

BackgroundCold environments reduce work efficiency and increase the risk of frostbite. ObjectiveTo investigate the effects on cold protection and manual performance of rescue gloves in cold environments, and to preliminarily verify the feasibility of related quantitative characterization methods. MethodsAn experiment was conducted in a large and a small artificial climate chamber. 12 male right-handed university students were recruited. The experiment was divided into two parts, with 0-10 min as the baseline phase and 10-50 min as the test phase. Subjects sat quietly in a 16 ℃ large chamber, and hands were exposed to a small chamber at 0 ℃ either barely (control group) or with rescue gloves (experimental group). Skin temperatures of the five fingers (thumb, index finger, middle finger, ring finger, and little finger), as well as the dorsal and palm of the hands were measured. In addition, grip strength, manual dexterity, maximum finger flexion, and tactile sensitivity of the hands were measured as the indicators of manual performance. ResultsIn the control group, cold-induced vasodilation occurred when the skin temperature of the five fingers were lowered to about 10 ℃. The maximum rate of change in skin temperature of the control group was in the following order: thumb＞index finger＞middle finger＞little finger＞ring finger＞dorsal＞palm, 165.7 ℃·h−1 in the thumb, 80.0 and 89.9 ℃·h−1 in the palm and dorsal respectively. In addition, the minimum skin temperature of the thumb was 6.6 ℃. Compared with the control group: the rate of change of skin temperature in the experimentalgroup decreased by about 50%; the grip strength decreased by 15% after wearing the rescue gloves (P0.05). ConclusionThis study proved that the rescue gloves improved the thermal comfort of hands while better balancing the effect of cold exposure on manual performance. The quantitative characterization methods can evaluate the protective performance and manual performance of the rescue gloves, which provides a reliable theoretical foundation and reference basis for further experiments.

The increasing consumption of paper products has led to a shortage of paper fiber raw materials. It is necessary to develop new plant materials to alleviate the shortage of fiber suitable for papermaking. In this study, the fast-growing plant golden bamboo grass (Arundo donax), which is cultivated and planted in Guangxi province of China, was used as a new material for pulping. The average pulp yield by cyclic-cooking method averaged 48.6%, being 4.1% greater than the pulp yield by the ordinary caustic soda method. Much of the increased yield was attributable to the reprecipitation of lignin onto the fibers. The paper properties of the pulp prepared by cycle-cooked method did not decrease significantly, compared with the pulp prepared by the usual single-cooked method. Therefore, the pulp met the requirements of national standards of many kinds of papers. However, the pulp was not suitable for bleaching, due to its high consumption of oxidizing agents to reach the required brightness. Therefore, this research demonstrates that the fast-growing plant, Arundo donax is a good raw material for pulp, and the innovative method of cycle-cooking method can significantly improve the pulp yield.

The popularity of the Internet of Things (IoT) has enabled a large number of vulnerable devices to connect to the Internet, bringing huge security risks. As a network-level security authentication method, device fingerprint based on machine learning has attracted considerable attention because it can detect vulnerable devices in complex and heterogeneous access phases. However, flexible and diversified IoT devices with limited resources increase difficulty of the device fingerprint authentication method executed in IoT, because it needs to retrain the model network to deal with incremental features or types. To address this problem, a device fingerprinting mechanism based on a Broad Learning System (BLS) is proposed in this paper. The mechanism firstly characterizes IoT devices by traffic analysis based on the identifiable differences of the traffic data of IoT devices, and extracts feature parameters of the traffic packets. A hierarchical hybrid sampling method is designed at the preprocessing phase to improve the imbalanced data distribution and reconstruct the fingerprint dataset. The complexity of the dataset is reduced using Principal Component Analysis (PCA) and the device type is identified by training weights using BLS. The experimental results show that the proposed method can achieve state-of-the-art accuracy and spend less training time than other existing methods.

Abstract Background This study aimed to evaluate the diagnostic abilities of the non-invasive serum biomarkers to predict liver fibrosis staging and evaluate the progress of hepatitis B. Methods We enrolled 433 patients with chronic HBV infection had complete medical data available for the study, who underwent percutaneous liver biopsy. The extent of fibrosis was assessed using the modified METAVIR score. The predictive values of the non-invasive serum biomarkers were evaluated by the areas under the receiving operator characteristics curves (AUROCs) with 95% confidence intervals. Results The proportion of males with progressive stages of liver fibrosis was relatively larger, and the average age of patients with cirrhosis stages is older than the non-cirrhotic stages. We found PLT, GGT, ALP, TB, FIB4 and GPR to be significantly associated with liver fibrosis in our cohort. GGT showed a sensitivity of 71.4% and specificity of 76.7% in distinguishing cirrhosis (F4) from non-cirrhotic stages (F1-3), with an AUROC of 0.775 (95%CI 0.711–0.840).The AUROCs of the GPR in distinguishing cirrhosis (F4) from non-cirrhotic stages (F1-3) was 0.794 (95%CI 0.734–0.853), but it had a lower sensitivity of 59.2%. Additionally, GGT, FIB4, and GPR could differentiate advanced fibrosis (F3-4) from non-advanced fibrosis (F1-2) among individuals with chronic hepatitis B, with AUROCs of 0.723 (95%CI 0.668–0.777), 0.729 (95%CI 0.675–0.782), and 0.760 (95%CI: 0.709–0.811) respectively. Conclusions GGT was a better biomarker to distinguish cirrhosis (F4) from non-cirrhotic stages (F1-3), while GPR was a better biomarker to identify advanced fibrosis (F3-4) and non-advanced fibrosis (F1-2) in patients with chronic hepatitis B.

Abstract Background 3% chloroprocaine (CP) has been reported as the common local anesthetic used in pregnant women undergoing urgent cesarean delivery during labor analgesia period. However, 0.75% ropivacaine is considered a promising and effective alternative. Therefore, we conducted a randomized controlled trial to compare the effectiveness and safety of 0.75% ropivacaine with 3% chloroprocaine for extended epidural anesthesia in pregnant women. Methods We conducted a double-blind, randomized, controlled, single-center study from November 1, 2022, to April 30, 2023. We selected forty-five pregnant women undergoing urgent cesarean delivery during labor analgesia period and randomized them to receive either 0.75% ropivacaine or 3% chloroprocaine in a 1:1 ratio. The primary outcome was the time to loss of cold sensation at the T4 level. Results There was a significant difference between the two groups in the time to achieve loss of cold sensation (303, 95%CI 255 to 402 S vs. 372, 95%CI 297 to 630 S, p = 0.024). There was no significant difference the degree of motor block (p = 0.185) at the Th4 level. Fewer pregnant women required additional local anesthetics in the ropivacaine group compared to the chloroprocaine group (4.5% VS. 34.8%, p = 0.011). The ropivacaine group had lower intraoperative VAS scores (p = 0.023) and higher patient satisfaction scores (p = 0.040) than the chloroprocaine group. The incidence of intraoperative complications was similar between the two groups, and no serious complications were observed. Conclusions Our study found that 0.75% ropivacaine was associated with less intraoperative pain treatment, higher patient satisfaction and reduced the onset time compared to 3% chloroprocaine in pregnant women undergoing urgent cesarean delivery during labor analgesia period. Therefore, 0.75% ropivacaine may be a suitable drug in pregnant women undergoing urgent cesarean delivery during labor analgesia period. Clinical trial number and registry URL The registration number: ChiCTR2200065201; http://www.chictr.org.cn , Principal investigator: MEN, Date of registration: 31/10/2022.

Retinal organoids are three-dimensional (3D) microscopic tissues that are induced and differentiated from stem cells or progenitor cells in vitro and have a highly similar structure to the retina. With the optimization and development of 3D retinal culture system and the improvement of induced differentiation technology, retinal organoids have broad application prospects in retinal development, regenerative medicine, biomaterial evaluation, disease mechanism investigation, and drug screening. In this review we summarize recent development of retinal organoids and their applications in ophthalmic regenerative medicine. In particular, we highlight the promise and challenges in the use of retinal organoids in disease modeling and drug discovery.

Abstract Teacher education research has recognised the importance of teacher resilience. However, the development of language teacher-researchers resilience remains in its early stages. To address this gap, this study adopted a qualitative approach to explore the resilience development of two Chinese secondary school English teacher-researchers and its contributing factors. Data from interviews and case documents indicated that teacher-researchers resilience was dynamic and developed over time. Two different patterns of resilience development were identified: low-to-high and W-shaped recovery. Furthermore, individual and environmental factors and their interactions jointly contributed to the resilience development of the two secondary school English teacher-researchers. Their participation in classroom research provided them with diverse ways to sustain their resilience. The implications for teacher development are offered to teachers in China and other similar contexts.

Abstract This study aimed to investigate the epidemiological characteristics and trends over time of carbapenemase-producing (e.g., KPC, NDM, VIM, IMP, and OXA-48) Gram-negative bacteria (CPGNB). Non-duplicated multi-drug resistant Gram-negative bacteria (MDRGNB) were collected from the First Affiliated Hospital of Zhengzhou University from April 2019 to February 2023. Species identification of each isolate was performed using the Vitek2 system and confirmed by matrix-assisted laser desorption ionization-time of flight mass spectrometry according to the manufacturer's instructions. PCR detected carbapenem resistance genes in the strains, strains carrying carbapenem resistance genes were categorized as CPGNB strains after validation by carbapenem inactivation assay. A total of 5705 non-repetitive MDRGNB isolates belonging to 78 different species were collected during the study period, of which 1918 CPGNB were validated, with the respiratory tract being the primary source of specimens. Epidemiologic statistics showed a significant predominance of ICU-sourced strains compared to other departments. Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa were the significant CPGNB in Henan, and KPC and NDM were the predominant carbapenemases. Carbapenem-resistant infections in Henan Province showed an overall increasing trend, and the carriage of carbapenemase genes by CPGNB has become increasingly prevalent and complicated. The growing prevalence of CPGNB in the post-pandemic era poses a significant challenge to public safety.

Abstract Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.

Abstract Background Diabetes, a health crisis afflicting millions worldwide, is increasing rapidly in prevalence. The microvascular complications triggered by diabetes have emerged as the principal cause of renal disease and blindness. The retinal microvascular network may be sensitive to early systemic vascular structural and functional changes. Therefore, this research endeavored to discern the systemic determinants influencing the retinal microvascular network in patients with and without diabetes. Methods The Kailuan Eye Study is a cross-sectional study based on the community-based cohort Kailuan Study. Participants underwent optical coherence tomography angiography (OCTA) (Zeiss Cirrus 5000; Carl Zeiss Meditec) and comprehensive systemic examination. Metrics such as perfusion density (PD), vascular density (VD), foveal avascular zone (FAZ) parameters of the superficial capillary plexus (SCP) in the macula were assessed. Results This study included 860 eligible participants (average age = 62.75 ± 6.52 years; 21.9% female), of which 449 were diabetics. People with diabetes had diminished PD and VD in the entire macular and parafoveal regions compared to people without diabetes. Reduced PD in the whole macular region was correlated with higher fasting plasma glucose (FPG, mmol/L) concentration (Beta = -0.19, 95% CI = -0.42 to -0.36, P

Abstract Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders that affect individuals' social interactions, communication skills, and behavioral patterns, with significant individual differences and complex etiology. This article reviews the definition and characteristics of ASD, epidemiological profile, early research and diagnostic history, etiological studies, advances in diagnostic methods, therapeutic approaches and intervention strategies, social and educational integration, and future research directions. The highly heritable nature of ASD, the role of environmental factors, genetic–environmental interactions, and the need for individualized, integrated, and technology-driven treatment strategies are emphasized. Also discussed is the interaction of social policy with ASD research and the outlook for future research and treatment, including the promise of precision medicine and emerging biotechnology applications. The paper points out that despite the remarkable progress that has been made, there are still many challenges to the comprehensive understanding and effective treatment of ASD, and interdisciplinary and cross-cultural research and global collaboration are needed to further deepen the understanding of ASD and improve the quality of life of patients.

Abstract The morbidity and mortality associated with type 2 diabetes mellitus (T2DM) have grown exponentially over the last 30 years. Together with its associated complications, the mortality rates have increased. One important complication in those living with T2DM is the acceleration of age‐related cognitive decline. T2DM‐induced cognitive impairment seriously affects memory, executive function, and quality of life. However, there is a lack of effective treatment for both diabetes and cognitive decline. Thus, finding novel treatments which are cheap, effective in both diabetes and cognitive impairment, are easily accessible, are needed to reduce impact on patients with diabetes and health‐care systems. Carnosine, a histidine containing dipeptide, plays a protective role in cognitive diseases due to its antioxidant, anti‐inflammation, and anti‐glycation properties, all of which may slow the development of neurodegenerative diseases and ischemic injury. Furthermore, carnosine is also involved in regulating glucose and insulin in diabetes. Herein, we discuss the neuroprotective role of carnosine and its mechanisms in T2DM‐induced cognitive impairment, which may provide a theoretical basis and evidence base to evaluate whether carnosine has therapeutic effects in alleviating cognitive dysfunction in T2DM patients.

Abstract Background Migraine, a neurological disorder with a significant female predilection, is the leading cause of disability-adjusted life years (DALYs) in women of childbearing age (WCBA). There is currently a lack of comprehensive literature analysis on the overall global burden and changing trends of migraines in WCBA. Methods This study extracted three main indicators, including prevalence, incidence, and DALYs, related to migraine in WCBA from the Global Burden of Disease(GBD) database from 1990 to 2021. Our study presented point estimates with 95% uncertainty intervals (UIs). It evaluated the changing trends in the burden of migraine in WCBA using the estimated annual percentage change (EAPC) and percentage change. Results In 2021, the global prevalence, incidence, and DALYs cases of migraine among WCBA were 493.94 million, 33.33 million, and 18.25 million, respectively, with percentage changes of 48%, 43%, and 47% compared to 1990. Over the past 32 years, global prevalence rates and DALYs rates globally have increased, with an EAPC of 0.03 (95% UI: 0.02 to 0.05) and 0.04 (95% UI: 0.03 to 0.05), while incidence rates have decreased with an EAPC of -0.07 (95% UI: -0.08 to -0.05). Among the 5 Socio-Demographic Index (SDI) regions, in 2021, the middle SDI region recorded the highest cases of prevalence, incidence, and DALYs of migraine among WCBA, estimated at 157.1 million, 10.56 million, and 5.81 million, respectively, approximately one-third of the global total. In terms of age, in 2021, the global incidence cases for the age group 15–19 years were 5942.5 thousand, with an incidence rate per 100,000 population of 1957.02, the highest among all age groups. The total number of migraine cases and incidence rate among WCBA show an increasing trend with age, particularly in the 45–49 age group. Conclusions Overall, the burden of migraine among WCBA has significantly increased globally over the past 32 years, particularly within the middle SDI and the 45–49 age group. Research findings emphasize the importance of customized interventions aimed at addressing the issue of migraines in WCBA, thus contributing to the attainment of Sustainable Development Goal 3 set by the World Health Organization.

Abstract Temperature and humidity variations in burial stone relics can easily cause water vapor condensation, which is an important factor leading to their deterioration. However, the water vapor condensation mechanism and the evaluation of risk ratings have always been difficult problems in the protection of cultural relics. In this study, the water vapor condensation mechanism in Yang Can's tomb was comprehensively investigated through on-site monitoring, indoor experiments and software simulations, on the basis of which a physical model of water vapor condensation in this tomb was established and a water vapor condensation risk rating assessment method was proposed. The proposed method considers the difference between the dew point and wall temperatures within the tomb (dew–wall temperature difference) and the duration of water vapor condensation, and corresponding preventive and control measures were formulated for different risk ratings. The study revealed that when the wall temperature of the chamber is lower than the dew point temperature, water vapor starts to condense. The larger the dew–wall temperature difference is, the greater the risk of condensation. In addition, specific water vapor condensation prevention and control measures were proposed for Yang Can's tomb, and the prevention and control effects were simulated. The simulation results showed that favorable prevention and control effects could be achieved, and the proposed measures could be applied in practice. This study holds notable significance for investigating the water vapor condensation mechanism and evaluating the risk ratings of burial stone relics and provides a theoretical basis and reference for water vapor condensation prevention and control in burial stone relics.

The borehole shear test is an important method to quickly measure the shear strength of rock in the field, but its application is limited due to its large measurement error. By analyzing the principle of borehole shear and the research results, it is found that incomplete shear is the reason for the large error of rock borehole shear test, and a correction method of borehole shear method based on the unequal area of pressure and shear was proposed. Experimental equipment was designed to carry out the simulated borehole shear test, and the characterization rules of sandstone shear mechanical parameters under different shear plate parameters were studied, which proved the effectiveness and correction effect of the proposed method. Finally, the applicability of the method was verified by literature data. Specific results are as follows: ① The root cause of large error in rock borehore shear test is that the selection of compression area and shear area is distorted and unequal, the actual shear failure area is less than the area between shear teeth, and the corrected compression area and shear area increase linearly with the increase of normal force under different shear tooth lengths. Based on the relationship between the parameters of shear tooth, compression area and shear area, a correction method of borehole shear test is proposed. ② The shear stress-shear displacement curve of rock borehole shear can be divided into compaction stage, elastic deformation stage, plastic deformation stage and post-peak stage. With the increase of normal force, the positive stress, shear stress and shear stiffness increase under different shear plate parameters, and the displacement decreases when the peak point of shear stress is reached. There are obvious rules between borehole shear parameters and the characteristic value of shear mechanical parameters. With the increase of the shear tooth length, the cohesion increases linearly, and the internal friction angle increases as a quadratic function. With the increase of the shear plate area, the cohesion increases linearly and the internal friction angle decreases as a quadratic function. ③ The increase of the shear tooth length and the shear plate area can reduce part of the measurement deviation. The shear tooth length increases from 1.0 mm to 2.5 mm, the total deviation of cohesion and internal friction angle decreases from 62.96% to 19.91%, the total improvement increases from 30.8% to 74.1%. The shear plate area increases from 400 mm2 to 520 mm2, the total deviation of cohesion and internal friction angle decreases from 64.07% to 37.69%, and the total improvement increases from 39.56% to 56.05%. Both experimental and literature data validation show that the correction method improves the accuracy of cohesion and internal friction angle by about 50% and 6%, respectively.

Abstract Objective There has been some confusion in earlier research on the connection between thyroid function and polycystic ovary syndrome (PCOS). This research is aimed to probe into the correlation between thyroid condition and the risk of PCOS from a new standpoint of thyroid hormone sensitivity. Methods This research comprised 415 females with PCOS from Drum Tower Hospital Affiliated with the Medical School of Nanjing University, and 137 non-PCOS individuals were selected as the normal control. Based on free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH), we calculated the thyroid hormone sensitivity indices, which consist of Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), Thyrotroph Thyroxine Resistance Index (TT4RI) and Free Triiodothyronine /Free thyroxine (FT3/FT4). The binary logistic regression model was adopted to investigate the correlation between thyroid hormone sensitivity indices with the risk of PCOS. Pearson or Spearman correlation analysis was employed to explore the association among thyroid-related measures with metabolic parameters in PCOS. Results Results of this research showed that females with PCOS had rising TFQI, TSHI, TT4RI, and FT3/FT4 levels compared with the control group. After adjustment for the impact of various covariates, there was no significant correlation between FT3/FT4 and the risk of PCOS; However, the odds ratio of the third and fourth vs. the first quartile of TFQI were 3.57(95% confidence interval [CI]:1.08,11.87) and 4.90(95% CI:1.38,17.38) respectively; The odds ratio of the fourth vs. the first quartile of TSHI was 5.35(95% CI:1.48,19.37); The odds ratio of the second vs. the first quartile of TT4RI was 0.27(95%CI 0.09,0.82). In addition, no significant correlation was observed between thyroid-related measures and metabolic measures in females with PCOS. Conclusions A reduction in the sensitivity of central thyroid hormone is closely correlated with a higher risk of PCOS. Further research is necessary to corroborate our findings and the supporting mechanisms.

Abstract Silk nanofibrils (SNFs), the fundamental building blocks of silk fibers, endow them with exceptional properties. However, the intricate mechanism governing SNF assembly, a process involving both protein conformational transitions and protein molecule conjunctions, remains elusive. This lack of understanding has hindered the development of artificial silk spinning techniques. In this study, we address this challenge by employing a graphene plasmonic infrared sensor in conjunction with multi-scale molecular dynamics (MD). This unique approach allows us to probe the secondary structure of nanoscale assembly intermediates (0.8–6.2 nm) and their morphological evolution. It also provides insights into the dynamics of silk fibroin (SF) over extended molecular timeframes. Our novel findings reveal that amorphous SFs undergo a conformational transition towards β-sheet-rich oligomers on graphene. These oligomers then connect to evolve into SNFs. These insights provide a comprehensive picture of SNF assembly, paving the way for advancements in biomimetic silk spinning.

Abstract Background and aims The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guideline has recently revised the hemodynamic definition of pulmonary arterial hypertension. However, there is currently limited research on the prognosis and treatment of system lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH) patients that have been reclassified by the new hemodynamic definition. This study aims to analyze the prognosis of newly reclassified SLE-PAH patients and provide recommendations for the management strategy. Methods This retrospective study analyzed records of 236 SLE-PAH patients who visited Peking Union Medical College Hospital (PUMCH) from 2011 to 2023, among whom 22 patients were reclassified into mild SLE-PAH (mean pulmonary arterial pressure (mPAP) of 21–24 mmHg, pulmonary vascular resistance (PVR) of 2–3 WU, and PAWP ≤ 15 mmHg) according to the guidelines and 14 were defined as unclassified SLE-PAH patients (mPAP 21–24 mmHg and PVR ≤ 2 WU). The prognosis was compared among mild SLE-PAH, unclassified SLE-PH, and conventional SLE-PAH patients (mPAP ≥ 25 mmHg and PVR > 3WU). Besides, the effectiveness of pulmonary arterial hypertension (PAH)-specific therapy was evaluated in mild SLE-PAH patients. Results Those mild SLE-PAH patients had significantly longer progression-free time than the conventional SLE-PAH patients. Among the mild SLE-PAH patients, 4 did not receive PAH-specific therapy and had a similar prognosis as patients not receiving specific therapy. Conclusions This study supports the revised hemodynamic definition of SLE-PAH in the 2022 ESC/ERS guideline. Those mild and unclassified SLE-PH patients had a better prognosis, demonstrating the possibility and significance of early diagnosis and intervention for SLE-PAH. This study also proposed a hypothesis that IIT against SLE might be sufficient for those reclassified SLE-PAH patients.

Abstract Background Neuroendocrine carcinoma (NEC) originating from the endometrium is rare, and there is limited knowledge regarding its diagnosis and optimal management. In this study, we present our experience with 11 patients with endometrial NEC, aiming to provide guidance for clinical practice. Methods We retrospectively collected the clinical, pathological, and treatment data of 11 patients with endometrial NEC who were treated at the First Affiliated Hospital of Zhengzhou University from January 2011 to July 2023. The clinicopathological characteristics, treatment and prognosis of these patients were analyzed. Results The median age of the patients was 55.0 (39.0–64.0) years, and the median tumor size was 40.0 (33.0–60.0) mm. Irregular vaginal bleeding was the most common symptom observed in 10 out of 11 patients, while metabolic syndrome occurred in only 2 out of 11 patients. Six out of the 11 patients were diagnosed at an early stage. Among the patients, 6 were diagnosed with endometrial NECs, while the remaining patients had a combination of endometrial NEC and other non-NEC endometrial carcinomas. All patients underwent surgery, except for one who received only chemotherapy due to multiple metastases. After surgery, adjuvant chemotherapy was administered to 5 patients, chemotherapy combined with radiotherapy was given to 3 patients, and 2 patients did not receive any adjuvant therapy. A total of 10 patients completed the follow-up, with a median follow-up time of 51.0 (14.3–81.0) months. Unfortunately, 2 patients died from the disease. Conclusion NECs originating from the endometrium might not be affected by metabolic disorders. Preoperative diagnosis of these tumors was challenging. The primary approach for managing endometrial NEC can be multimodal treatment centered around surgery.

Abstract Background We previously conducted a case-control study and found that exposure to electronic screen before nocturnal sleep was associated with hypertensive disorders in pregnancy (HDP). Hence, we carried out this cohort study aiming to identify the effects of screen exposure time on the incidence rate and severity of HDP. Methods A retrospective cohort study was conducted from January 2022 and July 2022 from three hospitals in Wuxi and Changzhou cities. A total of 732 women were recruited and the information included socio-demographic characteristics, screen exposure and outcomes. Generalized estimating equations and binary non-conditional logistic models were applied to multivariate analysis, calculating the odds ratios (ORs) and 95% confidence intervals (CIs) of screen exposure time. Results The duration order of total screen time was smartphone > computer > television, while the duration order of screen time before nocturnal sleep was smartphone > television > computer. Multivariate analyses showed that the susceptibility of HDP among women who exposed to television before nocturnal sleep was 81.5% percent higher than those not exposed (P = 0.018, OR[95%CI] = 1.815[1.106–2.981]). In addition, total daily exposure time of television in the third trimester of pregnancy significantly increased the severity of HDP (P = 0.021, OR[95%CI] = 3.641[1.213–10.927]). Conclusions Based on this preliminary study, we would suggest that pregnant women do not watch television before nocturnal sleep. While in the third trimester of pregnancy, total exposure time of television should be limited. Investigations from other areas and experimental studies should be conducted to verify the conclusion.

Abstract Background Formolase (FLS) is a computationally designed enzyme that catalyzes the carboligation of two or three C1 formaldehyde molecules into C2 glycolaldehyde or C3 dihydroxyacetone (DHA). FLS lays the foundation for several artificial carbon fixation and valorization pathways, such as the artificial starch anabolic pathway. However, the application of FLS is limited by its low catalytic activity and product promiscuity. Findings FLS, designed and engineered based on benzoylformate decarboxylase from Pseudomonas putida, was selected as a candidate for modification. To evaluate its catalytic activity, 25 residues located within an 8 Å distance from the active center were screened using single-point saturation mutagenesis. A screening approach based on the color reaction of the DHA product was applied to identify the desired FLS variants. After screening approximately 5,000 variants (approximately 200 transformants per site), several amino acid sites that were not identified by directed evolution were found to improve DHA formation. The serine-to-phenylalanine substitution at position 236 improved the activity towards DHA formation by 7.6-fold. Molecular dynamics simulations suggested that the mutation increased local hydrophobicity at the active site, predisposing the cofactor-C2 intermediate to nucleophilic attack by the third formaldehyde molecule for subsequent DHA generation. Conclusions This study provides improved FLS variants and valuable information into the influence of residues adjacent to the active center affecting catalytic efficiency, which can guide the rational engineering or directed evolution of FLS to optimize its performance in artificial carbon fixation and valorization.

Abstract The extracytoplasmic function (ECF) sigma factor AlgU is involved in the regulation of various virulence-related pathways in Pseudomonas syringae, especially alginate biosynthesis and motility, and the role of AlgU differs among P. syringae pathovars. However, to date, the mechanism of its regulation in virulence of P. syringae pv. actinidiae (Psa) is still unclear. ECF sigma factors are a class of alternative sigma factors that typically function with anti-sigma factors as part of cell-surface signaling systems. Under non-inducing conditions, AlgU remains inhibited by anti-sigma factors such as MucA and MucB. To investigate the function of AlgU in Psa, mutant strains lacking algU or lacking algU with mucA and mucB genes, as well as complementary and overexpression strains of algU were generated, respectively. The results showed that AlgU was highly conserved among P. syringae pathovars and positively regulated growth rate, pathogenicity, and resistance to osmotic and oxidative stress of Psa QSY6. While AlgU did not affect the motility and exopolysaccharide production of Psa, its abundant expression enhanced the swimming ability of QSY6 and reduced its production of extracellular polysaccharides. Furthermore, AlgU regulates a number of virulence-related factors, including the Hrp system, the type VI secretion system, and flagellar synthesis. Specifically, AlgU induced the expression of hrpL and hrpRS in vivo, and repressed the transcription of hrpL and tssC in vitro, while promoting the expression of hrpS, fliC, and tssJ. This study contributes to a better understanding of the mechanisms of virulence regulation of AlgU in Psa.

Abstract Ultrasound-driven bioelectronics could offer a wireless scheme with sustainable power supply; however, current ultrasound implantable systems present critical challenges in biocompatibility and harvesting performance related to lead/lead-free piezoelectric materials and devices. Here, we report a lead-free dual-frequency ultrasound implants for wireless, biphasic deep brain stimulation, which integrates two developed lead-free sandwich porous 1-3-type piezoelectric composite elements with enhanced harvesting performance in a flexible printed circuit board. The implant is ultrasonically powered through a portable external dual-frequency transducer and generates programmable biphasic stimulus pulses in clinically relevant frequencies. Furthermore, we demonstrate ultrasound-driven implants for long-term biosafety therapy in deep brain stimulation through an epileptic rodent model. With biocompatibility and improved electrical performance, the lead-free materials and devices presented here could provide a promising platform for developing implantable ultrasonic electronics in the future.

Abstract Background Anemia is a common complication of HIV/AIDS, particularly in adolescents and young adults across various countries and regions. However, little is known about the changing prevalence trends of anemia impairment in this population over time. Methods Data on anemia in adolescents and young adults with HIV/AIDS from 1990 to 2019 were collected from the Global Burden of Disease. Prevalence was calculated by gender, region, and country for individuals aged 10–24, and trends were measured using estimating annual percentage changes (EAPC). Results Globally, the prevalence of adolescents and young adults with HIV/AIDS increased from 103.95 per 100,000 population in 1990 to 203.78 in 2019. However, anemia impairment has decreased over the past three decades, with a global percentage decreasing from 70.6% in 1990 to 34.7% in 2019, mainly presenting as mild to moderate anemia and significantly higher in females than males. The largest decreases were observed in Central Sub-Saharan Africa, North America, and Eastern Sub-Saharan Africa, with EAPCs of -2.8, -2.34, and -2.17, respectively. Tajikistan (78.76%) and Madagascar (74.65%) had the highest anemia impairment percentage in 2019, while China (16.61%) and Iceland (13.73%) had the lowest. Anemia impairment was closely related to sociodemographic index (SDI) levels, with a high proportion of impairment in low SDI regions but a stable decreasing trend (EAPC = -0.37). Conclusion Continued anemia monitoring and management are crucial for patients with HIV, especially in high-prevalence regions and among females. Public health policies and interventions can improve the quality of life and reduce morbidity and mortality.

Abstract Background Pseudomonas syringae pv. actinidiae (Psa) is an important bacterial plant pathogen that causes severe damage to the kiwifruit industry worldwide. Three Psa strains were recently obtained from different kiwifruit orchards in Anhui Province, China. The present study mainly focused on the variations in virulence and genome characteristics of these strains based on the pathogenicity assays and comparative genomic analyses. Results Three strains were identified as biovar 3 (Psa3), along with strain QSY6 showing higher virulence than JZY2 and YXH1 in pathogenicity assays. The whole genome assembly revealed that each of the three strains had a circular chromosome and a complete plasmid. The chromosome sizes ranged from 6.5 to 6.6 Mb with a GC content of approximately 58.39 to 58.46%, and a predicted number of protein-coding sequences ranging from 5,884 to 6,019. The three strains clustered tightly with 8 Psa3 reference strains in terms of average nucleotide identity (ANI), whole-genome-based phylogenetic analysis, and pangenome analysis, while they were evolutionarily distinct from other biovars (Psa1 and Psa5). Variations were observed in the repertoire of effectors of the type III secretion system among all 15 strains. Moreover, synteny analysis of the three sequenced strains revealed eight genomic regions containing 308 genes exclusively present in the highly virulent strain QSY6. Further investigation of these genes showed that 16 virulence-related genes highlight several key factors, such as effector delivery systems (type III secretion systems) and adherence (type IV pilus), which might be crucial for the virulence of QSY6. Conclusion Three Psa strains were identified and showed variant virulence in kiwifruit plant. Complete genome sequences and comparative genomic analyses further provided a theoretical basis for the potential pathogenic factors responsible for kiwifruit bacterial canker.

Abstract Various substances in the blood plasma serve as prognostic indicators of the progression of COVID-19. Consequently, multi-omics studies, such as proteomic and metabolomics, are ongoing to identify accurate biomarkers. Cytokines and chemokines, which are crucial components of immune and inflammatory responses, play pivotal roles in the transition from mild to severe illness. To determine the relationship between plasma cytokines and the progression of COVID-19, we used four study cohorts to perform a systematic study of cytokine levels in patients with different disease stages. We observed differential cytokine expression between patients with persistent-mild disease and patients with mild-to-severe transformation. For instance, IL-4 and IL-17 levels significantly increased in patients with mild-to-severe transformation, indicating differences within the mild disease group. Subsequently, we analysed the changes in cytokine and chemokine expression in the plasma of patients undergoing two opposing processes: the transition from mild to severe illness and the transition from severe to mild illness. We identified several factors, such as reduced expression of IL-16 and IL-18 during the severe phase of the disease and up-regulated expression of IL-10, IP-10, and SCGF-β during the same period, indicative of the deterioration or improvement of patients’ conditions. These factors obtained from fine-tuned research cohorts could provide auxiliary indications for changes in the condition of COVID-19 patients.

Abstract Background Abusive supervision by the nurse manager significantly influences nurses’ withholding voice about patient safety. The role of impression management motivation and speak up-related climate is crucial in understanding their connection. This study aimed to explore the relationship between abusive supervision, impression management motivation, speak up-related climate, and withholding voice about patient safety. Methods This cross-sectional study employed a convenience sampling method to recruit 419 clinical nurses from Taizhou Hospital, Zhejiang Province, China, between 1 November 2022 and 31 January 2023. The study adhered to the STROBE checklist. Abusive supervision and impression management motivation were assessed using the Chinese versions of the Abusive Supervision Scale and the Impression Management Motivation Scale, respectively. Withholding voice about patient safety and speak up-related climate were identified using the Chinese version of the Speaking Up about Patient Safety Questionnaire. Results Nurse leaders’ abusive supervision (β=0.40, p

Abstract Background Patients with amyotrophic lateral sclerosis present perioperative challenges for clinical anesthesiologists for anesthesia-associated complications. Case presentation A 54-year-old Han woman with a 2-year history of amyotrophic lateral sclerosis was scheduled for hemorrhoidectomy and hemorrhoidal artery ligation. We performed real-time ultrasound-guided sacral plexus block with dexmedetomidine under standard monitoring. The anesthesia method met the surgical demands and avoided respiratory complications during the procedures. There was no neurological deterioration after the surgery and 3 months after, the patient was discharged. Conclusions Real-time ultrasound-guided sacral plexus block combined with mild sedation may be an effective and safe technique in patients with amyotrophic lateral sclerosis undergoing hemorrhoidectomy and hemorrhoidal artery ligation.

Abstract Background Patients with mood disorders usually require repeated and prolonged hospitalization, resulting in a heavy burden on healthcare resources. This study aims to identify variables associated with length of stay(LOS) of repeatedly hospitalized patients with mood disorders and to provide information for optimizing psychiatry management and healthcare resource allocation. Methods Electronic medical records (EMRs) of repeatedly hospitalized patients with mood disorders from January 2010 to December 2018 were collected and retrospectively analyzed. Chi-square and t-test were adopted to investigate the differences in characteristics between the two groups of short LOS and long LOS. Generalized estimating equation (GEE) was conducted to investigate potential factors influencing LOS. Results A total of 2,009 repeatedly hospitalized patients with mood disorders were enrolled, of which 797 (39.7%) had a long LOS and 1,212 (60.3%) had a short LOS. Adverse effects of treatment, continuous clinical manifestation, chronic onset type, suicide attempt, comorbidity and use of antidepressants were positively associated with long LOS among all repeatedly hospitalized patients with mood disorders (P

Abstract This study explores the role of financial support in the digital transformation of Chinese A-share-listed companies from 2001 to 2020. By utilizing the moderating effect model and threshold regression model, this study finds the following results: (1) Digital transformation positively impacts innovation, and the support of banking and capital markets further strengthens this impact. (2) With the development of banking and capital markets, the impact of digital transformation on innovation changes from negative to positive, which is also reflected in the subsamples of Eastern companies, small and medium-sized companies (SMEs), and non-SMEs. (3) The study reveals that only the capital market in the non-Eastern region has no threshold, and capital market support is effective only for non-SMEs when it reaches a higher level. These findings have important implications for policymakers in promoting digital transformation through financial support and help companies understand how to use financial support to improve competitiveness.

Abstract Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer. During the course of this study, we identified that autophagy serves as a cytoprotective mechanism during Nectin-4-MMAE treatment and proposed a strategy to enhance the antitumor effects of Nectin-4-MMAE in bladder cancer. Nectin-4-MMAE rapidly internalized into bladder cancer cells in 30 minutes and released MMAE, inducing the onset of caspase-mediated apoptosis and leading to the inhibition of tumor cell growth. Transcriptomics showed significant alterations in autophagy-associated genes in bladder cancer cells treated with Nectin-4-MMAE, which suggested autophagy was activated by Nectin-4-MMAE. Furthermore, autophagy activation was characterized by ultrastructural analysis of autophagosome accumulation, immunofluorescence of autophagic flux, and immunoblotting autophagy marker proteins SQSTM1 and LC3 I/II. Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells. Additionally, we detected the participation of the AKT/mTOR signaling cascade in the induction of autophagy by Nectin-4-MMAE. The combination of Nectin-4-MMAE and an autophagy inhibitor demonstrated enhanced antitumor effects in the HT1376 xenograft tumor model. After receiving a single dose of Nectin-4-MMAE, the group that received the combination treatment showed a significant decrease in tumor size compared to the group that received only one type of treatment. Notably, one mouse in the combination treatment group achieved complete remission of the tumor. The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.

Abstract Objective The aim of this study is to investigate the clinical value and potential prognostic significance of lung function assessment and Testin expression in non-small cell lung cancer (NSCLC) patients. Methods The NSCLC patients were classified into three groups according to lung function: group of normal lung function, group of PRISm (preserved ratio impaired spirometry) (FEV1, forced expiratory volume during the first second

Abstract Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic–related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/β-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/β-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders.

Abstract Background The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib‐refractory, anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. Methods In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two‐sided 95% confidence intervals (CIs). Next‐generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. Results At the data cut‐off date (August 31, 2022), with a median follow‐up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3‐53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. Conclusion Ensartinib led to a favorable OS in patients with advanced, crizotinib‐resistant, and ALK‐positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Abstract Osteoporosis is usually caused by excessive bone resorption and energy metabolism plays a critical role in the development of osteoporosis. However, little is known about the role of energy metabolism-related genes in osteoporosis. This study aimed to explore the important energy metabolism-related genes involved in the development of osteoporosis and develop a diagnosis signature for osteoporosis. The GSE56814, GSE62402, and GSE7158 datasets were downloaded from the NCBI Gene Expression Omnibus. The intersection of differentially expressed genes between high and low levels of body mineral density (BMD) and genes related to energy metabolism were screened as differentially expressed energy metabolism genes (DE-EMGs). Subsequently, a DE-EMG-based diagnostic model was constructed and differential expression of genes in the model was validated by RT-qPCR. Furthermore, a receiver operating characteristic curve and nomogram model were constructed to evaluate the predictive ability of the diagnostic model. Finally, the immune cell types in the merged samples and networks associated with the selected optimal DE-EMGs were constructed. A total of 72 overlapped genes were selected as DE-EMGs, and a five DE-EMG based diagnostic model consisting B4GALT4, ADH4, ACAD11, B4GALT2, and PPP1R3C was established. The areas under the curve of the five genes in the merged training dataset and B4GALT2 in the validation dataset were 0.784 and 0.790, respectively. Moreover, good prognostic prediction ability was observed using the nomogram model (C index = 0.9201; P = 5.507e−14). Significant differences were observed in five immune cell types between the high- and low-BMD groups. These included central memory, effector memory, and activated CD8 T cells, as well as regulatory T cells and activated B cells. A network related to DE-EMGs was constructed, including hsa-miR-23b-3p, DANCR, 17 small-molecule drugs, and two Kyoto Encyclopedia of Genes and Genomes pathways, including metabolic pathways and pyruvate metabolism. Our findings highlighted the important roles of DE-EMGs in the development of osteoporosis. Furthermore, the DANCR/hsa-miR-23b-3p/B4GALT4 axis might provide novel molecular insights into the process of osteoporosis development.

Abstract Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation. By combining phosphoproteomics and functional analysis in human and mouse neurons, we uncovered a function of neuronal autophagy in controlling cAMP-PKA and c-FOS-mediated neuronal activity through selective degradation of the protein kinase A - cAMP-binding regulatory (R)-subunit I (PKA-RI) complex. Lack of AKAP11 causes accumulation of the PKA-RI complex in the soma and neurites, demonstrating a constant clearance of PKA-RI complex through AKAP11-mediated degradation in neurons. Our study thus reveals the landscape of autophagy degradation in human neurons and identifies a physiological function of autophagy in controlling homeostasis of PKA-RI complex and specific PKA activity in neurons.

Abstract How to deal with large tibial bone defects is still controversial. The purpose of this research was to compare the semi-focal bone transport (SFBT) technique with traditional bone transport (TBT) technique for treating such patients. Sixty-two patients were included and retrospectively analyzed. In all cases, after radical debridement large tibial bone defects remained. Patients were treated by the SFBT or TBT technique. The distraction, consolidation duration and complications were recorded by the patients’ medical files. Based on the Association for the Study and Application of Methods of Ilizarov (ASAMI) standard, the bone and functional results were evaluated. The mean bone defect size was 7.7 ± 1.6 cm and 7.5 ± 2.1 cm for SFBT and TBT patients. The mean external fixation index (EFI) was 1.51 ± 0.14 months/cm and 1.89 ± 0.25 months/cm for SFBT and TBT patients (p 0.05). The mean number of complications per patient was 1.1 ± 0.6 and 1.6 ± 0.7 for SFBT and TBT patients (p

Abstract Background Bedtime procrastination refers to an individual’s inability to go to bed at a predetermined time without external obstacles. Previous researchers have found that the bedtime procrastination is harmful to human physical and mental health, but these research on bedtime procrastination have mostly focused on exploring individual factors, while ignoring the external environmental factors. Therefore, this is the first study to investigate bedtime procrastination from the perspective of family environments. Methods The study was conducted using a convenient sampling method and online questionnaires. Family Cohesion Scale, Coping Styles Questionnaire, Mobile Phone Addiction Tendency Scale and Bedtime Procrastination Scale were used to measure sleep and psychological condition of 1,048 college students. Results Family cohesion negatively predicted bedtime procrastination. Additionally, positive coping style and mobile phone addiction had significant independent mediating effects. Furthermore, positive coping style and mobile phone addiction had chain mediating effects between family cohesion and bedtime procrastination. Conclusion This study revealed the effect of coping styles and mobile phone addiction on the relationship between family cohesion and bedtime procrastination among Chinese college students. These findings explained the mechanisms of bedtime procrastination from the perspective of environment, so as to effectively intervene the bedtime procrastination of college students from the perspective of external environment.

Objective To compare the value of different doses of recombinant human brain natriuretic peptide(rhBNP) combined with bisoprolol after percutaneous coronary intervention(PCI) in elderly patients with acute myocardial infarction(AMI). Methods A total of 138 elderly patients with AMI in First Hospital of Qinhuangdao from January 2020 to October 2022 were prospectively selected, they were divided into 3 groups with 46 cases in each group by random number table.All groups were treated with PCI and bisoprolol, 2 hours before surgery, the low-dose group received 1.5 μg/(kg·min) rhBNP, the medium-dose group received 2.0 μg/(kg·min) rhBNP, and the high-dose group received 3.0 μg/(kg·min) rhBNP.Cardiac function [left ventricular ejection fraction(LVEF), cardiac index(CI), stroke volume per minute(SV), plasma brain natriuretic peptide(BNP)] , electrocardiographic parameters [standard diviation of NN intervals(SDNN), root mean square of successive RR interval differences(RMSSD), low frequency band/high frequency band(LF/HF)] , renal function [serum creatinine(Scr), β2-microglobulin(β2-MG), blood urea nitrogen(BUN)], nuclear factor E2-related factor 2/heme oxygenase-1(Nrf2/HO-1) pathway were compared between the groups before and after treatment.The occurrence of adverse reactions and adverse cardiovascular events after treatment were compared between the groups. Results After 72 h of treatment, LVEF, CI, SV, SDNN, RMSSD, Nrf2 and HO-1 protein levels in the high-dose group were higher than those in the medium-dose and low-dose groups(P0.05).Before treatment and 72 h after treatment, there was no significant difference in serum Scr, β2-MG and BUN levels between the groups(P>0.05).There was no significant difference in the total incidence of adverse reactions and the total incidence of adverse cardiovascular events between the groups(P>0.05). Conclusion The treatment of rhBNP combined with bisoprolol is effective in elderly AMI patients after PCI.Large doses of rhBNP can significantly improve cardiac function and heart rate variability, which may be related to the activation of the Nrf2/HO-1 signaling pathway, and has no significant effect on renal function damage, adverse reactions and adverse cardiovascular events.