Peripheral nerve injury (PNI) imposes a substantial burden due to its high disability rate. Although drug-delivering nerve guidance conduits (NGCs) are widely used for PNI repair, their efficacy remains limited, largely because of inefficient, poorly controllable drug release and the hostile early microenvironment driven by oxidative stress and iron metabolism imbalance. Ferroptosis is a key manifestation of this post-injury iron dysregulation. Here, we identify Schwann cell ferroptosis as an early, temporally confined pathological process after PNI and accordingly develop an electro-responsive conductive silk fibroin/polypyrrole (SF/PPy) NGC loaded with menaquinone-4 (MK-4) for temporally targeted local anti-ferroptotic therapy. Electrical stimulation (ES) markedly enhanced MK-4 release, increasing the 14-day cumulative release from 11.20 +/- 0.43% to 23.5 +/- 0.84%. In vitro, under ES, MK-4 suppressed Schwann cell ferroptosis mainly via activation of ferroptosis suppressor protein 1 (FSP1). In vivo, SF/PPy/MK-4 conduits combined with ES modulated the early post-injury microenvironment, inhibited Schwann cell ferroptosis, and significantly improved sensory and motor functional recovery. Overall, this study establishes Schwann cell ferroptosis as an early therapeutic target in PNI and presents a conductive NGC platform integrating ES responsiveness with temporally targeted microenvironmental modulation to promote peripheral nerve regeneration.

BACKGROUND:Tocilizumab, an interleukin-6 receptor inhibitor, is a promising cytoprotective agent selected by the Stroke Preclinical Assessment Network. It showed a protective effect on infarct volume and functional outcomes in animal stroke models. METHODS:In this investigator-initiated, multicentre, randomised, double-blind, placebo-controlled trial, patients with acute ischaemic stroke undergoing EVT were recruited. Eligible patients were randomly assigned (1:1) to receive tocilizumab or placebo treatment. Both patients and investigators were blinded to the treatment assignments. A single dose of tocilizumab (240 mg) or placebo was administered intravenously as soon as possible within 24 h after stroke onset and within 1 h after randomisation. The primary efficacy outcome was the change in infarct volume from baseline (before EVT and start of study drug) to 72 h. Primary and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT06238024. FINDINGS:A total of 108 patients were enrolled (n placebo = 57; n tocilizumab = 51). The median change in infarct core volume between baseline and 72 h was 27.0 mL (7.6-62.4) in the placebo group and 8.8 mL (IQR 3.4-20.6) in the tocilizumab group (adjusted mean difference in cubic root volume [ml1/3] -0.41, 95% CI -0.79 to -0.03, P = 0.04, wald-type test). Symptomatic intracranial haemorrhage occurred in 7 (12%) patients in the placebo group and 3 (6%) patients in the tocilizumab group. The incidence of all-cause death and serious adverse events were similar between the two groups. INTERPRETATION:Among patients with acute ischaemic stroke undergoing endovascular treatment, tocilizumab tended to reduce infarct volume growth at 72 h post-treatment and is well tolerated. Future trials are necessary to confirm the beneficial effect of tocilizumab on long-term functional outcome following stroke. FUNDING:Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Nova Program, National Natural Science Foundation of China, Beijing Natural Science Foundation.

Bone defects pose significant clinical challenges due to the limited regenerative capacity of adult bone and the shortcomings of existing biomaterials, which lack dynamic electromechanical signaling crucial for repair. Here, we present an injectable, ultrasound-responsive piezoelectric hydrogel engineered to synergize silk fibroin's (SF) structural adaptability with polyvinylidene fluoride's (PVDF) bioelectrical activity. Methacrylated silk fibroin (SM) enables rapid UV-triggered crosslinking via a cost-effective photoinitiator system, while electrospun PVDF nanofibers, cryosectioned into microscale units, confer dynamic piezoelectric responsiveness. Under ultrasound stimulation, PVDF generates localized electrical cues that transiently elevate reactive oxygen species (ROS), activating the NRF2 antioxidant pathway to resolve oxidative stress, which polarizes macrophages toward pro-regenerative M2 phenotypes, enhances osteogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) and promotes angiogenesis in vitro. Additionally, it was also confirmed that implantation of critical-sized femoral defects in rats could facilitate bone regeneration by micro-CT and histological analysis in vivo. This platform transcends beyond passive scaffolding by recapitulating bone's electromechanical-immune axis offers a paradigm shift toward smart biomaterials for complex skeletal defects. The integration of PVDF's ultrasound-triggered piezoelectricity with SM's bioactivity establishes a multifunctional system that dynamically regulates redox homeostasis, immune modulation, and tissue remodeling, addressing unmet needs in bone tissue engineering.

With four levels of formations and functional properties similar to biological tissues, protein hydrogel attracts great attention from researchers and clinical practitioners for broad applications. However, hydrogels with high water content usually exhibit poor mechanical properties, which limit their widespread application. In the study, a general and feasible approach was used to enhance the regenerated silk fibroin (RSF) hydrogel's mechanical strength by mimicking the human skeleton biomineralization process in vitro. The final mechanical strength was around 4.5 MPa, and the compressive modulus was around 0.90 MPa after combining the effects of ethanol induction of β-sheet and mineralization by SBF, reaching 3 times higher strength than the original RSF hydrogel. The mineral composition and chemical structure proved that the biomineralization of HAp apposition within amorphous hydrophilic domains enhanced the mechanical properties of RSF hydrogel. In vivo RSF hydrogel mineralization was observed after subcutaneous implantation in rats. The femoral bone defect model demonstrated that the biomineralized RSF hydrogel maintained the bone structure from collapse in the early phase. In summary, a straightforward method for fabricating high-strength biomineralized RSF hydrogel through a slow-and-low approach, i.e., low SBF concentration and longer immersion time, was developed and is promising for treating bone diseases.

ABSTRACT Visit‐to‐visit blood pressure variability (BPV) has been recognized as a cardiovascular risk factor, but its association with new‐onset atrial fibrillation (AF) remains underexplored. This study investigated the relationship between BPV and AF incidence among hypertensive patients using data from the Systolic Blood Pressure Intervention Trial (SPRINT). Visit‐to‐visit BPV was quantified using standard deviation (SD), coefficient of variation (CV), and average real variability (ARV) of systolic and diastolic blood pressure measurements. Participants were stratified into three groups based on systolic BPV tertiles. AF cases were identified via follow‐up electrocardiograms and reports of AF‐related serious adverse events. After excluding individuals with baseline AF or missing BPV data, 7378 patients were analyzed over a median follow‐up of 3.8 years. The incidence of new‐onset AF increased across ascending tertiles of systolic BPV (CV), with rates of 2.5% (62 cases), 4.1% (104 cases), and 5.2% (127 cases) observed in the lowest to highest tertiles, respectively. After adjusting for age, race, blood pressure, and cardiovascular risk factors, the hazard ratios for AF in the second and third tertiles compared to the lowest tertile were 1.52 (95% CI: 1.10–2.09) and 1.83 (95% CI: 1.34–2.49), respectively. Consistent trends were noted for systolic BPV measured via SD and ARV, as well as diastolic BPV. These findings indicate that elevated visit‐to‐visit BPV independently predicts AF development in hypertensive populations. Assessing BPV may enhance risk stratification and identify patients at heightened risk for AF, underscoring its clinical relevance in hypertension management.

Image restoration aims to recover the high-quality images from their degraded observations. Since most existing methods have been dedicated into single degradation removal, they may not yield optimal results on other types of degradations, which do not satisfy the applications in real world scenarios. In this paper, we propose a novel data ingredient-oriented approach that leverages prompt-based learning to enable a single model to efficiently tackle multiple image degradation tasks. Specifically, we utilize a encoder to capture features and introduce prompts with degradation-specific information to guide the decoder in adaptively recovering images affected by various degradations. In order to model the local invariant properties and non-local information for high-quality image restoration, we combined CNNs operations and Transformers. Simultaneously, we made several key designs in the Transformer blocks (multi-head rearranged attention with prompts and simple-gate feed-forward network) to reduce computational requirements and selectively determines what information should be persevered to facilitate efficient recovery of potentially sharp images. Furthermore, we incorporate a feature fusion mechanism further explores the multi-scale information to improve the aggregated features. The resulting tightly interlinked hierarchy architecture, named as CAPTNet, extensive experiments demonstrate that our method performs competitively to the state-of-the-art.

Open Relation Extraction (OpenRE) is a task that involves discovering new relation types by referring to labeled instances. Existing methods mainly rely on large pre-trained models to obtain the relation representation of entity pairs, and then jointly train the supervised and unsupervised data using a joint loss function. Some researchers enhance their relation representation by introducing additional information as prompt. However, these approaches have several major issues. Firstly, many of them rely on external knowledge bases, which require a large amount of high-quality data. Secondly, They fail to consider the rich semantic and prior knowledge existing in the labels. To this end, we propose a novel method to incorporate the prior knowledge into prompt-tuning and introduce a multi-view algorithm to optimize the relation representations. We conduct experiments on two common datasets, and the results show that our proposed method significantly outperforms the previous state-of-the-art methods.

The efficacy and safety of revision microscopic microvascular decompression (microscopic MVD) for treating residual or recurrent hemifacial spasm (HFS) remain uncertain. We conducted a systematic review and meta-analysis to evaluate the benefits and risks associated with this reoperation, focusing primarily on spasm relief, facial palsy, and hearing impairment. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. We performed a comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library for eligible articles from their inception through June 2024. A total of 17 studies involving 719 patients were included in this meta-analysis. Among these patients, 668 experienced overall symptom relief following reoperation, resulting in a relief rate of 94

Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to abnormal oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation, making the OP-related bone healing a significant clinical challenge. As the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) is closely related to bone regeneration; currently, this study assessed the effects of Picein on BMSCs in vitro and bone regeneration in osteoporotic bone defect in vivo. Cell viability was determined by CCK-8 assay. The production of (ROS), malonaldehyde, superoxide dismutase activities, and glutathione was evaluated by using commercially available kits, and a flow cytometry analysis was adopted to detect macrophage polarization. Osteogenic capacity of BMSCs was evaluated by alkaline phosphatase (ALP) activity, ALP staining, and Alizarin red S staining. The expression of osteogenic-related proteins (OPN, Runx-2, OCN) and osteogenic-related genes (ALP, BMP-4, COL-1, and Osterix) were evaluated by Western blotting and real-time PCR (RT-PCR). In addition, proliferation, migration ability, and angiogenic capacity of human umbilical vein endothelial cells (HUVECs) were evaluated by EdU staining, scratch test, transwell assay, and tube formation assay, respectively. Angiogenic-related genes (VEGF, vWF, CD31) were also evaluated by RT-PCR. Results showed that Picein alleviated erastin-induced oxidative stress, enhanced osteogenic differentiation capacity of BMSCs, angiogenesis of HUVECs, and protects cells against ferroptosis through Nrf2/HO-1/GPX4 axis. Moreover, Picein regulate immune microenvironment by promoting the polarization of M2 macrophages in vitro. In addition, Picein also reduce the inflammation levels and promotes bone regeneration in osteoporotic bone defect in OP rat models in vivo. Altogether, these results suggested that Picein can promote bone regeneration and alleviate oxidative stress via Nrf2/HO-1/GPX4 pathway, offering Picein as a novel antioxidant agent for treating osteoporotic bone defect.

Spacecraft Inverse Synthetic Aperture Radar (ISAR) imaging super-resolution aims to enhance the resolution of low-resolution images to produce high-resolution images. However, spacecraft ISAR imaging presents challenges such as sparse, fuzzy boundaries, and the intricate differentiation between background and spacecraft, rendering current methods less effective in achieving satisfactory super-resolution results. In this letter, we propose a sparse and selective feature fusion network for super-resolution spacecraft ISAR images. At the heart of our approach lies a multi-scale residual block featuring the following essential components: (a) parallel multi-resolution streams to extract multi-scale features, (b) trainable top-k selection operator that intelligently retains the most critical attention scores from the keys for each query, enhancing the distinction between background and spacecraft information within the local region, and (c) selective cross fusion to discriminatively determine which low-and high-scale information to retain when aggregating multi-scale features. The resulting tightly interlinked architecture, named as SSNet, learns a set of more accurate features. Extensive experiments on real ISAR images of spacecraft unequivocally illustrate the superior performance of the proposed method compared to state-of-the-art approaches, achieving an impressive 33.27dB. The code are released at https://github.com/Tombs98/SSNet.

Rationale Neuroprotective strategies based on reperfusion therapy hold substantial promise for acute ischaemic stroke (AIS). Preclinical research indicates that tocilizumab, an interleukin-6 receptor antagonist, can attenuate ischaemia-reperfusion damage by exerting anti-inflammatory and neuroprotective effects.Aim To determine tocilizumab's efficacy and safety when combined with endovascular thrombectomy (EVT) in patients with acute anterior circulation large vessel occlusion (LVO).Sample size estimates To determine a 30% decrease in average infarct core volume comparing the intervention and historical control groups (mean increase of 18.7 mL (SD=9.7 mL) post-thrombectomy) via a two-sided test (alpha=0.05, power=80%), accounting for a 10% drop-out rate, we plan to recruit 108 participants.Methods and design This trial is designed as a randomised, multicentre, double-blind, placebo-controlled trial. Patients will be randomly and evenly allocated to the tocilizumab or placebo groups.Study outcomes The primary endpoint is the change in infarct core volume between baseline and 72 hours post-treatment. Secondary outcomes include the 90-day modified Rankin scale score (0-2, indicating functional independence). The key safety endpoints include 90-day mortality and symptomatic intracerebral haemorrhage within 72 hours after EVT.Discussion Administering tocilizumab within 24 hours of stroke as an adjunct to EVT may effectively reduce the infarct core volume for patients experiencing AIS with anterior circulation LVO, potentially improving functional outcomes in these patients.

Image restoration is the task of aiming to obtain a high-quality image from a corrupt input image, such as deblurring and deraining. In image restoration, it is typically necessary to maintain a complex balance between spatial details and contextual information. Although a multi-stage network can optimally balance these competing goals and achieve significant performance, this also increases the system’s complexity. In this paper, we propose a mountain-shaped single-stage design, which achieves the performance of multi-stage networks through a plug-and-play feature fusion middleware. Specifically, we propose a plug-and-play feature fusion middleware mechanism as an information exchange component between the encoder-decoder architectural levels. It seamlessly integrates upper-layer information into the adjacent lower layer, sequentially down to the lowest layer. Finally, all information is fused into the original image resolution manipulation level. This preserves spatial details and integrates contextual information, ensuring high-quality image restoration. Simultaneously, we propose a multi-head attention middle block as a bridge between the encoder and decoder to capture more global information and surpass the limitations of the receptive field of CNNs. In order to achieve low system complexity, we removes or replaces unnecessary nonlinear activation functions. Extensive experiments demonstrate that our approach, named as M3SNet, outperforms previous state-of-the-art models while using less than half the computational costs, for several image restoration tasks, such as image deraining and deblurring. The code and the pre-trained models will be released at https://github.com/Tombs98/M3SNet .

More than 55 million individuals are suffering from Alzheimer's disease (AD), while the effective therapeutic strategies remain elusive. Our previous study identified a lysosome-enhancing lead compound LH2-051 with a tetrahydroisoquinoline scaffold through a novel dopamine transporter-cyclin-dependent kinase 9-transcription factor EB (DAT-CDK9-TFEB) regulation mechanism to promote TFEB activation and lysosome biogenesis. Here, we launched a comprehensive structure-activity relationship study for LH2-051, and 47 new derivatives were designed and synthesized, in which several compounds exhibited remarkable lysosome-enhancing activities. Notably, compounds 37 and 45 exhibited more favorable TFEB activation and lysosome biogenesis capabilities, good safety profiles, and excellent pharmacokinetic profiles with high brain penetration. Further investigations demonstrated that both compounds significantly enhance the clearance of A beta aggregates and ameliorate the impairment of learning, memory, and cognition in APP/PS1 mice. Overall, these results indicated that compounds 37 and 45 are promising preclinical drug candidates for the treatment of AD.

Background: Sirtuin 7 (SIRT7), as a nicotinamide adenine dinucleotide-dependent protein/histone deacetylase, has been implicated in the pathogenesis of cardiovascular diseases. However, whether SIRT7 is related to hypertension remains largely unclear. Thus, this study aims to explore the effects and correlation between SIRT7 and hypertension. Methods: A total of 72 patients with essential hypertension and 82 controls with non-hypertension were recruited at Beijing Tongren Hospital Affiliated with Capital Medical University from July 2022 to June 2023. Plasma SIRT7 expression was measured using enzyme-linked immunosorbent assay analysis. Clinical baseline characteristics, laboratory measurements, echocardiographic data, and medical therapy were collected. Results: Plasma levels of SIRT7 were lower in hypertensive patients compared with non-hypertensive patients [0.97 (0.58-1.30) vs. 1.24 (0.99-1.46) ng/mL, P < 0.001, respectively]. Furthermore, compared with the low SIRT7 group, there were lower levels of systolic blood pressure, hyperlipidemia, and the ultrasonic electrocardiogram parameters left ventricular end-diastolic diameter and left atrial in diastole in the high SIRT7 group (P < 0.05, respectively). More importantly, multivariate logistic regression analyses indicated that plasma SIRT7 was a predictor of hypertension [OR: 0.06, 95 % CI (0.02-0.19), P < 0.001]. Receiver operating characteristics curve analysis revealed that the optimal cutoff value for plasma SIRT7 levels in detecting hypertension was determined as 0.85 ng/mL with a sensitivity of 73.6 % and a specificity of 89.0 %. The area under the curve for SIRT7 was 0.821 (95 % CI, 0.751-0.878; P < 0.001). Conclusion: Plasma levels of SIRT7 are decreased in patients with essential hypertension, implying its potential as a biomarker for diagnosing essential hypertension..

This research was designed to demonstrate the pre-treatment prevalence of drug resistance (DR) and resistance mutation sites (MSs) in highly resistant human immunodeficiency virus (HIV) infected patients, along with assessing the differences between HIV -1 DNA and HIV -1 RNA resistance, and evaluating the efficacy of lopinavir and ritonavir application. The study focused on 420 newly diagnosed HIV -1 -infected patients. Prior to antiviral therapy, HIV -1 RNA resistance testing was performed to analyse the prevalence of resistance and resistance mutations. In addition, HIV -1 DNA genotypic resistance was simultaneously assessed in treatment -naive patients to evaluate its clinical significance. The effect of lopinavir/ritonavir treatment was observed on CD4+ cell count, HIV -1 RNA load and safety indicators (aspartate aminotransferase (AST), blood glucose (BG), triglyceride (TG), cholesterol (Cho)) before and after treatment. The results showed that the success rate of HIV -1 RNA pol region amplification (73.10%) was lower than that of HIV -1 DNA pol region amplification (92.86%). The median CD4+ cell count before treatment was 213 cells/mu L, and after 12, 24 , 36, 48 and 96 weeks of treatment, the median CD4+ cell counts were 303 cells/mu L, 352 cells/mu L, 381 cells/mu L, 399 cells/mu L and 476 cells/mu L, respectively. The virologic suppression rate of HIV RNA < 50 copies/mL with lopinavir/ritonavir was greater than 75% at all time points. In conclusion, lopinavir/ritonavir demonstrated remarkable efficacy in the treatment of highly resistant HIV infection and HIV -1 DNA resistance testing provided comprehensive information for resistance monitoring.

Aims:Our aim was to investigate the prevalence, incidence, and persistence of visual impairment (VI) and their correlates among the Chinese population with diabetes mellitus (DM) over 3 years.Materials and methods:The China Health and Retirement Longitudinal Survey is the first nationally representative longitudinal survey of the Chinese population. A cross-sectional analysis of prevalent VI in 2015 consisted of 2,173 participants with DM. A longitudinal observation of incident and persistent VI consisted of 1,633 participants from 2015 to 2018. Risk factors of VI were identified via univariate and multivariate logistic regression analyses.Results:Among our study population with DM, 11.8% reported VI in 2015, 4.5% had persistent VI from 2015 to 2018, and 8.9% developed VI in 2018. Factors identified to be correlated to VI (p < 0.05) were older age, being a woman, lower educational attainment, living in a rural area, application of DM medication and non-pharmacological treatment, receiving DM-related tests, use of spectacles, and poorer health status.Conclusion:This most recent national data provides a baseline for future public health initiatives on VI among the Chinese population with DM. With multiple risk factors identified, these could provide concurrent targets for various public health strategies and interventions with the aim of reducing the burden of VI among the population with DM in China.

In recent years, the incidence of cancer is high around the world, and the resistance of bacteria is increasing. To cope with the potentially adverse side effects of cancer chemotherapy and surgery, researchers are turning to the construction of new drug scaffolds. The indoline structure exists in a huge number of natural products, but drugs with indoline have only been formally studied in recent years. With the deepening of research, drugs containing indoline have played important roles in more disease treatment aspects, such as anti-tumor, anti-bacterial, anti-inflammatory and have been used as analgesics, to treat cardiovascular diseases and so on. The synthesis and pharmacological activity of indoline derivatives is summarized in this review in order to support the addition of the indoline component to the toolbox of medicinal chemists. This review focuses on the advantages of indoline compounds in development and synthesis of and for the use as anticancer drugs, antibacterial drugs, to treat cardiovascular diseases and as anti-inflammatory and analgesic drugs. Indoline structures are commonly found in natural and synthetic compounds with medicinal value and are now beginning to be exploited as the basic backbone of various drugs. As research continues, dihydroindoles and their derivatives will play a greater role in the medical field.

Objectives:To translate 20-item Meaningful and Enjoyable Activities Scale into Chinese and evaluate its psychometric properties amongst Chinese with mild dementia.Methods:A cross-sectional study of 450 people with mild dementia recruited from a memory disorders clinic was conducted with the C-MEAS. Raw data were randomly divided into two parts for exploratory factor analysis and confirmatory factor analysis, to evaluate the construct validity. Content validity and reliability were tested by content validity index and Cronbach's α coefficients, respectively.Results:Adaptation results showed that the Chinese version of the scale is adequate for linguistic and content validation. Confirmatory factor analysis indicated a significantly good fit for a three-factor model. Cronbach's alpha coefficient was 0.84 for the overall scale.Conclusion:The C-MEAS for people with mild dementia is a reliable and valid instrument with satisfactory psychometric properties. Future studies should recruit a more representative sample of people with mild dementia in China to verify the applicability of the scale.

The estimation of spacecraft pose is crucial in numerous space missions, including rendezvous and docking, debris removal, and on-orbit maintenance. Estimating the pose of space objects is significantly more challenging than that of objects on Earth, primarily due to the widely varying lighting conditions, low resolution, and limited amount of data available in space images. Our main proposal is a new deep learning neural network architecture, which can effectively extract orbiting spacecraft features from images captured by inverse synthetic aperture radar (ISAR) for pose estimation of non-cooperative on orbit spacecraft. Specifically, our model enhances spacecraft imaging by improving image contrast, reducing noise, and using transfer learning to mitigate data sparsity issues via a pre-trained model. To address sparse features in spacecraft imaging, we propose a dense residual U-Net network that employs dense residual block to reduce feature loss during downsampling. Additionally, we introduce a multi-head self-attention block to capture more global information and improve the model's accuracy. The resulting tightly interlinked architecture, named as SU-Net, delivers strong performance gains on pose estimation by spacecraft ISAR imaging. Experimental results show that we achieve the state of the art results, and the absolute error of our model is 0.128[Formula: see text] to 0.4491[Formula: see text], the mean error is about 0.282[Formula: see text], and the standard deviation is about 0.065[Formula: see text]. The code are released at https://github.com/Tombs98/SU-Net .