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Photodynamic therapy (PDT) has attracted widespread attention from researchers as an emerging cancer treatment method. There have been many reports on various types of NIR-II photosensitizers for imaging and treatment of tumor sites. However, there are few reports on the development of NIR-II organic small molecule photosensitizers that have intelligent response to the tumor microenvironment, precise imaging, real-time treatment, and high biocompatibility. In this work, we developed a series of NIR-II photosensitizers (RBTs) with near-infrared excitation, good photostability, and large Stokes shift. Among them, RBT-Br exhibited higher reactive oxygen species (ROS) generation efficiency due to the introduction of halogen heavy atoms to enhance intersystem crossing (ISC). It is noteworthy that RBT-Br can generate singlet oxygen (1O 2) and superoxide anion radicals (•O 2 −) simultaneously under 730 nm laser. Subsequently, we used molecular engineering technology to construct three pH-responsive NIR-II photosensitizers (RBT-pHs) by utilizing the closure of the lactam ring, among which RBT-pH-1 (p K a = 6.78) is able to be directionally activated under the stimulation of tumor micro-acid environment, with its fluorescence emission window reaching 933 nm. Subsequently, RBT-pH-1 NPs encapsulated in DSPE-mPEG 5k were applied for PDT treatment of mouse tumors. The results showed that RBT-pH-1 NPs were activated by the acidic tumor microenvironment and generated ROS under laser excitation, exhibiting precise tumor imaging and significant tumor growth inhibition. We look forward to these multifunctional NIR-II organic small molecule photosensitizers providing a more efficient approach for clinical treatment of tumors. A reversible pH-switchable NIR-II nano-photosensitizer RBT-pH-1 NPs (p K a = 6.76) is developed for precise imaging and PDT therapy of mouse tumors, which can be effectively used for targeted enrichment and activation of tumor micro-acid environments. The results show that this NIR-II photosensitizer generates ROS through tumor micro-acid environment stimulation and laser triggering, showing precise tumor imaging guidance and significant tumor growth inhibition. [Display omitted] [ABSTRACT FROM AUTHOR]

The immunosuppressive tumor microenvironment, such as lactic acid and matrix metalloproteinases (MMPs) overexpression, has been well confirmed to be adverse for tumor therapy. In current study, a tumor microenvironment modulatory hydrogel was successfully developed to treat melanoma by taking advantage of the synergistic effects of nano-hydroxyapatite (nHA) with well-documented selective anti-tumor action, lactate dehydrogenase A inhibitor (R)-GNE-140 (GNE), and matrix metalloproteinase-2 (MMP-2) sensitive peptide. The hydrogel was acquired by the reaction of 4-arm-polyethylene glycol-maleic anhydride (4-arm-PEG-MAL) and MMP-2 sensitive peptide (CC-14), in which nHA and GNE were co-encapsulated physically. The in vitro degradation tests confirmed the accelerated release of nHA and GNE from the hydrogel under less-acidic (pH 6.8) and MMP-2 containing conditions compared to those neutral or without MMP-2 conditions, demonstrating the pH and MMP-2 responsive properties of as-prepared hydrogel. Findings from in vitro cell experiments revealed that the hydrogel could stop the proliferation of melanoma cells by stacking cell cycle via lactic acid metabolic dysregulation and boosting cell apoptosis via nHA direct killing effect. Moreover, after hydrogel treatment, the rate of migration and aggressiveness of melanoma cells both reduced significantly. An in vivo anti-melanoma study showed that the hydrogel could inhibit tumor growth significantly and result in more CD8+ T cells and antigen-presenting cells but less T reg cells infiltration, ultimately leading to an enhanced therapeutic efficacy. As thus, the fabricated hydrogel demonstrated great promise for treating melanoma and could be a new potent strategy for efficient melanoma therapy. Nano-hydroxyapatite (nHA) has the capability of selectively killing cancer cells. The study reported a tumor microenvironment (TME) modulatory hydrogel with the goal of enhancing melanoma therapy efficacy by combining nHA administration with immunosuppressive microenvironment modulation. The hydrogel demonstrated pH and MMP-2 sensitivity. Hence, controlled release of nHA and lactate dehydrogenase A inhibitor (GNE) could be observed, and in situ MMP-2 consumption at the tumor site occurred. The hydrogel effectively inhibited the growth of melanoma cells. Furthermore, hydrogel increased the production of CD8+ T cells and antigen-presenting cells while decreasing the infiltration of T reg cells at the tumor site. This could transform the initial "cold" tumor into a "hot" tumor, ultimately resulting in an enhanced therapeutic effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Mitophagy influences the progression and prognosis of ischemic stroke (IS). However, whether DNA methylation in the brain is associated with altered mitophagy in hypoxia-injured neurons remains unclear. Here, miR-138–5p was found to be highly expressed in exosomes secreted by astrocytes stimulated with oxygen and glucose deprivation/re-oxygenation (OGD/R), which could influence the recovery of OGD/R-injured neurons through autophagy. Mechanistically, miR-138–5p promotes the stable expression of Ras homolog enriched in brain like 1(Rhebl1) through DNA-methyltransferase-3a (DNMT3A), thereby enhancing ubiquitin-dependent mitophagy to maintain mitochondrial homeostasis. Furthermore, we employed glycosylation engineering and bioorthogonal click reactions to load mirna onto the surface of microglia and deliver them to injured region utilising the inflammatory chemotactic properties of microglia to achieve drug-targeted delivery to the central nervous system (CNS). Our findings demonstrate miR-138–5p improves mitochondrial function in neurons through the miR-138–5p/DNMT3A/Rhebl1 axis. Additionally, our engineered cell vector-targeted delivery system could be promising for treating IS. In this study, we demonstrated that miR-138–5p in exosomes secreted by astrocytes under hypoxia plays a critical role in the treatment of hypoxia-injured neurons. And we find a new target of miR-138–5p, DNMT3A, which affects neuronal mitophagy and thus exerts a protective effect by regulating the methylation of Rbebl1. Furthermore, we have developed a carrier delivery system by combining miR-138–5p with the cell membrane of microglia and utilized the inflammatory chemotactic properties of microglia to deliver this system to the brain via intravenous injection. This groundbreaking study not only provides a novel therapeutic approach for ischemia-reperfusion treatment but also establishes a solid theoretical foundation for further research on targeted drug delivery for central nervous system diseases with promising clinical applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Presently, the clinical treatment of intervertebral disc degeneration (IVDD) remains challenging, but the strategy of simultaneously overcoming the overactive inflammation and restoring the anabolic/catabolic balance of the extracellular matrix (ECM) in the nucleus pulposus (NP) has become an effective way to alleviate IVDD. IL-1ra, a natural antagonist against IL-1β, can mitigate inflammation and promote regeneration in IVDD. Chondroitin sulfate (CS), an important component of the NP, can promote ECM synthesis and delay IVDD. Thus, these were chosen and integrated into functionalized microspheres to achieve their synergistic effects. First, CS-functionalized microspheres (GelMA-CS) with porous microstructure, good monodispersion, and about 200 µm diameter were efficiently and productively fabricated using microfluidic technology. After lyophilization, the microspheres with good local injection and tissue retention served as the loading platform for IL-1ra and achieved sustained release. In in vitro experiments, the IL-1ra-loaded microspheres exhibited good cytocompatibility and efficacy in inhibiting the inflammatory response of NP cells induced by lipopolysaccharide (LPS) and promoting the secretion of ECM. In in vivo experiments, the microspheres showed good histocompatibility, and local, minimally invasive injection of the IL-1ra-loaded microspheres could reduce inflammation, maintain the height of the intervertebral disc (IVD) and the water content of NP close to about 70 % in the sham group, and retain the integrated IVD structure. In summary, the GelMA-CS microspheres served as an effective loading platform for IL-1ra, eliminated inflammation through the controlled release of IL-1ra, and promoted ECM synthesis via CS to delay IVDD, thereby providing a promising intervention strategy for IVDD. The strategy of simultaneously overcoming the overactive inflammation and restoring the anabolic/catabolic balance of the extracellular matrix (ECM) in nucleus pulposus (NP) has shown great potential prospects for alleviating intervertebral disc degeneration (IVDD). From the perspective of clinical translation, this study developed chondroitin sulfate functionalized microspheres to act as the effective delivery platform of IL-1ra, a natural antagonist of interleukin-1β. The IL-1ra loading microspheres (GelMA-CS-IL-1ra) showed good biocompatibility, good injection with tissue retention, and synergistic effects of inhibiting the inflammatory response induced by lipopolysaccharide and promoting the secretion of ECM in NPCs. In vivo , they also showed the beneficial effect of reducing the inflammatory response, maintaining the height of the intervertebral disc and the water content of the NP, and preserving the integrity of the intervertebral disc structure after only one injection. All demonstrated that the GelMA-CS-IL-1ra microspheres would have great promise for the minimally invasive treatment of IVDD. [Display omitted] [ABSTRACT FROM AUTHOR]

• Design strategies of MBMs. • Functional properties of MBMs. • Signaling pathways associated with of MBMs for tissue regeneration. • Clinical applications and basic research of MBMs. • Challenges of MBMs. Magnesium-based biomaterials (MBMs) are one of the most promising materials for tissue engineering due to their unique mechanical properties and excellent functional properties. This review describes the development, advantages, and challenges of MBMs for biomedical applications, especially for tissue repair and regeneration. The history of the use of MBMs from the beginning of the 20th century is traced, and the transformative advances in contemporary applications of MBMs in areas such as orthopedics and cardiovascular surgery are emphasized. The review also provides insight into the signaling pathways affected by MBMs, such as the PI3K/Akt and RANKL/RANK/OPG pathways, which are critical for osteogenesis and angiogenesis. The review advocates that future research should focus on optimizing alloy compositions, surface modification and exploring innovative technologies such as 3D printing to improve the efficacy of MBMs in complex tissue repair. The potential of MBMs to tissue engineering and regenerative medicine is significant, urging further exploration and interdisciplinary collaboration to maximize their therapeutic effects. [Display omitted] [ABSTRACT FROM AUTHOR]

The cumulative burden of hypertrophic cardiomyopathy (HCM) is significant, with a noteworthy percentage (10%-15%) of patients with HCM per year experiencing major adverse cardiovascular events (MACEs). A current risk stratification scheme for HCM had only limited accuracy in predicting sudden cardiac death (SCD) and failed to account for a broader spectrum of adverse cardiovascular events and cardiac magnetic resonance (CMR) parameters. This study sought to develop and evaluate a machine learning (ML) framework that integrates CMR imaging and clinical characteristics to predict MACEs in patients with HCM. A total of 758 patients with HCM (67% male; age 49 ± 14 years) who were admitted between 2010 and 2017 from 4 medical centers were included. The ML model was built on the internal discovery cohort (533 patients with HCM, admitted to Fuwai Hospital, Beijing, China) by using the light gradient-boosting machine and internally evaluated using cross-validation. The external test cohort consisted of 225 patients with HCM from 3 medical centers. A total of 14 CMR imaging features (strain and late gadolinium enhancement [LGE]) and 23 clinical variables were evaluated and used to inform the ML model. MACEs included a composite of arrhythmic events, SCD, heart failure, and atrial fibrillation–related stroke. MACEs occurred in 191 (25%) patients over a median follow-up period of 109.0 months (Q1-Q3: 73.0-118.8 months). Our ML model achieved areas under the curve (AUCs) of 0.830 and 0.812 (internally and externally, respectively). The model outperformed the classic HCM Risk-SCD model, with significant improvement (P < 0.001) of 22.7% in the AUC. Using the cubic spline analysis, the study showed that the extent of LGE and the impairment of global radial strain (GRS) and global circumferential strain (GCS) were nonlinearly correlated with MACEs: an elevated risk of adverse cardiovascular events was observed when these parameters reached the high enough second tertiles (11.6% for LGE, 25.8% for GRS, −17.3% for GCS). ML-empowered risk stratification using CMR and clinical features enabled accurate MACE prediction beyond the classic HCM Risk-SCD model. In addition, the nonlinear correlation between CMR features (LGE and left ventricular pressure gradient) and MACEs uncovered in this study provides valuable insights for the clinical assessment and management of HCM. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • This study achieved label-free visualization of PD-L1 expression at tissue level for the first time. • MLC-Raman histopathology achieved an accuracy of 0.99 in classifying distinct PD-L1 expression cells in GBM IME. • MLC-Raman histopathology could identify glioma, CD8+ T cells, macrophages and normal cells. • The imaging results exhibited strong concordance with MxIF and traditional pathologists' scoring. • The entire process from signal collection to visualization could be completed within 30 min. Combination immunotherapy holds promise for improving survival in responsive glioblastoma (GBM) patients. Programmed death-ligand 1 (PD-L1) expression in immune microenvironment (IME) is the most important predictive biomarker for immunotherapy. Due to the heterogeneous distribution of PD-L1, post-operative histopathology fails to accurately capture its expression in residual tumors, making intra-operative diagnosis crucial for GBM treatment strategies. However, the current methods for evaluating the expression of PD-L1 are still time-consuming. To overcome the PD-L1 heterogeneity and enable rapid, accurate, and label-free imaging of PD-L1 expression level in GBM IME at the tissue level. We proposed a novel intra-operative diagnostic method, Machine Learning Cascade (MLC)-based Raman histopathology, which uses a coordinate localization system (CLS), hierarchical clustering analysis (HCA), support vector machine (SVM), and similarity analysis (SA). This method enables visualization of PD-L1 expression in glioma cells, CD8+ T cells, macrophages, and normal cells in addition to the tumor/normal boundary. The study quantified PD-L1 expression levels using the tumor proportion, combined positive, and cellular composition scores (TPS, CPS, and CCS, respectively) based on Raman data. Furthermore, the association between Raman spectral features and biomolecules was examined biochemically. The entire process from signal collection to visualization could be completed within 30 min. In an orthotopic glioma mouse model, the MLC-based Raman histopathology demonstrated a high average accuracy (0.990) for identifying different cells and exhibited strong concordance with multiplex immunofluorescence (84.31 %) and traditional pathologists' scoring (R 2 ≥ 0.9). Moreover, the peak intensities at 837 and 874 cm−1 showed a positive linear correlation with PD-L1 expression level. This study introduced a new and extendable diagnostic method to achieve rapid and accurate visualization of PD-L1 expression in GBM IMB at the tissular level, leading to great potential in GBM intraoperative diagnosis for guiding surgery and post-operative immunotherapy. [ABSTRACT FROM AUTHOR]

Modular reconstruction systems based on porous tantalum (PT) prosthetic components have been increasingly used for the treatment of complex acetabular bone defects in revision total hip arthroplasty. We report a novel technique that applies a revision cup as a "super-augment" to form a "double-cup" construct for Paprosky type III defects. A retrospective review was conducted on revision total hip arthroplasty cases, comparing those treated with double-cup constructs (DC group, n = 48) to those treated with PT shells and augments (PT group, n = 48). All procedures were performed at the same institute between 2017 and 2022. Clinical outcome evaluation utilized the Harris Hip Score, Oxford Hip Score, and the 36-Item Short Form Survey. Preoperative and postoperative radiographic assessments measured hip center of rotation (COR) position and leg length discrepancy. Additionally, postoperative complications and implant survivorship were monitored during the follow-up period. The clinical outcomes improved substantially in both groups, which showed no significant difference in the Harris Hip Score (P =.786), the Oxford Hip Score (P =.570), and the 36-Item Short Form Survey (P =.691). Compared to the PT group, the reconstruction COR was significantly closer to the anatomic COR (vertical distance: 2.630 versus 7.355 mm, P =.0034; horizontal distance: 1.881 versus −6.413 mm, P <.0001) in Paprosky 3B type defects. Additionally, postoperative leg length discrepancy was less in the DC group (−8.252 versus −1.821 mm, P =.0008). Dislocation was the main complication in the DC group, and only 1 patient received re-revision due to repeated dislocation. The cumulative survival rate of the DC group (100%; 95% confidence interval 100) was better than the PT group (83.4%; 95% confidence interval 70.5 to 98.6) when re-revisions for aseptic loosening were the endpoint (P =.046). The DC is a reliable revision technique for the reconstruction of Paprosky type III bone defects. Although dislocation remains challenging, the biomechanically superior restoration achieved by this technique lowers the risk of aseptic loosening. [ABSTRACT FROM AUTHOR]

The relationship between vitamin D and cardiovascular health (CVH) in children remains unclear. We aimed to explore the association between vitamin D and CVH metrics using the latest Life's Essential 8 (LE8) among Chinese children and adolescents. A cross-sectional study containing 2680 participants aged 7–18 years (1340 boys and 1340 girls) was performed in South China in 2013. Vitamin D levels were categorized as follows: ≥20 ng/mL (sufficiency), 12 - < 20 ng/mL (inadequacy), and <12 ng/mL (deficiency). The CVH metrics of LE8 was assessed by overall CVH score, health behavior score, health factor score and high CVH, among which the health behaviors included diet, physical activity, nicotine exposure, and sleep health, as well as the health factors contained body mass index, blood lipids, blood glucose, and blood pressure. Different regression models were used to assess the associations between vitamin D levels and CVH metrics of LE8. Results showed that the prevalence of vitamin D deficiency and inadequacy was 7.5% and 44.4%, respectively. Boys had lower levels in overall CVH score, health behavior score, and health factor score than girls. After adjusting for potential confounds, upward trends in diet score, health behavior score, and high CVH were observed with increasing vitamin D levels. Vitamin D levels were positively associated with high CVH based on LE8, and more attention should be paid on boys due to whose lower levels in CVH metrics. • This is the first study to explore the association between vitamin D and CVH basing on the latest LE8 among Chinese children. • Vitamin D levels were positively associated with diet score, health behavior score, and high CVH. • Boys had poorer CVH status than girls in overall CVH score, health behavior score, and health factor score. • More than half of children and adolescents aged 7–18 years had insufficient vitamin D. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a major risk factor for atrial structural remodeling and atrial fibrillation (AF). Calpain activity is hypothesized to promote atrial remodeling and AF. The purpose of this study was to investigate the role of calpain in diabetes-associated AF, fibrosis, and calcium handling dysfunction. DM-associated AF was induced in wild-type (WT) mice and in mice overexpressing the calpain inhibitor calpastatin (CAST-OE) using high-fat diet feeding followed by low-dose streptozotocin injection (75 mg/kg). DM and AF outcomes were assessed by measuring blood glucose levels, fibrosis, and AF susceptibility during transesophageal atrial pacing. Intracellular Ca2+ transients, spontaneous Ca2+ release events, and intracellular T-tubule membranes were measured by in situ confocal microscopy. WT mice with DM had significant hyperglycemia, atrial fibrosis, and AF susceptibility with increased atrial myocyte calpain activity and Ca2+ handling dysfunction relative to control treated animals. CAST-OE mice with DM had a similar level of hyperglycemia as diabetic WT littermates but lacked significant atrial fibrosis and AF susceptibility. DM-induced atrial calpain activity and downregulation of the calpain substrate junctophilin-2 were prevented by CAST-OE. Atrial myocytes of diabetic CAST-OE mice exhibited improved T-tubule membrane organization, Ca2+ handling, and reduced spontaneous Ca2+ release events compared to littermate controls. This study confirmed that DM promotes calpain activation, atrial fibrosis, and AF in mice. CAST-OE effectively inhibits DM-induced calpain activation and reduces atrial remodeling and AF incidence through improved intracellular Ca2+ homeostasis. Our results support calpain inhibition as a potential therapy for preventing and treating AF in DM patients. [ABSTRACT FROM AUTHOR]

Current cytotoxic T lymphocyte (CTL) activating immunotherapy requires a major histocompatibility complex I (MHC-I)-mediated presentation of tumor-associated antigens, which malfunctions in around half of patients with triple-negative breast cancer (TNBC). Here, we create a LCL161-loaded macrophage membrane decorated nanoparticle (LMN) for immunotherapy of MHC-I-deficient TNBC. SIRP α on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161, which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells. The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds. LMNs also block CD47-mediated phagocytosis suppression. LMNs inhibit the growth of MHC-I-deficient TNBC tumors, as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel, and prolong the survival of animals, during which process CTLs also play important roles. This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophage-mediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers. LCL161-loaded macrophage membrane-decorated nanoparticles (LMNs) target CD47 on cancer cells, delivering LCL161 and blocking immune checkpoints. This enhances phagocytosis, improving efficacy against MHC-I deficient triple-negative breast cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

The urinary albumin‒creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are important markers of renal dysfunction, but few studies have simultaneously examined their impact on long-term mortality in patients with heart failure (HF). This study included patients with HF from the National Health and Nutrition Survey from 1999 to 2018. The fully adjusted Cox proportional risk model was adopted, and propensity score matching (PSM) was also used for risk adjustment. Among 988 patients, a median follow-up of 7.75 years was recorded. A higher UACR corresponded to a higher risk of cardiovascular death (P < 0.001 for trend). No statistically significant difference was found in the trend of eGFR risk stratification on the risk of cardiovascular death (P = 0.09 for trend). After PSM, the results showed that when grouped by UACR, the high-risk group had a higher risk of cardiovascular death regardless of a cutoff value of 30 or 300 mg/g (all P < 0.05). When grouped by eGFR, regardless of a cutoff value of 45 or 30 mL/min/1.73 m2, compared to the low-risk group, the high-risk group did not have a statistically significant increase in cardiovascular death (P = 0.086 and P = 0.093, respectively). The subgroup analysis of the main outcome showed an interaction between the UACR and eGFR (P = 0.044). Both the UACR and eGFR are markers for predicting the progression of HF, but the UACR may be a more important indicator than the eGFR, and they synergistically and complementarily reflect the long-term cardiovascular risk of HF patients. • This study was the first to use PSM to investigate the impact of UACR and eGFR on the long-term prognosis in HF. • These findings indicated UACR may be a more important indicator than eGFR. • UACR should receive the same attention as eGFR and be included in the baseline data observation of HF trials. [ABSTRACT FROM AUTHOR]

With the increasing frequency of documents appearing in scenarios including online comments, car reviews and movie evaluations, the text length in sentiment analysis tasks has become longer. Since documents consist of multiple sentences, aspect terms and opinion terms in aspect sentiment triplets may not be in the same sentence, which requires multi-hop reasoning across sentences for extraction, which exceeds the scope of intra-sentence aspect sentiment triplet extraction. Apparently, the existing models at the sentence level are not suitable for extracting sentiment triples directly from documents. Therefore, a well-performing document sentiment analysis model is needed to address the degraded performance of triplet extraction caused by cross-sentence sentiment elements in long texts. To promote the development of aspect sentiment triplet extraction from documents, a dataset based on movie review texts is proposed and the existing methods are evaluated based on this dataset. Through error analysis, this study explores the difficulties and possible future research directions of document-level aspect sentiment triplet extraction. [ABSTRACT FROM AUTHOR]

Root caries is the main cause of oral pain and tooth loss in the elderly. Protecting root lesions from environmental disturbances, resisting pathogens, and facilitating remineralization over time are essential for addressing root caries, but are challenging due to the irregular root surface and the complex oral environment. Hagfish secretes slime when facing danger, which converts into gels upon contact with seawater, suffocating the predators. Inspired by hagfish's defense mechanism, a fluid-hydrogel conversion strategy is proposed to establish a mechanical self-regulating multifunctional platform for root caries treatment. The fluid system (silk fibroin-tannic acid-black phosphorene-urea, ST-BP-U), in which urea disrupts the hydrogen bonds between silk fibroin and tannic acid, can easily spread on the irregular root surface and permeate into dentinal tubules. Upon contact with the surrounding water, urea diffuses, prompting the hydrogel re-formation and creating intimate attachments with micromechanical inlay locks. Meanwhile, BP increases the crosslinking of the re-formed hydrogel network, resulting in reinforced cohesion for robust wet adhesion to the tooth root. This process establishes a structured platform for effective antimicrobial phototherapy and dentin remineralization promotion. This water-responsive fluid-hydrogel conversion system adapts to the irregular root surface in the dynamic wet environment, holding promise for addressing root caries. Root caries bring a heavy burden to the aging society, but the irregular root surface and dynamic moist oral environment always hinder non-surgical therapeutic effects. Here, we propose a water-responsive fluid-hydrogel conversion strategy aimed at mechanical self-regulation on the irregular and wet root interface to construct a functional structural platform. The liquid system (ST-BP-U) that prebreak intermolecular hydrogen bonds can easily spread on irregular surfaces and dentin tubules. When encountering water, hydrogen bonds re-form, and BP increases the crosslinking of the hydrogel formed in situ. Based on this firm wet-adhesion platform, it provides powerful phototherapy effects and promotes dentin remineralization. This fluid-hydrogel conversion system turns the disadvantages of wet environment into advantages, offering a promising strategy for root caries. [Display omitted] [ABSTRACT FROM AUTHOR]

The gut is a vital organ that is central to the absorption and metabolic processing of orally administered drugs. While there have been many models developed with the goal of studying the absorption of drugs in the gut, these models fail to adequately recapitulate the diverse, complex gastrointestinal microenvironment. The recent emergence of microfluidic organ-on-a-chip technologies has provided a novel means of modeling the gut, yielding radical new insights into the structure of the gut and the mechanisms through which it shapes disease, with key implications for biomedical developmental efforts. Such organ-on-a-chip technologies have been demonstrated to exhibit greater cost-effectiveness, fewer ethical concerns, and a better ability to address inter-species differences in traditional animal models in the context of drug development. The present review offers an overview of recent developments in the reconstruction of gut structure and function in vitro using microfluidic gut-on-a-chip (GOC) systems, together with a discussion of the potential applications of these platforms in the context of drug development and the challenges and future prospects associated with this technology. This paper outlines the characteristics of the different cell types most frequently used to construct microfluidic gut-on-a-chip models and the microfluidic devices employed for the study of drug absorption. And the applications of gut-related multichip coupling and disease modelling in the context of drug development is systematically reviewed. With the detailed summarization of microfluidic chip-based gut models and discussion of the prospective directions for practical application, this review will provide insights to the innovative design and application of microfluidic gut-on-a-chip for drug development. [Display omitted] [ABSTRACT FROM AUTHOR]

With the acceleration of globalization, machine translation (MT) plays an increasingly prominent role in cross-language communication. However, how to evaluate the quality of machine translation, especially considering the nuances in different semantic contexts, remains a challenge. This paper proposes an automatic scoring model for machine translation quality based on deep transfer learning, which aims to accurately perceive and evaluate the quality of translated texts in different semantic contexts. Firstly, a pre-trained deep neural network model is used to extract the semantic feature representation of the sentences in the source language and the target language, so as to capture the semantic information of the sentences. Then, deep transfer learning is used to map the semantic features of source language and target language into the shared feature space. By sharing feature space, an effective relationship is established between the semantic representations of two languages, so as to achieve cross-language quality evaluation. The experimental results show that the model has made significant progress in evaluating the quality of machine translation. Compared with traditional methods, this model can evaluate translation quality more accurately and has better generalization ability. The automatic scoring model of machine translation quality based on deep transfer learning not only improves the accuracy and efficiency of machine translation quality assessment, but also provides new ideas and methods for future research. [ABSTRACT FROM AUTHOR]

Hexavalent chromium (Cr(VI)) pollution poses significant health and ecological risks warranting cost-effective remediation. This study investigated the efficacy of zinc oxide nanoparticles (nZnO) and Miscanthus lutarioriparius synergism for Cr(VI) immobilization and stabilization. nZnO characterized by XRD, SEM-EDS and DLS was amended to 3 mg kg−1 Cr(VI) spiked soil pots at 0.5 % and 1 %. M. lutarioriparius seedlings were then transplanted and grown for 3 months. Results showed increase in residual soil Cr(III) from negligible to 68.9 % upon 1 % nZnO indicating reduction of Cr(VI). Maximum decline of 76.3 % in total Cr(VI) confirmed immobilization. Batch adsorption experiments revealed rising Cr(VI) removal from 61.3 % to 83.7 % by increase in nZnO dose from 0.2 to 1 g L−1. M. lutarioriparius demonstrated hyperaccumulator ability uptaking 208.3 and 156.8 mg kg−1 Cr in roots and shoots respectively. Restricted root-shoot translocation factor of 0.79 aided suitability for phytostabilization. The plant-nZnO synergy enhanced remediation efficiency as confirmed by tolerance index restoration from 38.6 % to 100 %. Increased growth performance reflected mitigation of toxicity by restricted bioavailability. Overall, the nanoremediation strategy displayed high potential for effective in situ stabilization of Cr(VI) contamination combining favorable properties of nZnO and plant tolerance mechanisms. [ABSTRACT FROM AUTHOR]

The propagation and coalescence of discontinuous cross-type joints are often the primary drivers of rock slope failures. Due to the inherent randomness of these joints, identifying suitable methods to accurately characterize progressive failure and quantitatively assess the stability of slopes with cross-type joints is particularly challenging. To address this, a Discrete Fracture Network-Spring Based-Smoothed Particle Hydrodynamics (DFN-SB-SPH) method is proposed, which considers cross-type DFN generation, rock matrix heterogeneity, cracking, block contact, and deposition within a unified SPH framework. In this approach, damage and contact of blocks are achieved by introducing a fracture sign to enhance the kernel function and applying Newton's law to the damaged particles to realize the point to point contact. A uniaxial compression test on rock samples with double fissures is carried out to verify the accuracy of the proposed method. The influence of joint density, geometric parameters (i.e., trace length, dominate dip angle) of cross joints, and rock mass heterogeneity on the failure characteristics of RSCD are investigated. The results revealed that the DFN-SB-SPH model possesses robust capabilities for crack tracking, mass movement, and contact slipping along fracture surfaces. Moreover, DFN generation, heterogeneous characterization, shear and tensile fractures within a single SPH framework without mesh distortion are realized. Five typical failure modes calculated by DFN-SB-SPH are primarily determined by the combination of joint dip angles and trace lengths. Furthermore, the dip angle, trace length, joint density, and rock mass heterogeneity significantly alter the stability of RSCD with sensitivity coefficients for factor safety of 27.7 %, 44.6 %, 72.9 % and 35.0 %, respectively. Higher dominant dip angles (above 60°) lead to significantly longer run-out distances for RSCD compared to lower angles (below 30°) once instability occurs. The sudden rise in major principal stress at the slope's top and toe, along with the shift of tensile stress concentration towards the middle, predicts the stages of crack propagation and sliding in slope failure. [ABSTRACT FROM AUTHOR]

The duodenal papillae are the primary and essential pathway for ERCP, greatly determining its complexity and outcome. We investigated the association between papilla morphology and post-ERCP pancreatitis (PEP) and constructed a robust model for PEP prediction. We retrospectively enrolled patients who underwent ERCP in 2 centers from January 2019 to June 2022. Radiomic features of the papilla were extracted from endoscopic images with deep learning. Potential predictors and their importance were evaluated with 3 machine learning algorithms. A predictive model was developed using best subset selection by logistic regression, and its performance was evaluated in terms of discrimination, calibration, and clinical utility based on the area under curve (AUC) of the receiver-operating characteristic curve, calibration curve, and clinical decision curve, respectively. From 2 centers, 2038 and 334 ERCP patients were enrolled in this study with PEP rates of 7.9% and 9.6%, respectively. The radiomic score was significantly associated with PEP and showed great diagnostic value (AUC,.755-.821). Six hub predictors were selected to conduct a predictive model. The radiomics-based model demonstrated excellent discrimination (AUC,.825-.857) and therapeutic benefits in the training, testing, and validation cohorts. The addition of the radiomic score significantly improved the diagnostic accuracy of the predictive model (net reclassification improvement,.151-.583 [ P <.05]; integrated discrimination improvement,.097-.235 [ P <.001]). The radiomic signature of the papilla is a crucial independent predictor of PEP. The papilla radiomics-based model performs well for the clinical prediction of PEP. [Display omitted] [ABSTRACT FROM AUTHOR]

To investigate the association between cardiovascular risk estimated using the Framingham Risk Score (FRS) and carotid stiffening determined using ultrafast pulse wave velocity (ufPWV) measurements in apparently healthy individuals. We enrolled 1034 apparently healthy participants without known cardiovascular disease who underwent ufPWV measurements. Clinical and laboratory findings, carotid intima–media thickness (cIMT), pulse wave velocity at the beginning of systole (PWV-BS), and pulse wave velocity at the end of systole (PWV-ES) were assessed. In FRS assessments based on major cardiovascular risk factors (CVRFs), participants were assigned into three risk categories: low risk (<10%, n = 679), intermediate risk (10–20%, n = 191), and high risk (>20%, n = 164); the low-risk category was further subdivided into three subcategories: < 1% (n = 58), 1%− 5% (n = 374) and > 5% (n = 247). Multivariate logistic regression analyses with crude and adjusted odds ratios (ORs) were used to evaluate the association of carotid stiffening and FRS-based risk stratification. Carotid stiffening indicated by PWV-BS and PWV-ES differed notably between the FRS-estimated low-risk vs. intermediate-risk and high-risk categories, but only PWV-ES differed notably among the low-risk subcategories (all p < 0.010), and correlated notably with the FRS-estimated risk most obviously in low-risk participants (r = 0.517). In participants with cIMT < 0.050 cm, only PWV-ES differed significantly among the FRS-estimated risk categories (all p < 0.001). Increased PWV-BS (adjusted OR: 1.49; p = 0.003) and PWV-ES (adjusted OR: 1.29; p = 0.007) were both associated with FRS categories independent of conventional CVRFs in low- vs. intermediate-risk categories, but not in low- vs. high-risk categories (all p > 0.050). In vivo imaging of carotid stiffening by ufPWV measurements is independently linked to FRS categories, and ufPWV indices may help stratify differing levels of cardiovascular risk in apparently healthy young people. Data generated or analyzed during the study are available from the corresponding author by reasonable request. • Carotid stiffening quantified by ufPWV measurements differed notably among FRS-estimated risk categories and low-risk subcategories. • ufPWV indices correlated notably with FRS-estimated risk and major CVRFs. • PWV-ES increased steeply with higher FRS categories, even with normal cIMT. • ufPWV indices were associated with cardiovascular risk stratification independently in low- vs. intermediate-risk populations. • ufPWV may be a promising quantitative predictor for cardiovascular risk stratification in apparently healthy young people. [ABSTRACT FROM AUTHOR]

Relatively little is known about the plaque characteristics of border-zone infarcts and how they differ between cortical border-zone (CBZ) and internal border-zone (IBZ) infarcts. We conducted a retrospective observational cohort study of patients with intracranial atherosclerotic disease who underwent high-resolution magnetic resonance imaging (HR-MRI) examination. Individuals with border-zone infarcts in the middle cerebral artery (MCA) territory, detected by diffusion-weighted imaging, were enrolled. Plaque morphological and compositional parameters of both IBZ and CBZ groups were compared. Independent predictors were identified using a binary logistic regression model, and the sensitivity and specificity of the model were assessed using a receiver operating characteristic curve. Kaplan–Meier survival analysis further explored differences in stroke recurrence between BZ patients with mono or dual antiplatelet therapy. We reviewed 101 symptomatic patients with border-zone infarcts (BZ) within the MCA territory in the study. Out of the patients meeting the imaging eligibility criteria, we detected 34 cases with isolated IBZ, 23 cases with isolated CBZ, and six cases with both IBZ and CBZ infarcts. Those with IBZ infarcts had a higher plaque burden than those without (p < 0.001), and those with CBZ infarcts exhibited a complicated plaque less frequently than those without (37.9% vs 67.6%, p = 0.018). In those with isolated IBZ or CBZ infarcts, plaque burden was independently associated with isolated IBZ infarcts (odd ratio = 1.08; 95% CI, 1.02–1.15; p = 0.023). During the median follow-up period of 37 (27, 50) months, 13.8% of patients receiving early dual antiplatelet treatment and 30.4% of those on single antiplatelet therapy experienced stroke recurrence (p = 0.182). Intracranial atherosclerotic plaque morphology and composition differ between patients with IBZ and those with CBZ infarcts. Higher plaque burden is more associated with IBZ infarcts. [Display omitted] [ABSTRACT FROM AUTHOR]

Investigate the feasibility of using deep learning-based accelerated 3D T1-weighted volumetric isotropic turbo spin-echo acquisition (VISTA) for vessel wall magnetic resonance imaging (VW-MRI), compared to traditional Compressed SENSE and optimize acceleration factor (AF) to obtain high-quality clinical images. 40 patients with atherosclerotic plaques in the intracranial or carotid artery were prospectively enrolled in our study from October 1, 2022 to October 31, 2023 underwent high-resolution vessel wall imaging on a 3.0 T MR system using variable Compressed SENSE (CS) AFs and reconstructed by an optimized artificial intelligence constrained Compressed SENSE (CS-AI). Images were reconstructed through both traditional CS and optimized CS-AI. Two radiologists qualitatively assessed the image quality scores of CS and CS-AI across different segments and quantitatively evaluated SNR (signal-to-noise ratio) and CNR (contrast-to-noise ratio) metrics. Paired t-tests, ANOVA, and Friedman tests analyzed image quality metrics. Written informed consent was obtained from all patients in this study. CS-AI groups demonstrated good image quality scores compared to reference scans until AF up to 12 (P < 0.05). The CS-AI 10 protocol provided the best images in the lumen of both normal and lesion sites (P < 0.05). The plaque SNR was significantly higher in CS-AI groups compared to CS groups until the AF increased to 12 (P < 0.05). CS-AI protocols had higher CNR compared to CS with whichever AF on both pre-and post-contrast T1WI (P < 0.05), The CNR was highest in the CS-AI 10 protocol on pre-contrast T1WI and in CS-AI 12 on post-contrast T1WI (P < 0.05). The study demonstrated the feasibility of using CS-AI technology to diagnose arteriosclerotic vascular disease with 3D T1 VISTA sequences. The image quality and diagnostic efficiency of CS-AI images were comparable or better than traditional CS images. Higher AFs are feasible and have potential for use in VW-MRI. The determination of standardized AFs for clinical scanning protocol is expected to help for empirical evaluation of new imaging technology. [ABSTRACT FROM AUTHOR]

To evaluate radiomics in soft tissue sarcomas (STSs) for diagnostic accuracy, grading, and treatment response assessment, with a focus on clinical relevance. In this diagnostic accuracy study, radiomics was applied using multiple MRI sequences and AI classifiers, with histopathological diagnosis as the reference standard. Statistical analysis involved meta-analysis, random-effects model, and Deeks' funnel plot asymmetry test. Among 579 unique titles and abstracts, 24 articles were included in the systematic review, with 21 used for meta-analysis. Radiomics demonstrated a pooled sensitivity of 84% (95% CI: 80–87) and specificity of 63% (95% CI: 56–70), AUC of 0.93 for diagnosis, sensitivity of 84% (95% CI: 82–87) and specificity of 73% (95% CI: 68–77), AUC of 0.91 for grading, and sensitivity of 83% (95% CI: 67–94) and specificity of 67% (95% CI: 59–74), AUC of 0.87 for treatment response assessment. Radiomics exhibits potential for accurate diagnosis, grading, and treatment response assessment in STSs, emphasizing the need for standardization and prospective trials. Radiomics offers precise tools for STS diagnosis, grading, and treatment response assessment, with implications for optimizing patient care and treatment strategies in this complex malignancy. ● Radiomic studies of soft tissue sarcomas are limited, often due to unvalidated results and a retrospective study design. ● Meta-analyses of studies predicting radiomic models for soft tissue sarcomas have shown success in differentiating benign and malignant tumors, but methodological quality is a major concern. ● The collection and integration of multimodal data and the standardization of research processes can facilitate the development and validation of radiomic models. [ABSTRACT FROM AUTHOR]

Effective risk communication is essential for achieving patient-centered oral health care, but the limited understanding of patients' subjective perceptions of orthodontic-related risks hinders this process. This study aimed to investigate adults' awareness, concerns, and risk-avoidance behaviors about long-term orthodontic risks, exploring their relationship with psychosocial factors. We included 498 adult patients (mean age, 27.3 ± 6.8 years; women, 75.5%) during their initial visits to the orthodontic department at a hospital in Chengdu, China. Participants' understanding of orthodontic risks was gauged before and after exposure to the Oral Health Education Comics (OHEC), a specifically designed digital tool. Concurrently, we used logistic regression models to investigate the associations between patients' depression, anxiety, self-esteem, perfectionism, and dentofacial esthetics with risk perceptions. Approximately 79.5% of participants initially reported low awareness of orthodontic risks, with most knowledge from online sources. Notably, the percentage of participants with high awareness increased to 64.8% after OHEC. The negative facial soft-tissue change was most concerning for participants: 53.4% showed high concerns, and 28.1% showed high avoidance. Furthermore, linear regression indicated positive associations between depression (β = 0.42 [95% confidence interval {CI}, 0.07-0.77]) and anxiety (β = 0.76 [95% CI, 0.35-1.18]) with orthodontic risk concerns, whereas risk avoidance was positively associated with depression (β = 0.62 [95% CI, 0.27-0.97]), anxiety (β = 1.09 [95% CI, 0.68-1.50]), and perfectionism (β = 0.24 [95% CI, 0.02-0.46]). Findings emphasize the imperative of streamlined risk communication in orthodontics. By incorporating comprehensible tools such as OHEC and integrating psychosocial evaluations, more refined patient-practitioner communication and psychosomatic-based dental care can be achieved. • Adult patients have varying risk perceptions, but little is known about relevant factors. • Oral Health Education Comics raised low orthodontic risk understanding in adult patients. • Esthetic-related facial soft-tissue change elicited the highest concern and avoidance. • Depression and anxiety are linked to concerns and avoidance, while perfectionism is linked to avoidance. • Psychosocial screening aids in patient-centered risk communication and health care. [ABSTRACT FROM AUTHOR]

• A novel case of ALG11-CDG, a very rare disease, is reported. • Novel compound heterozygous variants: c.1307G> T (p.G436V) and c.1403G> A (p.R468H) are identified in ALG11 gene. • These two variants decreased stability of the mutant protein and concurrent hypoglycosylation of GP130, a hyperglycosylated protein. Congenital disorders of glycosylation (CDG) represent a heterogeneous group of rare inherited metabolic disorders due to abnormalities in protein or lipid glycosylation pathways, affecting multiple systems, and frequently being accompanied by neurological symptoms. ALG11-CDG, also known as CDG-1p, arises from a deficiency in a specific mannosyltransferase encoded by the ALG11 gene. To date, only 17 cases have been documented, and these patients have prominent clinical phenotypes, including seizures, developmental delay, and microcephaly. We describe a novel case of a four-month-old boy from a Chinese family exhibiting developmental delay, seizures, and microcephaly. Trio whole-exome sequencing (WES) and subsequent Sanger sequencing were employed to identify the potential genetic cause, and functional study was performed to evaluate the pathogenicity of genetic variant identified. Trio WES unveiled novel compound heterozygous variants: c.1307G> T (p.G436V) and c.1403G> A (p.R468H) within exon 4 of the ALG11 gene, inherited from the father and mother, respectively. Subsequent in vitro functional analysis revealed decreased stability of the mutant protein and concurrent hypoglycosylation of GP130, a hyperglycosylated protein. Our findings not only expand the clinical and variant spectrum of ALG11-CDG, but also emphasize the importance of WES as a first-tier genetic test in determining the molecular diagnosis. [ABSTRACT FROM AUTHOR]

• Novel mutations (c.3543T > A, c.1850A > G, c.2536C > T) have never been reported. • c.4233_4236del may be a hotspot mutation. • CHD2 patients had varying degrees of developmental delay and intellectual disability. • A significant clustering of the mutations was found near the C-terminus of the CHD2 protein. Increasing evidence reveals critical roles for CHD2 in children with developmental and epileptic encephalopathy. The aim was to present clinical analysis results of five cases with CHD2 mutations and 157 reported cases with non-copy number variations (non-CNV) of CHD2. This study recruited pediatric epilepsy patients with CHD2 mutations and clinical data from November 2016 to October 2023 in the Linyi People's Hospital, China. Whole-exome and gene panel sequencing were employed to find mutations. The HGMD and PubMed databases were examined for documented cases that had CHD2 mutations. This study reports five cases with CHD2 mutations: c.3543T > A, c.1850A > G, c.2536C > T, c.4233_4236del, c.3782G > C. Three novel mutations (c.3543T > A, c.1850A > G, c.2536C > T) have never been reported. c.4233_4236del has been reported in three cases, indicating that this locus may be a mutation hotspot. c.3782G > C has been reported in one case. All five patients had seizures before the age of four. Three patients had varying degrees of developmental delay, and four patients had varying degrees of intellectual disability. All of them had controlled seizures after Valproic acid (VPA) monotherapy or VPA in combination with other medications. Furthermore, we reviewed 157 reported cases having non-CNV mutations of CHD2. Most mutations of these cases were de novo. Epilepsy, developmental delay, and intellectual disability were the typical clinical phenotypes. We also found a significant clustering of the mutations near the C-terminus of the CHD2 protein (P < 0.001). This study reports new CHD2 genotypes and analyzes reported CHD2 mutation cases. Given its significance in epileptic encephalopathies, research on the CHD2 gene may provide new insights into epileptogenesis. [ABSTRACT FROM AUTHOR]

Ferroptosis is greatly restricted by low reactive oxygen species (ROS) generation efficiency, and the inherent self-protection mechanism originating in heat shock proteins (HSPs) seriously impedes the efficiency of photothermal therapy (PTT). Herein, we designed an intelligent strategy utilizing cascade catalytic nanoassemblies (Au@COF@MnO 2) with triple-enzyme activity for amplifying ferroptosis therapy and improving the efficiency of PTT in tumor. Gold nanozyme was encapsulated within a hollow manganese dioxide (MnO 2) shell with the help of covalent organic frameworks (COFs). The nanoassemblies possess the ability of photothermal conversion. Mechanism studies suggested that glutathione (GSH) depletion by Au@COF@MnO 2 leads to the inactivation of glutathione peroxidase 4 (GPX4). This effect synergized with Mn2+-mediated reactive oxygen species (ROS) generation to enhance the accumulation of lipid peroxide (LPO), thereby inducing high-efficiency ferroptosis. Notably, gold nanozyme facilitated the conversion of glucose into gluconic acid and hydrogen peroxide (H 2 O 2). This process augmented the endogenous H 2 O 2 levels necessary for Fenton chemistry, which could effectively promote the generation of ROS. Simultaneously, glucose depletion downregulated the expression of HSPs induced by hyperthermia, consequently reducing cellular heat resistance for enhancing PTT. Therefore, the cascade catalytic nanoassembly not only exhibits high tumor inhibition and admirable biosafety, but also possesses trimodal imaging performance for imaging-guided tumor therapy in vivo , holding great potential for clinical application. This study engineered multi-responsive cascade catalytic nanoassembly (Au@COF@MnO 2) with triple enzymatic functions for amplifying ferroptosis therapy and improving the efficiency of PTT in tumor. The nanoassembly exhibited multi-responsive release and great photothermal conversion performance. Glucose consumption-evoked starvation downregulated the hyperthermia-induced expression of HSPs in tumor cells, thereby improving the efficacy of PTT. Mechanism studies suggested that GSH depletion by Au@COF@MnO 2 lead to the inactivation of GPX4, which synergized with Mn2+-mediated ROS generation to bolster the accumulation of LPO, thereby inducing high-efficiency ferroptosis. Moreover, the nanoassembly demonstrated trimodal (PT, PA, and MR) imaging in vivo , enabling the visualization of the tumor treatment with nanoassembly. Such nanoassembly exhibited high tumor inhibition and admirable biosafety in tumor therapy in vivo , holding a great potential for clinical application. [Display omitted] [ABSTRACT FROM AUTHOR]

Although immunogenic cell death (ICD) induced by lysosomal membrane permeabilization (LMP) evidently enhance the effectiveness of antitumor immunity for triple-negative breast cancer (TNBC) with poor immunogenicity, their potential is increasingly restricted by the development of other death pathways and the repair of lysosomes by endoplasmic reticulum (ER) during LMP induction. Herein, a polydopamine nanocomposite with i-motif DNA modified and BNN6 loaded is prepared toward boosting LMP and immunotherapy of TNBC by synergy of spatially confined photoacoustic (PA) effects and nitric oxide. Combining the high-frequency pulsed laser (4000 kHz) with the intra-lysosomal assembly of nanocomposites produced spatially confined and significantly boosted PA effects (4.8-fold higher than the individually dispersed particles extracellular), suppressing damage to other cellular components and selectively reducing lysosomal integrity to 19.2 %. Simultaneously, the releasing of nitric oxide inhibited the repair of lysosomes by ER stress, causing exacerbated LMP. Consequently, efficient immune activation was achieved, including the abundant releasing of CRT/HMGB1 (5.93–6.8-fold), the increasing maturation of dendritic cells (3.41-fold), and the fostered recruitment of CD4+/CD8+ T cells (3.99–3.78-fold) in vivo. The study paves a new avenue for the rational design and synergy of confined energy conversion and responsive nanostructures to achieve the treatment of low immunogenicity tumors. A strategy of boosting lysosomal membrane permeabilization (LMP) and concomitantly preventing the repair was developed to address the immunotherapy challenge of triple-negative breast cancer. Spatially confined and significantly enhanced photoacoustic (PA) effects were achieved through DNA-guided pH-responsive assembly of polydopamine nanocomposites in lysosomes and application of a high-frequency pulsed laser. Efficient immunogenic cell death was guaranteed by selective and powerful damage of lysosomal membranes through the significant contrast of PA intensities for dispersed/assembled particles and nitric oxide release induced endoplasmic reticulum stress. The study paves a new avenue for the rational design and synergy of confined energy conversion and responsive nanostructures to achieve the treatment of low immunogenicity tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

Balancing biocompatibility and drug-loading efficiency in nanoparticles presents a significant challenge. In this study, we describe the facile fabrication of poly (acrylic acid)-mesoporous zinc phosphate/polydopamine (PAA-mZnP/PDA) Janus nanoparticles (JNPs). The PDA half-shell itself can serve as a photothermal agent for photothermal therapy (PTT), as well as to offers sites for polyethylene glycol (PEG) to enhance biocompatibility. Concurrently, the mesoporous ZnP core allows high loading of doxorubicin (DOX) for chemotherapy and the Cy5.5 dye for fluorescence imaging. The resultant PAA-mZnP/PDA-PEG JNPs exhibit exceptional biocompatibility, efficient drug loading (0.5 mg DOX/1 mg JNPs), and dual pH/NIR-responsive drug release properties. We demonstrate the JNPs' satisfactory anti-cancer efficacy, highlighting the synergistic effects of chemotherapy and PTT. Furthermore, the potential for synergistic fluorescence imaging-guided chemo-phototherapy in cancer treatment is illustrated. Thus, this work exemplifies the development of biosafe, multifunctional JNPs for advanced applications in cancer theranostics. Facile fabrication of monodispersed nanomedicine with multi-cancer killing modalities organically integrated is nontrivial and becomes more challenging under the biocompatibility requirement that is necessary for the practical applications of nanomedicines. In this study, we creatively designed PAA-mZnP/PDA JNPs and fabricated them under mild conditions. Our method reliably yields uniform JNPs with excellent monodispersity. To maximize functionalities, we achieve fourfold advantages including efficient drug/fluorescent dye loading, PTT, pH/NIR dual-responsive properties, and optimal biocompatibility. The as-fabricated JNPs exhibit satisfactory anti-cancer performance both in vitro and in vivo , and demonstrate the potential of JNPs in fluorescence imaging-guided synergistic cancer chemo-phototherapy. Overall, our research establishes a pathway in versatile inorganic/polymer JNPs for enhanced cancer diagnosis and therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Biomaterials with osteoinductivity are widely used for bone defect repair due to their unique structures and functions. Machine learning (ML) is pivotal in analyzing osteoinductivity and accelerating new material design. However, challenges include creating a comprehensive database of osteoinductive materials and dealing with low-quality, disparate data. As a standard for evaluating the osteoinductivity of biomaterials, ectopic ossification has been used. This paper compiles research findings from the past thirty years, resulting in a robust database validated by experts. To tackle issues of limited data samples, missing data, and high-dimensional sparsity, a data enhancement strategy is developed. This approach achieved an area under the curve (AUC) of 0.921, a precision of 0.839, and a recall of 0.833. Model interpretation identified key factors such as porosity, bone morphogenetic protein-2 (BMP-2), and hydroxyapatite (HA) proportion as crucial determinants of outcomes. Optimizing pore structure and material composition through partial dependence plot (PDP) analysis led to a new bone area ratio of 14.7 ± 7 % in animal experiments, surpassing the database average of 10.97 %. This highlights the significant potential of ML in the development and design of osteoinductive materials. This study leverages machine learning to analyze osteoinductive biomaterials, addressing challenges in database creation and data quality. Our data enhancement strategy significantly improved model performance. By optimizing pore structure and material composition, we increased new bone formation rates, showcasing the vast potential of machine learning in biomaterial design. [Display omitted] [ABSTRACT FROM AUTHOR]

Time-restricted eating (TRE) and low-carbohydrate diet (LCD) can improve multiple cardiometabolic parameters in patients with metabolic syndrome (MetS), but their effects on psychosocial health and satiety are unclear. In this study, we aimed to evaluate the effects of TRE, LCD, and their combination (TRE + LCD) on quality of life (QoL), sleep, mood, appetite, and metabolic hormones in patients with MetS. This is a secondary analysis of a single-center, 3-month, open-label, randomized clinical trial investigating the effects of TRE, LCD, and TRE + LCD on weight and cardiometabolic parameters in individuals with MetS. This secondary analysis examined QoL, sleep, mood, and appetite using the Rand 36-Item Short Form (SF-36); Pittsburgh Sleep Quality Index (PSQI); Depression, Anxiety, and Stress Scale; and Eating Behavior Rating Scale, respectively, as well as measured levels of metabolic hormones including leptin, amylin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and peptide YY. Between-group comparisons were conducted via one-way ANOVAs and post hoc LSD tests for normally distributed variables or Kruskal‒Wallis H tests and the Nemenyi test for abnormally distributed variables. P < 0.017 was considered significant in multiple comparisons following Bonferroni adjustment. A total of 162 participants (mean [SD] age, 41.2 [9.9] years; mean [SD] body mass index, 29.3 [3.4] kg/m2; 102 [63%] men) who started the intervention were analyzed. After 3 months, only the TRE group decreased GLP-1 levels (−0.9 [IQR, −1.9 to −0.3] pg/mL; P = 0.002), increased PP levels (8.9 [IQR, −7.6 to 71.8] pg/mL; P = 0.011), physical functioning in the SF-36 (5.2 [95% CI, 1.9 to 8.5]; P = 0.001), social functioning in the SF-36 (9.1 [95% CI, 2.5 to 15.6]; P = 0.005), role-physical in the SF-36 (24.1 [95% CI, 11.8 to 36.4]; P < 0.001), role-emotional in the SF-36 (22.4 [95% CI, 12.6 to 32.2]; P < 0.001), and sleep efficiency in the PSQI (0.29 [95% CI, 0.03 to 0.55]; P = 0.021). Compared with changes in LCD, TRE further increased general health in the SF-36 (9.7 [95% CI, 3.3 to 16.0]; P = 0.006). Relative to the changes of TRE + LCD, TRE significantly increased role-emotional in the SF-36 (19.9 [95% CI 4.9 to 34.8]; P = 0.006). Changes in sleep quality, mood status, appetite, and metabolic hormones did not differ among three groups. Greater weight loss was associated with decreased leptin levels (r = 0.538), decreased amylin levels (r = 0.294), reduced total appetite scores (r = 0.220), and improved general health (r = −0.253) (all P ≤ 0.01). TRE, LCD, and TRE + LCD all could improve psychosocial health and reduce appetite. Notably, TRE yielded greater benefits in QoL compared with LCD or TRE + LCD in individuals with MetS. ClinicalTrials.gov Identifier: NCT04475822. [ABSTRACT FROM AUTHOR]

[Display omitted] • We elaborate on the role of gut microbiota and microbial metabolites in the efficacy and adverse effects of chemotherapeutics. • We further summarize the clinical potential of various ways to harness gut microbiota for cancer chemotherapy. • The potential of gut microbiota severing as predictive markers for chemotherapy efficacy is discussed. • Finally, we discuss current limitations and suggest potential approaches to facilitate utilization of gut microbiota in chemotherapy. The microbiota inhabits the epithelial surfaces of hosts, which influences physiological functions from helping digest food and acquiring nutrition to regulate metabolism and shaping host immunity. With the deep insight into the microbiota, an increasing amount of research reveals that it is also involved in the initiation and progression of cancer. Intriguingly, gut microbiota can mediate the biotransformation of drugs, thereby altering their bioavailability, bioactivity, or toxicity. The review aims to elaborate on the role of gut microbiota and microbial metabolites in the efficacy and adverse effects of chemotherapeutics. Furthermore, we discuss the clinical potential of various ways to harness gut microbiota for cancer chemotherapy. Recent evidence shows that gut microbiota modulates the efficacy and toxicity of chemotherapy agents, leading to diverse host responses to chemotherapy. Thereinto, targeting the microbiota to improve efficacy and diminish the toxicity of chemotherapeutic drugs may be a promising strategy in tumor treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] Inhalable biologics represent a promising approach to improve the efficacy and safety of asthma treatment. Although several mAbs targeting IL-4 receptor α chain (IL-4Rα) have been approved or are undergoing clinical trials, the development of inhalable mAbs targeting IL-4Rα presents significant challenges. Capitalizing on the distinctive advantages of nanobodies (Nbs) in maintaining efficacy during storage and administration, we sought to develop a novel inhalable IL-4Rα Nb for effectively treating asthma. Three IL-4Rα immunized Nb libraries were used to generate specific and functional IL-4Rα Nbs. LQ036, a bivalent Nb comprising 2 HuNb103 units, was constructed with a high affinity and specificity for human IL-4Rα. The efficacy, pharmacokinetics, and safety of inhaled LQ036 were evaluated in B-hIL4/hIL4RA humanized mice. LQ036 inhibited secreted embryonic alkaline phosphatase reporter activity, inhibited TF-1 cell proliferation, and suppressed phosphorylated signal transducer and activator of transduction 6 in T cells from patients with asthma. Crystal structure analysis revealed a binding region similar to dupilumab but with higher affinity, leading to better efficacy in blocking the signaling pathway. HuNb103 competed with IL-4 and IL-13 for IL-4Rα binding. Additionally, LQ036 significantly inhibited ovalbumin-specific IgE levels in serum, CCL17 levels in bronchoalveolar lavage fluid, bronchial mucous cell hyperplasia, and airway goblet cell hyperplasia in B-hIL4/hIL4RA humanized mice. Inhaled LQ036 exhibited favorable pharmacokinetics, safety, and tissue distribution, with higher concentrations observed in the lungs and bronchi. These findings from preclinical studies establish the safety and efficacy of inhaled LQ036, underscoring its potential as a pioneering inhalable biologic therapy for asthma. [ABSTRACT FROM AUTHOR]

Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in the portal vein (PV) on PH. PH models were induced by thioacetamide injection, bile duct ligation, or partial PV ligation. HTR1A expression was detected using real-time polymerase chain reaction, in situ hybridization, and immunofluorescence staining. In situ intraportal infusion was used to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a -knockout (Htr1a –/–) rats and vascular smooth muscle cell (VSMC)–specific Htr1a -knockout (Htr1a ΔVSMC) mice were used to confirm the regulatory role of HTR1A on PP. HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased, but WAY-100635 decreased, the PP in rats without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMC-specific Htr1a knockout in mice prevented the development of PH. Moreover, 5-HT triggered adenosine 3′,5′-cyclic monophosphate pathway–mediated PV smooth muscle cell contraction via HTR1A in the PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in rats with thioacetamide-, bile duct ligation–, and partial PV ligation–induced PH. Our findings reveal that 5-HT promotes PH by inducing the contraction of the PV and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment. HTR1A antagonist, such as alverine, decreases portal hypertension in preclinical animals by targeting the portal vein and is expected to become a candidate for the clinical treatment of portal hypertension. [ABSTRACT FROM AUTHOR]

There is significant practice variation in the use of antithrombotic therapy after endovascular intervention for lower limb peripheral arterial disease, with differences in medication choice and duration. Prescriber decision making is complex, and patient factors have been shown to substantially contribute to prescribing variation. To determine the influence of patient factors on antithrombotic prescribing, a discrete choice experiment was distributed to vascular surgeons and trainees across Australia and Aotearoa New Zealand. After pilot testing, the discrete choice experiment questionnaire was distributed to 300 vascular surgeons and trainee members of the Australian and New Zealand Society for Vascular Surgery. Multinomial logistic regression models were used to analyse patient factors that had the most influence on decisions to prescribe a second antithrombotic agent, and the preferred choice of antithrombotic (clopidogrel 75 mg daily or rivaroxaban 2.5 mg twice daily) in addition to aspirin 100 mg daily. The odds ratio (OR) with 95% confidence interval (CI) reported preference strength. A total of 44 questionnaires were completed between September and October 2023, reaching the 15% targeted response rate. Prescribing a second antithrombotic was more likely after femoropopliteal stenting compared with angioplasty (OR 1.89, 95% CI 1.20 – 2.13), and in chronic limb threatening ischaemia compared with intermittent claudication (OR 1.58, 95% CI 1.20 – 2.13). Most respondents preferred clopidogrel over rivaroxaban (62%), with over a third of respondents exclusively prescribing clopidogrel. Patients with stents (OR 1.77, 95% CI 1.32 – 2.37) or moderate bleeding risk (OR 1.38, 95% CI 0.97 – 1.84) were more likely to receive clopidogrel than rivaroxaban. This study demonstrates that vascular surgeons primarily prioritise antithrombotic prescribing decisions by procedure type. Clopidogrel is more likely to be prescribed than rivaroxaban as a second agent in combination with aspirin, especially after stenting. Knowing these clinician preferences can target implementation strategies towards supporting decision making in subgroups of patients according to individual risk profiles. [ABSTRACT FROM AUTHOR]

To confirm whether the pathological response of lymph node metastasis (LNM) to neoadjuvant chemotherapy (NCT) can predict the prognosis of patients with gastric cancer (GC). A total of 979 patients with locally advanced GC were included. χ2 test was used to analyze the relationship between LNM TRG and clinicopathological factors. Cox proportional hazards model was used to analyze the relationship between LNM TRG, clinicopathological factors, and overall survival (OS). A total of 21,162 lymph nodes were evaluated, with 237 patients (35.4%) in the response group and 433 patients (64.6%) in the non-response group. The non-responsive group was strongly associated with higher ypT, ypN, ypTNM, primary tumor (PT) TRG (all p < 0.001), positive cancer nodules (p = 0.001), and more distant LNM location (p < 0.001). Patients with the same PT TRG but different LNM TRG had different prognosis. There was no difference in OS between the responding and non-responding groups of LNM at location 2, 3, and M. YpN, tumor location, and LNM location were independent prognostic factors. The combination of LNM TRG and PT TRG could better predict patient prognosis. Lymph node dissection should be routinely performed after NCT to provide the reference of radical resection. [ABSTRACT FROM AUTHOR]

Segmental mandibulectomy and reconstruction of resulting defect can be performed via intraoral approach (IOA) or extraoral approach (EOA). Both approaches have advantages, disadvantages, indications, and contraindications to consider during their selection. To compare IOA vs EOA of segmental mandibulectomy and microvascular reconstruction with fibula free flap (FFF). We conducted a retrospective cohort study in which 51 patients who underwent segmental mandibulectomy and microvascular reconstruction with FFF from 2020 to 2024 were included, especially 17 patients by IOA and 34 patients by EOA, representing both groups of this study. Clinical characteristics, surgery parameters, and patients' prognosis were evaluated. Patients' satisfaction and Derriford Appearance Scale (DAS59) were assessed during follow-up. Ameloblastoma was the most frequent diagnosis (52.9% managed by IOA vs 70.6% by EOA); FFF was frequently positioned as double barrel (94.1% managed by IOA vs 88.2% by EOA). Compared with EOA group, IOA group had less intraoperative blood loss (mean difference [MD] = −112.2, 95% confidence interval [CI]: −178.9 to −45.5, p = 0.001), higher satisfaction score (MD = 1.3, 95% CI: 0.9 to 1.7, p ˂ 0.001), and lower DAS59 score (MD = −0.5, 95% CI: −0.7 to −0.2, p ˂ 0.001). Both IOA and EOA were found safe and feasible, presenting similar perioperative features and postoperative outcomes. Patients managed with IOA were more satisfied with aesthetic outcomes than patients managed with EOA. In the absence of simultaneous immediate implant during mandibular FFF reconstruction, after stability of FFF on the defect site, patients should always be referred to an implantologist and/or prosthodontist for teeth restoration to improve functional and aesthetic outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

The objective of the present study was to evaluate the effect of dexmedetomidine administration during video-assisted thoracoscopic surgery for lung cancer on perioperative inflammatory response and chronic post-surgical pain. A cohort of 152 patients with lung cancer scheduled for elective video-assisted thoracoscopic surgery participated in this randomized controlled trial. Patients were randomly divided into 2 groups and administered an equivalent volume of dexmedetomidine (n = 63) or normal saline (n = 63). Dexmedetomidine was administered at a dose of 0.6 μg/kg 10 minutes before anesthesia induction and maintained at 0.5 μg/kg/h until 0.5 hours before surgery completed. Anesthesia and postoperative pain management protocols were standardized for both groups. The analysis included vital signs, numerical rating scales of pain, blood inflammatory and oxidative stress biomarkers, pain type and location, patient-controlled intravenous analgesia usage, consumption of general anesthetics and pain rescue medications, as well as complications. The administration of dexmedetomidine resulted in decreased levels of inflammatory cytokines (interleukin-1 beta, interleukin-6, alongside tumor necrosis factor-alpha) and oxidative stress biomarkers (reactive oxygen species alongside malondialdehyde) but elevated levels of interleukin-10 and superoxide dismutase. In addition, the dexmedetomidine group showed lower postoperative numerical rating scale scores, reduced consumption of anesthetics, faster chest-tube removal, fewer patient-controlled intravenous analgesia presses, and shorter postoperative hospital stays. The administration of dexmedetomidine effectively attenuated surgical inflammation, oxidative stress, and postoperative pain, thereby promoting patient recovery after lung cancer surgery without increasing the risk of adverse effects or complications. [ABSTRACT FROM AUTHOR]

The inflammatory nutritional status is widely associated with the long-term prognosis of non-fatal stroke. The objective of this study is to examine the correlation between the C-reactive protein to albumin ratio (CAR), a new marker indicating both inflammatory and nutritional status, and the overall mortality rate among stroke patients. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) database and corresponding public-use mortality data from the linked National Death Index (NDI). The study utilized maximally selected rank statistics to determine the optimal cutoff points for the CAR. Subsequently, participants were stratified into higher- and lower-CAR groups based on these cutoff points. The Kaplan-Meier survival method was used to study overall survival probability. Multivariable Cox proportional regression models were employed to calculate the Hazard Ratio (HR) and corresponding confidence interval (CI). Restricted cubic spline (RCS) model was applied to detect potential non-linear relationship between CAR and mortality risk. Furthermore, stratified and sensitive analyses were performed to examine the robustness and reliability of the results. The study, encompassing 1043 participants with an average age of 64.61 years, identified a cutoff value of 0.32 for CAR, with notable variances observed across gender and age cohorts. Over an average follow-up period of 116 months, 679 instances of all-cause mortality were documented. Kaplan-Meier survival analysis unveiled noteworthy disparities in survival probabilities between groups categorized by high and low CAR levels (p = 0.00081). Continuous CAR analysis consistently demonstrated a positive correlation between elevated CAR values and heightened risk (HR = 1.78 (1.36, 2.33)) of all-cause mortality among stroke patients. Similarly, individuals in the high CAR group exhibited adjusted HR of 1.34 (0.96, 1.89) for all-cause mortality compared to their low CAR counterparts. Subgroup and sensitive analysis consistently reinforced these findings. Smoothing curve fitting further validated CAR's significance as a prognostic indicator of all-cause mortality, indicating a linear relationship. Elevated CAR is associated with increased long-term risk of mortality for individuals who have experienced a stroke, suggesting that CAR could serve as a survival indicator. • The inflammatory nutritional status is widely associated with the long-term prognosis of non-fatal stroke. • The relationship between C-reactive protein to albumin ratio (CAR) with the prognosis of patients of stroke is unknown. • Elevated CAR is associated with increased long-term risk of mortality for individuals who have experienced a stroke. • CAR should be thoroughly considered in the long-tern outcome management of patients with history of stroke. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? We conducted a four-armed, quasi-experimental intervention to assess the effects of simultaneous combined intervention (cycling while playing a video game), single aerobic exercise, and single video game training on executive functions and brain connectivity in older adults. • What is the main finding of this study? Both video game training alone and combined intervention could improve executive functions, while combined intervention holds greater potential to boost gains. • What is the meaning of the study? Combining aerobic exercise with challenging cognitive activities simultaneously is especially beneficial for postponing the decline in executive functions in older adults. The study was designed to examine the effects of simultaneous combination of aerobic exercise and video game training on executive functions (EFs) and brain functional connectivity in older adults. A four-armed, quasi-experimental study. Community-dwelling adults aged 55 years and older. A total of 97 older adults were divided into one of four groups: aerobic exercise (AE), video game (VG), combined intervention (CI), and passive control (PC). Participants in intervention groups received 32 sessions of training over a 4-month period at a frequency of twice a week. EFs was evaluated using a composite score derived from a battery of neuropsychological tests. The Montreal Cognitive Assessment (MoCA) was employed to evaluate overall cognitive function, while the 6-Minute Walking Test (6MWT) was utilized to gauge physical function. Additionally, the functional connectivity (FC) of the frontal-parietal networks (FPN) was examined as a neural indicator of cognitive processing and connectivity changes. In terms of EFs, both VG and CI groups demonstrated improvement following the intervention. This improvement was particularly pronounced in the CI group, with a large effect size (Hedge's g = 0.83), while the VG group showed a medium effect size (Hedge's g = 0.56). A significant increase in MoCA scores was also observed in both the VG and CI groups, whereas a significant increase in 6MWT scores was observed in the AE and CI groups. Although there were no group-level changes observed in FC of the FPN, we found that changes in FC was behaviorally relevant as increased FC was associated with greater improvement in EFs. The study offers preliminary evidence that both video game training and combined intervention could enhance EFs in older adults. Simultaneous combined intervention may hold greater potential for facilitating EFs gains. The initial evidence for correlated changes in brain connectivity and EFs provides new insights into understanding the neural basis underlying the training gains. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? Exercise, including Tai Chi (TC) was beneficial for cognitive function of older adults with aMCI. However, the underlying molecular mechanism of TC on neuroprotection remains largely unknown. Exercise-released exosomes have been identified as novel mediators of cell-to-cell communication, playing a significant role in regulating hippocampal synaptic plasticity and nerve regeneration, as evidenced by ex vivo trials. No previous studies were done to address the gap in understanding the relationship between exercise-induced exosome, therapeutically hippocampus plasticity, and neurocognitive function response to TC training by using proteomics technology. • What is the main finding of this study? Tai Chi exercise ameliorated cognitive function, increased right hippocampus volume, enhanced rsFC between hippocampus and cuneus which mediated the group effect on cognition and promoted circulating LRP1 release via exosome. Significant relationship was found between upregulated LRP1, memory function and hippocampus plasticity. • What is the meaning of the finding? To our knowledge, this is the first RCT to demonstrate the potential peripheral processes of circulating exosomes in response to TC exercise and its relationship with cognitive protection and hippocampus plasticity based on large-scale proteomics analysis. Our findings provided an insight into potential therapeutic neurobiological targets for aMCI by focusing on peripheric exosome in respond to TC exercise. The study was designed to identify the potential peripheral processes of circulating exosome in response to Tai Chi (TC) exercise and the possibility of its loaded cargos in mediating the effects of TC training on cognitive function among older adults with amnestic mild cognitive impairment (aMCI). This was a multicenter randomized controlled trial. One hundred community-dwelling old adults with aMCI were randomly assigned (1:1) to experimental (n = 50) and control groups (n = 50). The experimental group participated in TC exercise 5 times/week, with each session lasting 60 minutes for 12 weeks. Both experimental and control groups received health education every 4 weeks. The primary outcome was global cognitive function. Neurocognitive assessments, MRI examination, and large-scale proteomics analysis of peripheric exosome were conducted at baseline and after 12-week training. Outcome assessors and statisticians were blinded to group allocation. A total of 96 participants (96%) completed all outcome measurements. TC training improved global cognitive function (adjusted mean difference [MD] = 1.9, 95%CI 0.93–2.87, p <0.001) and memory (adjusted MD = 6.42, 95%CI 2.09–10.74, p = 0.004), increased right hippocampus volume (adjusted MD = 88.52, 95%CI 13.63–163.4, p = 0.021), and enhanced rest state functional connectivity (rsFC) between hippocampus and cuneus, which mediated the group effect on global cognitive function (bootstrapping CIs: [0.0208, 1.2826], [0.0689, 1.2211]) and verbal delay recall (bootstrapping CI: [0.0002, 0.6277]). Simultaneously, 24 differentially expressed exosomal proteins were detected in tandem mass tag-labelling proteomic analysis. Of which, the candidate protein low-density lipoprotein receptor-related protein 1 (LRP1) was further confirmed by parallel reaction monitoring and ELISA. Moreover, the up-regulated LRP1 was both positively associated with verbal delay recall and rsFC (left hippocampus-right cuneus). TC promotes LRP1 release via exosome, which was associated with enhanced memory function and hippocampus plasticity in aMCI patients. Our findings provided an insight into potential therapeutic neurobiological targets focusing on peripheric exosome in respond to TC exercise. [ABSTRACT FROM AUTHOR]

[Display omitted] • Vertical variations in trace elements within the Shijuligou VMS deposit are mainly controlled by physicochemical conditions, magmatic degassing, and seawater circulation. • A broad sulfur isotope range of −3.36 to 19.84 ‰ in the Shijuligou VMS deposit is caused by deep magmatic degassing and shallow seawater circulation. • Elemental and sulfur isotopic signatures of magmatic degassing could be obscured by subsequent shallow seawater circulation. • Chemical variations, along with Pb and S isotopic data, suggest the Shijuligou VMS deposit resembles a fossil analog of immature, subduction-influenced submarine hydrothermal systems. Limited access to modern subseafloor sulfides hampers our understanding of the link between magmatic volatile influx and the cycling of trace elements and sulfur, as well as the effect of the subsequent shallow seawater circulation on these processes. Hence, we studied a well-preserved fossil analog of submarine hydrothermal systems – the Shijuligou volcanogenic massive sulfide (VMS) deposit from the North Qilian Mountains in North China to examine variations in elements and isotopes of subseafloor sulfides vertically. The vertical distribution of trace elements in subseafloor sulfides is strongly controlled by temperature gradients and redox states during the interaction between hot fluids and seawater beneath the paleo-seafloor. While the enrichment of elements like As, Sb, and Au (median: 1335, 43.7, and 0.30 ppm, respectively, n = 21) and negative δ34S values (mean: −3.07 ‰, n = 7) of euhedral pyrites in the jasper, along with the precipitation of high sulfidation minerals (e.g., enargite), suggest the input of magmatic volatiles into hydrothermal systems. During the shallow seawater-hydrothermal circulation, pyrites in the veined and stockwork zones exhibit distinctly elevated δ34S values (up to 15.74 ‰), accompanied by increased concentrations of wall-rock-derived elements (e.g., Cu, Ni, Si, and Ti) and low-temperature-responsive elements (e.g., Pb, Zn, and Cd). Sulfur isotopes of sulfides vary significantly from the surface to the deep ore zones, ranging from −3.36 to 19.84 ‰ (mean: 9.25 ‰, n = 37). The negative δ34S values of pyrites at the paleo-seafloor are due to the addition of H 2 S derived from the disproportionation of magmatic SO 2. The increased δ34S values of stockwork and disseminated sulfides at depth are attributed to the progressive reduction of seawater sulfates by ferrous iron released from the alteration of fresh basalts. The trace elemental and isotopic characteristics of sulfides suggest the Shujuligou VMS deposit resembles the fossil analog of immature, subduction-related submarine hydrothermal systems. [ABSTRACT FROM AUTHOR]

Randomized clinical trials (RCTs) often suffer from a lack of representation from historically marginalized populations, and it is uncertain whether virtual RCTs (vRCTs) enhance representativeness or if elements of their consent and enrollment processes may instead contribute to underrepresentation of these groups. In this study, we aimed to identify disparities in enrollment demographics in a vRCT, the BE ACTIVE study, which recruited patients within a single health system. We discovered that the proportions of eligible patients who were randomized differed significantly by gender and race/ethnicity (men 1.2%, women 2.0%, P <.001; White 1.8%, Black 1.3%, Hispanic 0.7%, Asian 0.9%; P <.001), and compared with White patients, non-White patients were less likely to have a valid email address on file and were less likely to click on the email link to the study webpage and begin enrollment. [ABSTRACT FROM AUTHOR]

It is a deep-rooted and already observed reality that probabilistic models play an important role in describing and explaining the events/situations under consideration. Focusing attention on the fundamental role and applicability of the probabilistic models, this article considers the development of a new probability model derived through the implementation of a trigonometric function. The suggested model is named as a new cosine flexible Weibull (NCF-Weibull) distribution. This model is accomplished by exploiting the cosine functional approach. Some statistical characteristics of the NCF-Weibull distribution are given. Alongside, the estimates of the NCF-Weibull model are also obtained. Besides them, a simulation study for different settings of the parameter values of the NCF-Weibull model is also provided. Through the simulation study it is evidenced that the estimators of the NCF-Weibull distribution consistently perform well in terms of stability, consistency, and efficiency. Finally, the optimality of the NCF-Weibull distribution is judged by using two applications from different sectors. Based on five evaluation criteria alongside the p -value, the NCF-Weibull distribution shows optimal performances for both data sets. [ABSTRACT FROM AUTHOR]