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In anticipation of potential future pandemics, we examined the challenges and opportunities presented by the COVID-19 outbreak. This analysis highlights how artificial intelligence (AI) and predictive models can support both patients and clinicians in managing subsequent infectious diseases, and how legislators and policymakers could support these efforts, to bring learning healthcare system (LHS) from guidelines to real-world implementation. This report chronicles the trajectory of the COVID-19 pandemic, emphasizing the diverse data sets generated throughout its course. We propose strategies for harnessing this data via AI and predictive modelling to enhance the functioning of LHS. The challenges faced by patients and healthcare systems around the world during this unprecedented crisis could have been mitigated with an informed and timely adoption of the three pillars of the LHS: Knowledge, Data and Practice. By harnessing AI and predictive analytics, we can develop tools that not only detect potential pandemic-prone diseases early on but also assist in patient management, provide decision support, offer treatment recommendations, deliver patient outcome triage, predict post-recovery long-term disease impacts, monitor viral mutations and variant emergence, and assess vaccine and treatment efficacy in real-time. A patient-centric approach remains paramount, ensuring patients are both informed and actively involved in disease mitigation strategies.

Abstract Combined with the advanced drilling of the central return air shaft in Kekegai Coal Mine, the distribution law of slag discharge flow field by drilling method and the influencing factors of slag discharge effect are studied. Firstly, the numerical model of gas–liquid–solid coupling slag discharge is established by CFD-DEM (computational fluid dynamics coupled discrete element method). Then, the flow field distribution law of the site slag outlet layout model and the optimization model is compared and analyzed. Finally, the influence of drilling parameters on slag discharge effect is studied. The results show that the best arrangement of slag suction ports is: the number is two, the length-diameter ratio is 0.4, the area ratio is 1, and the total area ratio is 1.94%. The fluid movement at the bottom of the well is mainly tangential flow, while the fluid in the slag discharge pipe is mainly axial flow. The construction parameters of efficient slag discharge are put forward: bit rotation speed is 8.7 r/min, gas injection rate is 4200 m3/h, air duct sinking ratio is 0.84, and mud viscosity is 165 MPa·s. The research results can provide useful theoretical reference for large-scale sinking construction in deep wells.

Abstract Inverse kinematics of redundant robots presents a challenging problem for real-time applications due to the lack of uniqueness of solution and the low computational efficiency caused by redundancy and hard limits. In this work, a general and efficient method for addressing the real-time optimized inverse kinematics of redundant robots is proposed, taking into account hard limits in joint and Cartesian space that can never be violated. The proposed method proceeds by using constrained linear programming instead of quadratic programming to solve the inverse kinematics problem. Various hard limits such as joint range, bounds on velocity and acceleration are handled explicitly as inequality constraints. This method resolves the redundancy in real-time and enable to simultaneously guarantee that the additional motion constraints will never be violated. Its performance allows real-time kinematic control of redundant robots executing sensor-driven online tasks. The effectiveness of this method is demonstrated through simulations and experiments conducted on a 7-DOF KUKA IIWA robot, showcasing its ability to control redundant robots executing sensor-driven tasks in dynamic environments with numerous hard limits.

Abstract Background PMP is a rare clinical syndrome characterized by the accumulation of mucinous material in the peritoneal cavity. The combination of CRS and HIPEC is the standard treatment, known to improve survival outcomes. However, follow-up adherence is critical for early detection of recurrence and extending survival. This study is the first to specifically investigate postoperative follow-up adherence in PMP patients treated with CRS and HIPEC. Aims To explore the socio-demographic and clinical determinants of follow-up adherence and its impact on survival in PMP patients treated with CRS and HIPEC. Methods This single-center, six-year retrospective study included 111 PMP patients who underwent CRS and HIPEC. Patients were categorized into compliant (control) and non-compliant (study) groups. Follow-up was initiated by the physician, with patients returning for regular visits as recommended. Kaplan-Meier analysis was used to evaluate survival outcomes, while univariate analysis identified factors influencing follow-up adherence. Results Among 111 patients, 32 died by August 2024, with 1-, 3-, and 5-year survival rates of 88%, 66%, and 53%, respectively. High PCI scores (P

Abstract Objectives Gut-brain axis dysfunction has emerged as a key contributor to the pathogenesis of Crohn’s disease (CD). The elucidation of neural alterations may provide novel insights into its management. We aimed to develop a multiparameter brain MRI-based radiomics model (RM) for characterizing neural alterations in CD patients and to interpret these alterations using multiomics traits. Methods This prospective study enrolled 230 CD patients and 46 healthy controls (HCs). Participants voluntarily underwent brain MRI and psychological assessment (n = 155), blood metabolomics analysis (n = 260), and/or fecal 16S rRNA sequencing (n = 182). The RM was developed using 13 features selected from 13,870 first-order features extracted from multiparameter brain MRI in training cohort (CD, n = 75; HCs, n = 32) and validated in test cohort (CD, n = 34; HCs, n = 14). Multiomics data (including gut microbiomics, blood metabolomics, and brain radiomics) were compared between CD patients and HCs. Results In the training cohort, area under the receiver operating characteristic curve (AUC) of RM for distinguishing CD patients from HCs was 0.991 (95% confidence interval (CI), 0.975–1.000). In test cohort, RM showed an AUC of 0.956 (95% CI, 0.881–1.000). CD-enriched blood metabolites such as triacylglycerol (TAG) exhibited significant correlations with both brain features detected by RM and CD-enriched microbiota (e.g., Veillonella). One notable correlation was found between Veillonella and Ctx-Lh-Middle-Temporal-CBF-p90 (r = 0.41). Mediation analysis further revealed that dysbiosis, such as of Veillonella, may regulate the blood flow in the middle temporal cortex through TAG. Conclusion We developed a multiparameter MRI-based RM that characterized the neural alterations of CD patients, and multiomics data offer potential evidence to support the validity of our model. Our study may offer clues to help provide potential therapeutic targets. Critical relevance statement Our brain-gut axis study developed a novel model using multiparameter MRI and radiomics to characterize brain changes in patients with Crohn’s disease. We validated this model’s effectiveness using multiomics data, making it a potential biomarker for better patient management. Key Points Utilizing multiparametric MRI and radiomics techniques could unveil Crohn’s disease’s neurophenotype. The neurophenotype radiomics model is interpreted using multiomics data. This model may serve as a novel biomarker for Crohn’s disease management. Graphical Abstract

Abstract Radiotherapy (RT) stands as a frontline treatment modality in clinical breast oncology, yet challenges like ROS reduction, high toxicity, non-selectivity, and hypoxia hinder efficacy. Additionally, RT administered at different doses can induce varying degrees of radioimmunotherapy. High doses of radiation (>10 Gy) may result in immune suppression, while moderate doses (4–10 Gy), although capable of mitigating the immune suppression caused by high-dose radiation, are often insufficient in effectively killing tumor cells. Therefore, enhancing the generation of ROS and ameliorating the tumor hypoxic immune-suppressive microenvironment at moderate radiation doses could potentially drive radiation-induced immune responses, offering a fundamental solution to the limitations of RT. In this study, a novel multifunctional nanoplatform, RMLF, integrating a Ru (II) complex into folate-functionalized liposomes with BSA-MnO2 nanoparticles was proposed. Orthogonal experimental optimization enhances radiosensitization via increasing accumulation in cancer cells, elevating ROS, and contributing to a dual enhancement of the cGAS-STING-dependent type I IFN signaling pathway, aimed to overcome the insufficient DAMPs typically seen in the conventional RT at 4 Gy. Such a strategy effectively activated cytotoxic T lymphocytes for infiltration into tumor tissues and promoted the polarization of tumor-associated macrophages from the M2 to M1 phenotype, substantially bolstering immune memory responses. This pioneering approach represents the first use of a ruthenium complex in radioimmunotherapy, activating the cGAS-STING pathway to amplify immune responses, overcome RT resistance, and extend immunotherapeutic potential.

Abstract Induced pluripotent stem cells (iPSCs) technology holds great potential in both scientific research and clinical applications. It enables the generation of naïve and primed iPSCs from various cell types through different strategies. Despite extensive characterizations of transcriptional and epigenetic factors, the intricacies of chromatin landscape dynamics during naïve and primed reprogramming, particularly in humans, remain poorly understood. In this study, we employed ATAC-seq and RNA-seq analyses to delineate and compare the chromatin landscape of naïve and primed pluripotency through the human secondary reprogramming system. Our investigations revealed several key transcriptional and epigenetic factors pivotal for reprogramming-associated chromatin remodeling. Notably, we found two isoforms of PRDM1, PRDM1α, and PRDM1β, bind to distinct genomic loci and play different roles in the naïve reprogramming process. We proposed an auto-regulatory model explaining the distinct functions of PRDM1α and PRDM1β. Overall, our findings highlight the complexity and diversity of transcription factors in shaping chromatin landscape dynamics and directing the fates of pluripotent cells.

Abstract Phosphorus deficiency is a major influence on growth and development of soybean. Therefore, improving phosphorus utilization efficiency in soybean is a research priority for the soybean community. In this experiment, Liaodou 13 (high phosphorus utilization: HPE) and Tiefeng 3 (low phosphorus utilization: LPE) were used as test varieties. We investigated changes in root morphology, amino acid content, and content of key substances of the nitrogen metabolic pathway with normal phosphorus (0.5 mM) and low phosphorus (0.005 mM) treatments. The results showed that the root length, root surface area and number of lateral roots of HPE roots were higher than those of LPE roots under normal and low phosphorus conditions. The contents of different types of amino acids showed different trends in two varieties. The HPE showed small change in the content of total hydrolyzed amino acids under the low phosphorus condition when compared to the normal phosphorus treatment by a 6.67% decrease, on the contrary LPE showed a drastic decrease by 20.36%. However, HPE exhibited similar decreasing trends in the contents of hydrolyzed and free aspartic acid with the low phosphorus treatment. Moreover, the contents of free histidine and valine in LPE were significantly increased by 657.84% and 149.29% respectively, in contrast to significant decreases in HPE. In aspects of major nutrient elements, the contents of phosphorus, total nitrogen and ammonia nitrogen in both HPE and LPE varieties decreased to dramatic levels. However, the nitrate nitrogen content significantly increased 78.51% for HPE and 65.12% for LPE. Compare to the normal condition, the GOGAT activity in HPE decreased by 5.18% but increased by 33.10% in LPE. Compare to the normal condition, the GS activity in HPE increased by 7.26% but decreased by 21.72% in LPE under phosphorus deficiency. In summary, the phosphorus-efficient soybean variety HPE exhibited superior tolerance to low phosphorus deficiency through advantageous root morphology, phosphorus uptake and transfer capability, and balanced amino acid metabolism and nitrogen metabolism pathways.

Abstract Cytokinin Response Factors (CRFs) play a crucial role in plant growth and development, hormone signaling, and responses to biotic and abiotic stresses. However, there have been no reports on CRF genes in rice until now. We analyzed the CRF families in four rice subspecies: cultivated rice Oryza sativa Japonica Group, Oryza sativa Indica Group, and Oryza sativa (circum-Aus1 var. N22), as well as wild rice Oryza rufipogon. We identified 7, 6, 6, and 7 CRF in their genomes, respectively, distributed across different chromosomes. The protein motifs and gene structures of CRF in these four types of rice show high conservation. Cis-regulatory element analysis revealed that the promoter regions of the CRF contain numerous hormone and stress-related elements. The number of CRF in these four types of rice is not influenced by gene duplication. The expression pattern showed that OsCRF exhibit significant tissue-specific expression. The qRT-PCR results showed that OsCRF strongly responded to low-temperature stress and can be induced by melatonin and cytokinin to increase expression levels. In addition, the nuclear localisation of OsCRF4/5 was confirmed to be as predicted. The results above will provide a foundation for further and deeper investigation of CRFs.

Abstract Planting forests is an effective way to improve desertification. In order to elucidate the impacts of different vegetation types on soil development and restoration of degraded lands, we compared the properties of soils at different depths in three plantation forests in the Hunsandak Sandy Land in the Chinese agro-pastoral ecotone (Ulmus pumila, Pinus sylvestris var. mongolica, and Populus simonii). The results show that all three plantation forests were able to significantly improve the soil properties, and they resulted in soil nutrient enrichment in the surface layer. As the soil depth increased, the soil became progressively poorer in nutrients, the fine particle content decreased, and the bulk density and water content increased. The orders of the fractal dimension characterization and soil improvement effects of the different tree species were as follows: U. pumila > P. sylvestris var. mongolica > P. simonii. Compared with the bare sand, the soil bulk density under the U. pumila plantation was 19% lower; the soil water content was 74% higher; the soil organic matter, total N, P, and K were 336%, 207%, 106%, and 31% higher; the available N, P, and K were 41%, 125%, and 21% higher; and the clay and silt contents were 498% and 387% higher, respectively. The ranges of the soil fractal dimension were 1.67–2.08 for the bare sandy land and 2.14–2.32 for the planted forests. The soil fractal dimension was strongly correlated with the soil physicochemical properties, especially with the soil nutrients and fine particle content, which exhibited highly significant correlations (p

Abstract In order to figure out actual shaft resistance, axial forces of pile shaft have to be calculated based on strain test, which is a challenge for heat and steam cured prestressed high-strength concrete pipe piles. Disadvantages of three common methods of strain test and the empirical linear equation between axial force and strain are analyzed. A new strain test method, namely the slot-forming wood method, is proposed and applied in laboratory and field test. Taking pipe pile PHC500AB-125 as an example, laboratory tests were performed to establish the nonlinear function between axial force and strain. Field tests were performed and strains were tested by the slot-forming wood method. Results calculated by the nonlinear function between axial force and strain were compared with that by traditional linear equation to reveal the difference. The tests indicated that the new method of strain test was applicable and useful since the survival rate of strain gauges was high and the accuracy has been improved. Overcoming the disadvantages of the traditional linear equation, the proposed function between axial force and strain is more accurate. The study provides theoretical basis for technology innovation in pile test and for revision of related technical standards.

Abstract Anesthesia can influence cerebral blood flow by altering vessel diameter. Using in vivo two-photon imaging, we examined the effects of volatile anesthetics, sevoflurane and isoflurane, on vessel diameter in young and adult mice. Our results show that these anesthetics induce robust dilation of cortical arterioles and arteriole-proximate capillaries in adult mice, with milder effects in juveniles and no dilation in infants. This anesthesia-induced vasodilation correlates with decreased cytosolic Ca2+ levels in NG2+ vascular mural cells. Optogenetic manipulation of these cells bidirectionally regulates vessel diameter, and their ablation abolishes the vasodilatory response to anesthetics. In immature brains, NG2+ mural cells are fewer in number and express lower levels of Kir6.1, a subunit of ATP-sensitive potassium channels. This likely contributes to the age-dependent differences in vasodilation, as Kir6.1 activation promotes, while its inhibition reduces, anesthesia-induced vasodilation. These findings highlight the essential role of NG2+ mural cells in mediating anesthesia-induced cerebral vasodilation.

Abstract Background Osteoporosis is characterized by low systemic bone mineral content and destruction of bone microarchitecture. Promoting bone regeneration and reversing its loss by infusion of exogenous bone marrow mesenchymal stem cells (BMSCs) is a potentially effective treatment for osteoporosis. However, their limited migration to target organs reduces the therapeutic effect of the cells. Stromal cell-derived factor 1 (SDF1) is a chemokine that induces targeted cell migration through the SDF1/CXCR4 (C-X-C chemokine receptor 4) axis and can induce migration of exogenous mesenchymal stem cells to sites of high SDF1 concentration. There are no studies on BMSCs overexpressing SDF1 (SDF1-BMSCs) in osteoporotic mice in vivo. We aimed to investigate if the increased SDF1 concentration facilitated cell migration to the bone. Methods We used lentivirus to construct BMSCs overexpressing SDF1 or knocking down CXCR4. We verified the proliferation ability of the cells in vitro using Cell Counting Kit-8 (CCK8) and 5-Bromodeoxyuridinc (BrdU), the migration ability of the cells using Transwell, and the osteogenic and lipogenic ability of the cells using osteogenic and lipogenic induction solutions. In in vivo experiments, we induced osteoporosis in 72 female mice by ovariectomy and injected different groups of cells via the tail vein. Femoral tissue samples were collected for a fixed time, and the osteogenic and homing abilities of the cells were verified by MicroCT and tissue section staining. Results We successfully demonstrated that high expression of SDF1 promoted cell proliferation and migration in vitro, without affecting their cell differentiation ability. In an ovariectomized mouse model, SDF1-BMSCs were more likely to be home to the femur than the BMSCs, had a better pro-osteogenic ability, and had higher expression of Wnt-1. Blocking the SDF1/CXCR4 axis reduced the homing of exogenous mesenchymal stem cells (MSCs) to the femur and their osteogenic capacity. Conclusions SDF1-BMSCs can further promote bone formation by increasing the number of cells homing to the femur in osteoporotic mice. Our study shows that stem cells can promote their proliferation and home to the femur via the SDF1/CXCR4 axis and further help bone formation via Wnt-1 signaling.

Metabolizing ellagic acid (EA) to urolithin A with numerous bioactivities significantly improve the nutritional value of food rich in EA. In the present study, Streptococcus thermophilus FUA329 was applied to prepare pomegranate juice yogurt. The best process formula was investigated through single-factor experiments and response surface methodology. With S. thermophilus CGMCC1.8748 as control, the viability of strain, rheological properties and antioxidant activity of pomegranate juice yogurt fermented with strain FUA329 were evaluated. The content of urolithin A in pomegranate juice yogurt fermented with strain FUA329 were analyzed by high-performance liquid chromatography. The results showed that the optimal fermentation conditions for preparing pomegranate juice yogurt by S. thermophilus FUA329 were 15.79% pomegranate juice content, 7.08% sucrose content and 3.04% starter inoculum size, fermentation at 37 ℃ for 7 h and comprehensive sensory score was 79.4 points. Under the optimal conditions, the results of basic indicators showed that yogurt acidity was (82.5±1.3)°T, whey precipitation was 9.6%±0.97%, color difference was 68.17±2.75, bacterial activity was 2.01±0.31 (OD600). In terms of antioxidant activity, DPPH radical, ABTS+ radical and superoxide anion radical scavenging rates of fermented pomegranate juice yogurt by strain FUA329 were 82.87%±1.48%, 88.20%±2.10% and 76.92%±1.02%, respectively, which was significantly better than plain yogurt fermented by strain FUA329 and pomegranate juice yogurt fermented by S. thermophilus CGMCC1.8748. In addition, urolithin A content was 3.31 μmol/L in fermented pomegranate juice yogurt by strain FUA329 after 7 h. The results of this study would provide a theoretical basis for fermenting a functional pomegranate juice yogurt, and lay a foundation for the development and utilization of S. thermophilus FUA329.

In order to evaluate the effect of Streptococcus thermophilus fermentation on green tea extract and its storage characteristics, this study used Streptococcus thermophilus FUA329 and S. thermophilus ST1.8748 (control group) to conduct experiments on green tea extracts. After fermentation and storage at 4 ℃ for 0, 30, 60, 120 and 180 d, pH, viable bacterial count, tea polyphenol content, ellagic acid content, and urolithin A content were used as the main evaluation indicators, combined with anti-oxidation activity to evaluate the storage quality of fermented green tea extract. The results showed that compared with the S. thermophilus ST1.8748 control group, the pH of S. thermophilus FUA329 fermented green tea extract during the storage period was between 5.39 and 5.71. The highest number of viable bacteria at 48 h was 9.97×108 CFU/mL. The content of tea polyphenols gradually decreased and the ellagic acid content tended to be stable. Urolithin A was produced at 48 h, and its concentration was 0.664 μmol/L. The antioxidant activity was always maintained at a high level. In summary, S. thermophilus FUA329 fermented green tea extract can significantly delay the quality decline and nutrient loss of green tea extract during storage.

Abstract Background Autism spectrum disorder (ASD) poses a significant challenge due to its diverse impact on individuals, emphasizing the need for personalized treatment plans. The financial burden of ASD-related healthcare is substantial, necessitating a comprehensive understanding of its prevalence and evolving trends. Methods This study aims to analyze the prevalence and trends of ASD, treatment patterns, gender differences, and racial-ethnic disparities in the United States from 2017 to 2020, utilizing nationally representative data from the National Survey of Children's Health (NSCH). The NSCH, a leading annual national survey, provided rich data on child health. A total of 108,142 participants aged 3–17 years were included, with ASD prevalence assessed based on self-reported diagnoses. Results Between 2017 and 2020, ASD prevalence in children aged 3–17 was 2.94% (95% confidence interval: 2.68–3.18). Significant disparities were observed: older age and male gender correlated with higher prevalence, while family income-to-poverty ratio and insurance coverage influenced prevalence. Racial/ethnic disparities existed, with Hispanics showing the highest prevalence. Treatment trends showed stability overall, but age influenced behavioral and medication interventions. The prevalence remained stable from 2017 to 2020, with variations in age groups and a significant increase among non-Hispanic Whites. Conclusions This study highlights a higher but stable overall ASD prevalence, with nuanced disparities among different demographic groups. Gender differences persist, emphasizing the need for tailored interventions. Racial-ethnic disparities call for targeted healthcare strategies. The stability in treatment trends underscores the persistent challenge of addressing core ASD symptoms.

Abstract Osteotomy can correct kyphosis, restore the spinal sequence, and restore the healthy appearance of a patient. However, the aorta is stretched during pedicle subtraction osteotomy (PSO), and some surgeons are concerned about aortic injury. We used finite element analysis to construct an aortic model to simulate hemodynamic changes during osteotomy. 16 patients with ankylosing spondylitis kyphosis who had undergone a two-level osteotomy at the L1 and L3 levels was included in this study. Aortic computed tomography angiography (CTA) was performed, and a 3D image model was constructed. The length, transverse diameter, and curvature of the aorta were used to evaluate morphological changes. Finite element analysis was used to analyze the changes in aortic fluid dynamics. Blood pressure, wall shear stress, and blood flow velocity were compared pre- and postoperatively. The overall length of the aorta before surgery was 424.3 ± 42.9 mm, and the overall length of the aorta after surgery was 436.2 ± 54.8 mm. The aortic curvature decreased from 0.27 ± 0.13 to 0.17 ± 0.09. The mean transverse diameter of the aorta did not change (19.3 ± 6.6 vs. 19.2 ± 7.4 mm, P > 0.05). The blood flow velocity (2.8 ± 1.1 vs. 1.5 ± 0.8 m/s, P

Abstract Simultaneous manipulation of multiple degrees of freedom of light lies at the heart of photonics. Nonlinear wavefront shaping offers an exceptional way to achieve this goal by converting incident light into beams of new frequencies with spatially varied phase, amplitude, and angular momenta. Nevertheless, the reconfigurable control over structured light fields for advanced multimode nonlinear photonics remains a grand challenge. Here, we propose the concept of nonlinear geometric phase in an emerging ferroelectric nematic fluid, of which the second-order nonlinear susceptibility carries spin-dependent nonlinearity phase. A case study with photopatterned q-plates demonstrates the generation of second-harmonic optical vortices with spin-locked topological charges by using cascaded linear and nonlinear optical spin-orbit interactions. Furthermore, we present the dynamic tunability of second-harmonic structured light through temperature, electric field, and twisted elastic force. The proposed strategy opens new avenues for reconfigurable nonlinear photonics, with potential applications in optical communications, quantum computing, high-resolution imaging, etc.

Abstract Denticleless E3 ubiquitin protein ligase homolog (DTL), the substrate receptor of the CRL4A complex, plays a central role in genome stability. Even though the oncogenic function of DTL has been investigated in several cancers, its specific role in hepatocellular carcinoma (HCC) still needs further elucidation. Data from a clinical cohort (n = 209), RNA-sequencing, and public database (TCGA and GEO) were analyzed, indicating that DTL is closely related to patient prognosis and could serve as a promising prognostic indicator in HCC. Functionally, DTL promoted the proliferation, metastasis, and sorafenib resistance of HCC in vitro. In the orthotopic tumor transplantation and tail vein injection model, DTL promoted the growth and metastasis of HCC in vivo. Mechanically, we revealed for the first time that DTL was transcriptionally activated by hypoxia-inducible factor 1α (HIF-1α) under hypoxia and functioned as a downstream effector molecule of HIF-1α. DTL promotes the ubiquitination of SAFB-like transcription modulator (SLTM) and subsequently relieves the transcriptional repression of Notch1. These results suggested that DTL may be a potential biomarker and therapeutic target for HCC.

Abstract Endothelial cells (ECs) are pivotal in maintaining vascular health, regulating hemodynamics, and modulating inflammatory responses. Nanocarriers hold transformative potential for precise drug delivery within the vascular system, particularly targeting ECs for therapeutic purposes. However, the complex interactions between vascular ECs and nanocarriers present significant challenges for the development and clinical translation of nanotherapeutics. This review assesses recent advancements and key strategies in employing nanocarriers for drug delivery to vascular ECs. It suggested that through precise physicochemical design and surface modifications, nanocarriers can enhance targeting specificity and improve drug internalization efficiency in ECs. Additionally, we elaborated on the applications of nanocarriers specifically designed for targeting ECs in the treatment of cardiovascular diseases, cancer metastasis, and inflammatory disorders. Despite these advancements, safety concerns, the complexity of in vivo processes, and the challenge of achieving subcellular drug delivery remain significant obstacles to the effective targeting of ECs with nanocarriers. A comprehensive understanding of endothelial cell biology and its interaction with nanocarriers is crucial for realizing the full potential of targeted drug delivery systems. Graphical Abstract

Abstract Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.

In response to global carbon neutrality targets, there is an urgent need for large-scale, clean hydrogen production technologies to supplant fossil fuels and underpin the establishment of a ‘hydrogen economy’. The prospect of large-scale on-site green hydrolysis of Mg-based materials for hydrogen production has attracted wide attention. Aiming at the problems of easy formation of inert oxide layer on its surface and the production of Mg(OH)2 to hinder the hydrolysis process, it is urgent to explore efficient, low-cost and green modification strategies. In this work, the green modification strategy for hydrolyzing hydrogen production of Mg-based materials was summarized, and the fast initial kinetics and high hydrogen production rate could be achieved by adjusting hydrolysis medium conditions and modifying Mg-based material. The significance of hydrolytic hydrogen production technology and device development for the realization of Mg-based hydrolytic hydrogen production was evaluated. Meanwhile, this work looks forward to the future direction of hydrogen production modification by hydrolysis of Mg-based alloy, and gradually optimizes the hydrolysis performance of industrial multi-component waste Mg alloy under the premise of green hydrogen production, and proposes the goal of efficient modification of waste Mg alloy, high-quality utilization of seawater, and low-cost and controllable hydrogen production process.

Abstract Some patients with polycystic ovarian syndrome (PCOS) suffered from metabolic syndrome (MetS) including dyslipidemia, hyperinsulinism, but the underlying mechanism is unclear. Although C-terminal Binding Protein 1 (CTBP1) is a transcriptional co-repressor frequently involved in hormone secretion disorders and MetS-associated diseases, the role of CTBP1 in PCOS is rarely reported. In the present study, we found that CTBP1 expression was significantly elevated in primary granulosa cells (pGCs) derived from the PCOS with MetS patients and was positively associated with serum triglyceride, but negatively correlated with serum estradiol (E2) or high-density lipoprotein. Mechanistic study suggested that CTBP1 physically bound to the promoter II of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) to inhibit the aromatase gene transcription and expression, resulting in the reduced E2 synthesis. Moreover, CTBP1 interacted with the phosphorylated SREBP1a at S396 in nuclei, leading to the FBXW7-dependent protein degradation, resulting in the reduced lipid droplets formation in pGCs. Therefore, we conclude that CTBP1 in GCs dysregulates the synthesis of steroid hormones and lipids through suppression of aromatase expression and promotion of SREBP1a protein degradation in PCOS patients, which may offer some fresh insights into the potential pathological mechanism for this tough disease.

Abstract The Hippo-Yes-associated protein (Hippo-YAP) signaling pathway, a conserved pathway that regulates organ size, participates in tumor progression. However, there are few comprehensive analyses of tumor prognosis and immunity. In the present study, TCGA, GTEx, GEO, TIMER2, STRING, GSCA, ImmuCellAI, and other bioinformatics tools were used to reveal the involvement of the Hippo-YAP signaling pathway in the prognosis and immunity of pan-cancers. The obtained results showed that mRNA expression differences of Hippo-YAP pathway genes between normal samples and tumor samples in pan-cancers and some genes (such as TEAD4, MAP4K4, and STK3) might affect the prognosis of patients with skin cutaneous melanoma (SKCM) and pancreatic adenocarcinoma (PAAD). Furthermore, mutation and methylation of the Hippo-YAP signaling pathway genes in normal and primary tumor tissues differ in various cancers (KIRP, BRCA). Additionally, the relationship between the tumor microenvironment, molecular pathways, and the Hippo-YAP pathway indicated that it might lead to a suppressive immune microenvironment that affects the efficacy of immunotherapy. This is a pan-cancer overview of the Hippo-YAP signaling pathway genes, which explores the aberrant expression or mutation of this pathway that regulates the tumor microenvironment and immunotherapy.

Abstract The direct laser writing (DLW) of photoluminescent metal clusters is inspiring intensive research in functional glasses. However, understanding the influence of the host structure on cluster formation and visualizing DLW-induced clusters at the atomic scale remains challenging. In this work, we develop a highly photosensitive fluorophosphate glass through fluorine incorporation. The addition of fluorine establishes a conducive environment for Ag+ ions before DLW and enhances the availability of reducing agents and diffusion pathways during DLW. These advantages facilitate the formation of Ag clusters under low-energy single-pulsed DLW. Increasing laser energy results in a combination of Ag clusters and glasses defect, forming a dot + ring photoluminescent pattern. Atom probe tomography (APT), a technique capable of mapping the elemental spatial distribution and identifying clustering, is employed to gain more information on laser-induced clusters. Comparison of APT results between samples without and with DLW reveals the formation of Ag clusters after laser writing. The design concept and characterization enrich the understanding of Ag cluster behavior in glasses. This knowledge opens the possibility of rational design of clusters confined in glasses and inspires their synthesis for various applications.

Abstract Accurately predicting ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties early in drug development is essential for selecting compounds with optimal pharmacokinetics and minimal toxicity. Existing ADMET-related benchmark sets are limited in utility due to their small dataset sizes and the lack of representation of compounds used in drug discovery projects. These shortcomings hinder their application in model building for drug discovery. To address this issue, we propose a multi-agent data mining system based on Large Language Models that effectively identifies experimental conditions within 14,401 bioassays. This approach facilitates merging entries from different sources, culminating in the creation of PharmaBench. Additionally, we have developed a data processing workflow to integrate data from various sources, resulting in 156,618 raw entries. Through this workflow, we constructed PharmaBench, a comprehensive benchmark set for ADMET properties, which comprises eleven ADMET datasets and 52,482 entries. This benchmark set is designed to serve as an open-source dataset for the development of AI models relevant to drug discovery projects.

Abstract Diabetes mellitus (DM) is a well-documented risk factor of intervertebral disc degeneration (IVDD). The current study was aimed to clarify the effects and mechanisms of NADH: ubiquinone oxidoreductase subunit A3 (NDUFA3) in human nucleus pulposus cells (HNPCs) exposed to high glucose. NDUFA3 was overexpressed in HNPCs via lenti-virus transduction, which were co-treated with high glucose and rotenone (a mitochondrial complex I inhibitor) for 48 h. Cell activities were assessed for cell viability, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) ratio, oxygen consumption rate (OCR) and mitochondrial complexes I activities. High glucose decreased cell viability, increased apoptotic cells, increased ROS production, decreased MMP levels and OCR values in HNPCs in a dose-dependent manner. Rotenone co-treatment augmented the high glucose-induced injuries on cell viability, apoptosis, ROS production and mitochondrial function. NDUFA3 overexpression counteracted the high glucose-induced injuries in HNPCs. HDAC/H3K27ac mechanism was involved in regulating NDUFA3 transcription. NDUFA3 knockdown decreased cell viability and increased apoptotic cells, which were reversed by ROS scavenger N-acetylcysteine. HDAC/H3K27ac-mediated transcription of NDUFA3 protects HNPCs against high glucose-induced injuries through suppressing cell apoptosis, eliminating ROS, improving mitochondrial function and oxidative phosphorylation. This study sheds light on candidate therapeutic targets and deepens the understanding of molecular mechanisms behind DM-induced IVDD.

To determine the promoting effects of enzyme hydrolysis products of Larimichthys polyactis on the proliferation of Streptococcus thermophilus FUA329. The in vitro antioxidant activity of the enzymatic hydrolysis with different molecular weights were determined. Papain was selected for the enzymatic hydrolysis of its by-products on the basis of selecting different enzymes to hydrolyze the processing by-products of Larimichthys polyactis. Taking the proliferative effect of enzymatic degradation products on Streptococcus thermophilus as an indicator of evaluation. The enzymatic hydrolysis conditions were optimized through single factor and response surface methodology. The in vitro antioxidant activity of the hydrolysis products of the by-products of Larimichthys polyactis (HPBL) were determined. The results showed that the best enzymatic hydrolysis conditions included the hydrolysis time, material-liquid ratio and enzyme loading were 5 h, 1:5.1 (w/v) and 2.8% (w/v), respectively. The HPBL prepared under the optimized conditions was separated by ultrafiltration into four fragments, according to the molecular weight: >10000 Da, 5000~10000 Da, 3000~5000 Da,

Cancer stem cells (CSCs) play a pivotal role in tumor initiation, proliferation, metastasis, drug resistance, and recurrence. Consequently, targeting CSCs has emerged as a promising avenue for cancer therapy. Recently, 3-phosphoglycerate dehydrogenase (PHGDH) has been identified as being intricately associated with the regulation of numerous cancer stem cells. Yet, reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited. In this study, the novel “molecular glue” LXH-3-71 was identified, and it robustly induced degradation of PHGDH, thereby modulating the stemness of colorectal cancer cells (CRCs) both in vitro and in vivo. Remarkably, LXH-3-71 was observed to form a dynamic chimera, between PHGDH and the DDB1-CRL E3 ligase. These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors. Additionally, compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase, facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.

Abstract MicroRNAs (miRNAs) are a key class of endogenous non-coding RNAs that play a pivotal role in regulating diseases. Accurately predicting the intricate relationships between miRNAs and diseases carries profound implications for disease diagnosis, treatment, and prevention. However, these prediction tasks are highly challenging due to the complexity of the underlying relationships. While numerous effective prediction models exist for validating these associations, they often encounter information distortion due to limitations in efficiently retaining information during the encoding-decoding process. Inspired by Multi-layer Heterogeneous Graph Transformer and Machine Learning XGboost classifier algorithm, this study introduces a novel computational approach based on multi-layer heterogeneous encoder—machine learning decoder structure for miRNA-disease association prediction (MHXGMDA). First, we employ the multi-view similarity matrices as the input coding for MHXGMDA. Subsequently, we utilize the multi-layer heterogeneous encoder to capture the embeddings of miRNAs and diseases, aiming to capture the maximum amount of relevant features. Finally, the information from all layers is concatenated to serve as input to the machine learning classifier, ensuring maximal preservation of encoding details. We conducted a comprehensive comparison of seven different classifier models and ultimately selected the XGBoost algorithm as the decoder. This algorithm leverages miRNA embedding features and disease embedding features to decode and predict the association scores between miRNAs and diseases. We applied MHXGMDA to predict human miRNA-disease associations on two benchmark datasets. Experimental findings demonstrate that our approach surpasses several leading methods in terms of both the area under the receiver operating characteristic curve and the area under the precision-recall curve.

Abstract Background Circulating tumor cells (CTCs) are pivotal in tumor metastasis across cancers, yet their specific role in renal cancer remains unclear. Methods This study investigated C–C motif chemokine ligand 5 (CCL5)'s tumorigenic impact on renal cancer cells and CTCs using bioinformatics, in vivo, and in vitro experiments. It also assessed renal cancer patients' CTCs prognostic value through Lasso regression and Kaplan–Meier survival curves. Results Bioinformatics analysis revealed differential genes focusing on cellular adhesion and migration between CTCs and tumor cells. CCL5 exhibited high expression in various CTCs, correlating with poor prognosis in renal cancer. In 786-O-CTCs, CCL5 enhanced malignancy, while in renal cell carcinoma cell line CAKI-2 and 786-O, it promoted epithelial-mesenchymal transition (EMT) via smad2/3, influencing cellular characteristics. The nude mouse model suggested CCL5 increased CTCs and intensified EMT, enhancing lung metastasis. Clinical results shown varying prognostic values for different EMT-typed CTCs, with mesenchymal CTCs having the highest value. Conclusions In summary, CCL5 promoted EMT in renal cancer cells and CTCs through smad2/3, enhancing the malignant phenotype and facilitating lung metastasis. Mesenchymal-type CTC-related factors can construct a risk model for renal cancer patients, allowing personalized treatment based on metastatic risk prediction.

From the 1950s to the 1970s, China exported 16 foreign aid stadiums, which occupied a considerable proportion of China’s foreign aid construction and stood out due to their unique qualities. This study aims to explore the historical development of these stadiums in the initial period to clarify the development trends of early China’s stadium aid and the main factors influencing it. According to an exploration based on a series of historical studies, qualitative comparative analyses, interviews and case studies, this study reveals that China’s foreign stadium aid transitioned from labour support to design support under the influence of governmental, architectural and additional factors. This study fills a gap in the academic literature, provides new perspectives for current research into China’s foreign aid construction, and provides indispensable supplements for Chinese sports architecture and modern architecture.

Abstract With the rapid growth of social media, fake news (rumors) are rampant online, seriously endangering the health of mainstream social consciousness. Fake news detection (FEND), as a machine learning solution for automatically identifying fake news on Internet, is increasingly gaining the attentions of academic community and researchers. Recently, the mainstream FEND approaches relying on deep learning primarily involves fully supervised fine-tuning paradigms based on pre-trained language models (PLMs), relying on large annotated datasets. In many real scenarios, obtaining high-quality annotated corpora are time-consuming, expertise-required, labor-intensive, and expensive, which presents challenges in obtaining a competitive automatic rumor detection system. Therefore, developing and enhancing FEND towards data-scarce scenarios is becoming increasingly essential. In this work, inspired by the superiority of semi-/self- supervised learning, we propose a novel few-shot rumor detection framework based on semi-supervised adversarial learning and self-supervised contrastive learning, named Detection Yet See Few (DetectYSF). DetectYSF synergizes contrastive self-supervised learning and adversarial semi-supervised learning to achieve accurate and efficient FEND capabilities with limited supervised data. DetectYSF uses Transformer-based PLMs (e.g., BERT, RoBERTa) as its backbone and employs a Masked LM-based pseudo prompt learning paradigm for model tuning (prompt-tuning). Specifically, during DetectYSF training, the enhancement measures for DetectYSF are as follows: (1) We design a simple but efficient self-supervised contrastive learning strategy to optimize sentence-level semantic embedding representations obtained from PLMs; (2) We construct a Generation Adversarial Network (GAN), utilizing random noises and negative fake news samples as inputs, and employing Multi-Layer Perceptrons (MLPs) and an extra independent PLM encoder to generate abundant adversarial embeddings. Then, incorporated with the adversarial embeddings, we utilize semi-supervised adversarial learning to further optimize the output embeddings of DetectYSF during its prompt-tuning procedure. From the news veracity dissemination perspective, we found that the authenticity of the news shared by these collectives tends to remain consistent, either mostly genuine or predominantly fake, a theory we refer to as “news veracity dissemination consistency”. By employing an adjacent sub-graph feature aggregation algorithm, we infuse the authenticity characteristics from neighboring news nodes of the constructed veracity dissemination network during DetectYSF inference. It integrates the external supervisory signals from “news veracity dissemination consistency” to further refine the news authenticity detection results of PLM prompt-tuning, thereby enhancing the accuracy of fake news detection. Furthermore, extensive baseline comparisons and ablated experiments on three widely-used benchmarks demonstrate the effectiveness and superiority of DetectYSF for few-shot fake new detection under low-resource scenarios.

This is an article in the field of mineral processing engineering. In order to accurately grasp the influence of various types of ores on field production, the process mineralogy of various types of ores was systematically and deeply studied by means of chemical analysis and automatic mineral analysis system (AMICS). Based on the process mineralogy, the ore blending scheme was drawn up, and the whole process test was carried out according to the optimal ore blending ratio. The results show that all kinds of ores are lean iron ores with high silicon, low iron and low sulfur and phosphorus. The embedding characteristics of various types of ores are complex, which has a certain influence on the grindability of ores and monomer dissociation. According to the washability test results of various types of ores in the mining area, the comprehensive ore blending ratio is determined as follows: (magnetic ore∶ sub-iron ore∶ eastern red ore∶mixed ore∶ chlorite ore∶ iron carbonate ore) =(25∶25∶25∶10∶10∶5). Through the closed-circuit process of weak magnetic field-strong magnetic field-mixed magnetic fine anion reverse flotation, the comprehensive ore blending obtained good indexes of comprehensive concentrate grade of 66.06%, yield of 34.60%, comprehensive tailings grade of 15.20% and yield of 65.40%.

Abstract Objective Employing whole‐exome sequencing (WES) technology to investigate the etiology of infantile epileptic spasm syndrome (IESS), and determining whether different etiologies exhibit phenotypic variations, while elucidating the potential associated factors, might improve short‐term responses to first‐line treatment. Methods We retrospectively evaluated patients with IESS admitted for treatment between January 2018 and June 2023. Clinical phenotypic differences among etiological classifications and clinical manifestations were analyzed. Variable selection using the best subset method was performed, followed by logistic regression analysis to identify the factors influencing treatment response. Results A total of 577 patients were included; 412 completed trio‐WES. Magnetic resonance imaging abnormalities were detected in 387 patients (67.1%). Patients with etiology as structural abnormalities were likelier to have non‐spasms at the initial seizure onset. A total of 532 patients completed the first‐line treatment; 273 patients received it for the first time at our hospital (initial response rates: 30.1% and 42.1%, respectively). The response group had a lower proportion of early‐onset seizures (≤3 months) than the no‐response group (11.3% vs. 23.7%, p

Abstract Background This study investigates the effectiveness of a self-developed intelligent monitoring system for home-based knee rehabilitation following total knee arthroplasty (TKA). Methods In this randomized controlled trial, 120 patients undergoing TKA were divided using random digit allocation. Preoperative and one-month postoperative assessments of knee function, quality of life, and isometric knee extension strength were conducted with the Intelligent Monitoring System. Patients received group-specific rehabilitation instructions pre-discharge and performed exercises for one month. Results Changes in isometric knee extensor strength on the affected side within one month post-surgery for the brace-monitored rehabilitation group showed a significant decrease three days after surgery compared to one day before surgery. Subsequent measurements taken at postoperative days 5, 7, 14, and 21 indicated a gradual increase in strength, although these increases did not reach statistical significance when compared with previous measurements. One month post-surgery, all groups demonstrated significant improvements in knee joint function and mobility compared to pre-surgery levels. Notably, the brace-monitored group showed statistically significant improvements in 36-Item Short-Form Health Survey (SF-36) scores over the conventional rehabilitation group. Conclusions The Intelligent Monitoring System provides effective real-time monitoring and guidance for home-based knee rehabilitation post-TKA. It significantly enhances knee joint function, isometric knee extension strength, and quality of life shortly after surgery compared to traditional rehabilitation methods. This system offers a promising approach for improving postoperative recovery in TKA patients. Trial registration This study was approved by the Medical Ethics Committee of Xiangya Hospital, Central South University (Ethics Approval Number 202209008-2). It was registered with the China Clinical Trial Registry, a primary registry of the World Health Organization’s International Clinical Trials Registry Platform (Registration Number ChiCTR2300068852).

Abstract As cross‐shelf gradients of most properties are typically much steeper than those in the alongshore direction, transport across isobaths tends to be inhibited, particularly at oceanic fronts where cross‐shelf gradients are markedly pronounced. Consequently, variations in cross‐shelf gradients may exert a significant influence on offshore transport; however, this influence is not yet well understood. This study employs reconstructed daily suspended sediment concentration (SSC) data from the Yellow Sea's offshore region to investigate the dynamics of offshore transport. Our analysis on an interannual scale shows that offshore SSC correlates more with temperature gradients at the oceanic front than with winter storms, despite the latter's vital role in causing frontal instability. The observed increase in offshore transport over the past two decades is likely connected to Kuroshio Current warming, which has strengthened the horizontal density gradient at the oceanic front, driving the strengthened offshore transport of coastal sediments during instability episodes.

Abstract Background Mitochondria play crucial roles in the growth, development, and adaptation of plants. Blackcurrant (Ribes nigrum L.) stands out as a significant berry species due to its rich nutritional profile, medicinal properties, and health benefits. Despite its importance, the mitochondrial genome of blackcurrant remains unassembled. Results This study presents the first assembly of the mitochondrial genome of R. nigrum in the Grossulariaceae family. The genome spans 450,227 base pairs (bp) and encompasses 39 protein-coding genes (PCGs), 19 transfer RNAs (tRNAs), and three ribosomal RNAs (rRNAs). Protein-coding regions constitute 8.88% of the entire genome. Additionally, we identified 180 simple sequence repeats, 12 tandem repeats, and 432 pairs of dispersed repeats. Notably, the dispersed sequence R1 (cotig3, 1,129 bp) mediated genome recombination, resulting in the formation of two major conformations, namely master and double circles. Furthermore, we identified 731 C-to-U RNA editing sites within the PCGs. Among these, cox1-2, nad1-2, and nad4L-2 were associated with the creation of start codons, whereas atp6-718 and rps10-391 were linked to termination codons. We also detected fourteen plastome fragments within the mitogenome, constituting 1.11% of the total length. Phylogenetic analysis suggests that R. nigrum might have undergone multiple genomic reorganization and/or gene transfer events, resulting in the loss of two PCGs (rps2 and rps11) during its evolutionary history. Conclusions This investigation unveils the molecular characteristics of the R. nigrum mitogenome, shedding light on its evolutionary trajectory and phylogenetic implications. Furthermore, it serves as a valuable reference for evolutionary research and germplasm identification within the genus.

Abstract In the last decade, laboratory-scale single-junction perovskite solar cells have achieved a remarkable power conversion efficiency exceeding 26.1%. However, the transition to industrial-scale production has unveiled a significant efficiency gap. The central challenge lies in the difficulty of achieving uniform, high-quality perovskite films on a large scale. To tackle this issue, various innovative strategies for manipulating crystallization have emerged in recent years. Based on an in-depth fundamental understanding of the nucleation and growth mechanisms in large-area perovskite films prepared through blade/slot-die coating methods, this review offers a critical examination of crystallization manipulation strategies for large-area perovskite solar modules. Lastly, we explore future avenues aimed at enhancing the efficiency and stability of large-area PSMs, thereby steering the field toward commercially viable applications.

Abstract The function of proteins depends on their correct structure and proper dynamics. Understanding the dynamics of target proteins facilitates drug design and development. However, dynamic information is often hidden in the spatial structure of proteins. It is important but difficult to identify the specific residues that play a decisive role in protein dynamics. Here, we report that a critical glycine residue (Gly463) dominates the motion of threonyl-tRNA synthetase (ThrRS) and the sensitivity of the enzyme to antibiotics. Obafluorin (OB), a natural antibiotic, is a novel covalent inhibitor of ThrRS. The binding of OB induces a large conformational change in ThrRS. Through five crystal structures, biochemical and biophysical analyses, and computational simulations, we found that Gly463 plays an important role in the dynamics of ThrRS. Mutating this flexible residue into more rigid residues did not damage the enzyme’s three-dimensional structure but significantly improved the thermal stability of the enzyme and suppressed its ability to change conformation. These mutations cause resistance of ThrRS to antibiotics that are conformationally selective, such as OB and borrelidin. This work not only elucidates the molecular mechanism of the self-resistance of OB-producing Pseudomonas fluorescens but also emphasizes the importance of backbone kinetics for aminoacyl-tRNA synthetase-targeting drug development.

Abstract Bioengineering and regenerative medicine strategies are promising for the treatment of vascular diseases. However, current limitations inhibit the ability of these approaches to be translated to clinical practice. Here we summarize some of the big bottlenecks that inhibit vascular regeneration in the disease applications of aortic aneurysms, stroke, and peripheral artery disease. We also describe the bottlenecks preventing three-dimensional bioprinting of vascular networks for tissue engineering applications. Finally, we describe emerging technologies and opportunities to overcome these challenges to advance vascular regeneration.

Abstract Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/β-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis.

Abstract Objective Through a randomized controlled trial on older adults with sarcopenia, this study compared the training effects of an AI-based remote training group using deep learning-based 3D human pose estimation technology with those of a face-to-face traditional training group and a general remote training group. Methods Seventy five older adults with sarcopenia aged 60–75 from community organizations in Changchun city were randomly divided into a face-to-face traditional training group (TRHG), a general remote training group (GTHG), and an AI-based remote training group (AITHG). All groups underwent a 3-month program consisting of 24-form Taichi exercises, with a frequency of 3 sessions per week and each session lasting 40 min. The participants underwent Appendicular Skeletal Muscle Mass Index (ASMI), grip strength, 6-meter walking pace, Timed Up and Go test (TUGT), and quality of life score (QoL) tests before the experiment, during the mid-term, and after the experiment. This study used SPSS26.0 software to perform one-way ANOVA and repeated measures ANOVA tests to compare the differences among the three groups. A significance level of p 0.05). The same was in post-term tests (p > 0.05). Conclusion Compared to the pre-experiment, there was no significant difference at the post- experiment in the recovery effects on the muscle quality, physical activity ability, and life quality of patients with sarcopenia between the AI-based remote training group and the face-to-face traditional training group. 3D pose estimation is equally as effective as traditional rehabilitation methods in enhancing muscle quality, functionality and life quality in older adults with sarcopenia. Trial registration The trial was registered in ClinicalTrials.gov (NCT05767710).