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The high proportion of renewable energy connected to the grid poses new challenges to the safe and economic operation of active distribution networks (ADNs). However, most of the existing research focuses on single-objective optimization or ignores the influence of the uncertainty of renewable energy output and the demand response mechanism, and lacks verification of the scalability of models in large-scale systems. For an active distribution network system with distributed wind power and photovoltaic access, this paper establishes a multi-objective day-ahead optimal dispatching model that takes into account economy, reliability, and safety. The research adopts a scenario-based method and chance-constrained programming (CCP) to handle the uncertainty of wind and solar output. It combines the quasi-Monte Carlo (QMC) method and Kantorovich distance to achieve scenario generation and reduction, and introduces price-based and incentivized demand response mechanisms to form four combined optimization models. The multi-objective optimization solution was carried out based on the multi-objective evolutionary algorithm based on decomposition (MOEA/D), verifying the effectiveness of the proposed method in terms of operation cost, load shedding expectation, and node voltage limit control. The case study is based on the improved IEEE 30-node and 200-node 49-generator systems. The results indicate that this method can effectively balance multiple objectives such as operation costs, load shedding expectations, and node voltage limit; can significantly enhance the renewable energy consumption capacity of active distribution networks; and can provide an effective solution for the optimal dispatching of active distribution networks with a high proportion of renewable energy.

Hydrocephalus commonly occurs after subarachnoid hemorrhage (SAH) and is associated with increased morbidity and disability in patients with SAH. Choroid plexus cerebrospinal fluid (CSF) hypersecretion, obliterative arachnoiditis occluding the arachnoid villi, lymphatic obstruction, subarachnoid fibrosis, and glymphatic system injury are considered the main pathological mechanisms of hydrocephalus after SAH. Although the mechanisms of hydrocephalus after SAH are increasingly being revealed, the clinical prognosis of SAH still has not improved significantly. Further research on SAH is needed to reveal the underlying mechanisms of hydrocephalus and develop translatable therapies. A model that can stably mimic the histopathological and neuroethological features of hydrocephalus is critical for animal experiments. There have been fewer animal studies on hydrocephalus after SAH than on other stroke subtypes. The development of a reproducible and effective model of hydrocephalus after SAH is essential. In this study, we establish a mouse model of SAH that stably mimics brain injury and hydrocephalus after SAH through injections of autologous blood into the cisterna magna via different methods and characterize the model in terms of neurological behavior, histology, imaging, neuronal damage, and white matter damage.

Background Liver fibrosis and fibrosis‐related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor‐β (TGF‐β) is a critical mediator of chronic liver fibrosis, targeting TGF‐β isoforms and receptors lead to unacceptable side effect. This study was designed to explore the antifibrotic effect of Compound kushen injection (CKI), an approved traditional Chinese medicine formula, via a therapeutic strategy of rebalancing TGF‐β/Smad7 signaling. Methods A meta‐analysis was performed to evaluate CKI intervention on viral hepatitis‐induced fibrosis or cirrhosis in clinical randomized controlled trials (RCTs). Mice were given carbon tetrachloride (CCl4) injection or methionine‐choline deficient (MCD) diet to induce liver fibrosis, followed by CKI treatment. We examined the expression of TGF‐β/Smad signaling and typical fibrosis‐related genes in hepatic stellate cells (HSCs) and fibrotic liver tissues by qRT‐PCR, Western blotting, RNA‐seq, immunofluorescence, and immunohistochemistry. Results Based on meta‐analysis results, CKI improved the liver function and relieved liver fibrosis among patients. In our preclinical studies by using two mouse models, CKI treatment demonstrated promising antifibrotic effects and postponed hepatocarcinogenesis with improved liver function and histopathologic features. Mechanistically, we found that CKI inhibited HSCs activation by stabilizing the interaction of Smad7/TGF‐βR1 to rebalance Smad2/Smad3 signaling, and subsequently decreased the extracellular matrix formation. Importantly, Smad7 depletion abolished the antifibrotic effect of CKI in vivo and in vitro. Moreover, matrine, oxymatrine, sophocarpine, and oxysophocarpine were identified as material basis responsible for the antifibrosis effect of CKI. Conclusions Our results unveil the approach of CKI in rebalancing TGF‐β/Smad7 signaling in HSCs to protect against hepatic fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. Our study suggests that CKI can be a candidate for treatment of hepatic fibrosis and related oncogenesis. 1. CKI ‐suppresses liver fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. 2. CKI inhibits HSCs activation by stabilizing the interaction of Smad7/TGFβR1 to rebalance Smad2/Smad3 signaling, acting as an alternative approach to target TGF‐β signaling. 3. High expression of Smad7 and low expression of TGFβR1 in HCC tumors and surrounding normal liver tissues can be tumor suppressive.

Human embryonic stem cell-derived β cells (SC-β cells) hold great promise for treatment of diabetes, yet how to achieve functional maturation and protect them against metabolic stresses such as glucotoxicity and lipotoxicity remains elusive. Our single-cell RNA-seq analysis reveals that ZnT8 loss of function (LOF) accelerates the functional maturation of SC-β cells. As a result, ZnT8 LOF improves glucose-stimulated insulin secretion (GSIS) by releasing the negative feedback of zinc inhibition on insulin secretion. Furthermore, we demonstrate that ZnT8 LOF mutations endow SC-β cells with resistance to lipotoxicity/glucotoxicity-triggered cell death by alleviating endoplasmic reticulum (ER) stress through modulation of zinc levels. Importantly, transplantation of SC-β cells with ZnT8 LOF into mice with preexisting diabetes significantly improves glycemia restoration and glucose tolerance. These findings highlight the beneficial effect of ZnT8 LOF on the functional maturation and survival of SC-β cells that are useful as a potential source for cell replacement therapies. Immature function and fragility hinder application of hESC-derived β cells (SC-β cell) for diabetes cell therapy. Here, the authors identify ZnT8 as a gene editing target to enhance the insulin secretion and cell survival under metabolic stress by abolishing zinc transport in SC-β cells.

BackgroundAntineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer chemotherapeutic agents, render apoptosis immunologically silent. Whether they are dispensable for chemotherapy-induced cell death and the apoptotic clearance of cells in vivo is still elusive.MethodsA rational cell-based anticancer drug library screening was performed to explore the immunogenic apoptosis pathway and therapeutic targets under apoptotic caspase inhibition. Based on this screening, the potential of caspase inhibition in enhancing chemotherapy-induced antitumor immunity and the mechanism of actions was investigated by various cells and mouse models.ResultsHeat shock protein 90 (Hsp90) inhibition activates caspases in tumor cells to produce abundant genomic and mitochondrial DNA fragments and results in cell apoptosis. Meanwhile, it hijacks Caspase-9 signaling to suppress intrinsic DNA sensing. Pharmacological blockade or genetic deletion of Caspase-9 causes tumor cells to secrete interferon (IFN)-β via tumor intrinsic mitochondrial DNA/the second messenger cyclic GMP–AMP (cGAS) /stimulator of interferon genes (STING) pathway without impairing Hsp90 inhibition-induced cell death. Importantly, both Caspase-9 and Hsp90 inhibition triggers an ICD, leading to the release of numerous damage-associated molecular patterns such as high-mobility group box protein 1, ATP and type I IFNs in vitro and remarkable antitumor effects in vivo. Moreover, the combination treatment also induces adaptive resistance by upregulating programmed death-ligand 1 (PD-L1). Additional PD-L1 blockade can further overcome this acquired immune resistance and achieve complete tumor regression.ConclusionsBlockade of Caspase-9 signaling selectively provokes Hsp90-based chemotherapy-mediated tumor innate sensing, leading to CD8+ T cell-dependent tumor control. Our findings implicate that pharmacological modulation of caspase pathway increases the tumor-intrinsic innate sensing and immunogenicity of chemotherapy-induced apoptosis, and synergizes with immunotherapy to overcome adaptive resistance.

The main challenge of Multiple Object Tracking (MOT) is that there is great uncertainty in data association when using the tracked predicted values and tracked trajectories. Meanwhile, the MOT is complex and time‐consuming. When equipment resources are limited or real‐time requirement is high, its application is very limited. Therefore, we propose a Lightweight Deep Appearance Embedding (LDAE) to assist the association of trajectories. Firstly, in addition to motion information in data association, we also introduce more discriminative appearance features to participate in the affinity measure to effectively distinguish similar targets. Secondly, according to the idea of feature mapping, we design a lightweight deep appearance embedding module. It can help extract appearance features with less computation. Finally, we propose a simulated occlusion strategy for the training of the LDAE, which helps improve the ability to recognise different targets in dense scenes. The LDAE dramatically reduces the computational cost and improves the accuracy of data association. Extensive experiments are conducted on the MOT datasets (MOT16, MOT17 and MOT20), which prove that the LDAE outperforms several state‐of‐the‐art trackers in the tracking accuracy and anti‐occlusion performance. Furthermore, we apply the LDAE to escalators, which can achieve fast and stable tracking effect.

Efficient reprogramming of pancreatic acinar cells in vivo generates cells that mature toward a beta cell phenotype over many months. Direct lineage conversion is a promising approach to generate therapeutically important cell types for disease modeling and tissue repair. However, the survival and function of lineage-reprogrammed cells in vivo over the long term has not been examined. Here, using an improved method for in vivo conversion of adult mouse pancreatic acinar cells toward beta cells, we show that induced beta cells persist for up to 13 months (the length of the experiment), form pancreatic islet–like structures and support normoglycemia in diabetic mice. Detailed molecular analyses of induced beta cells over 7 months reveal that global DNA methylation changes occur within 10 d, whereas the transcriptional network evolves over 2 months to resemble that of endogenous beta cells and remains stable thereafter. Progressive gain of beta-cell function occurs over 7 months, as measured by glucose-regulated insulin release and suppression of hyperglycemia. These studies demonstrate that lineage-reprogrammed cells persist for >1 year and undergo epigenetic, transcriptional, anatomical and functional development toward a beta-cell phenotype.

Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific cell subtypes. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin+ β-cells, glucagon+ α-cells, and somatostatin+ δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprograms pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells, and also promotes δ-specification in the absence of other factors. δ-specification is in turn suppressed by Mafa and Pdx1 during α- and β-cell induction. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. In mammals, the pancreas is responsible for controlling blood sugar by secreting insulin from specialized β-cells. Other cells in the pancreas, called δ-cells and α-cells, secrete other hormones to assist the β-cells. Diabetes is caused when this system breaks down: either the body attacks its own β-cells (type I diabetes), or the body stops responding properly to insulin (type II). Type I diabetes is usually treated with insulin injections, but there is increasing interest in the possibility of replacing the defective β-cells instead. Building on previous work in which a fourth type of pancreatic cell, called an acinar cell, was reprogrammed to become a β-cell, Li et al. have now shown that the same technique can be used to produce α- and δ-cells as well. Just as the reprogrammed β-cells secreted insulin, like real β-cells, the reprogrammed α- and δ-cells also behaved like real α- and δ-cells. The reprogramming technique relies on using a combination of three transcription factors—which are called Ngn3, Pdx1 and Mafa—to treat the acinar cells from mice. Previously, it was shown that using a combination of all three transcription factors reprogrammed the acinar cells to become β-cells. Now, Li et al. show that the Ngn3 transcription factor on its own appears to suppress certain genes that are usually expressed in acinar cells, and goes on to cause the acinar cells to become δ-cells. However, a combination of Ngn3 and Mafa produces a mixture of α- and δ-cells. The next challenge is to adapt this reprogramming technique to generate different types of hormone secreting cells from human tissue sources in order to explore its therapeutic potential.

Traditional positioning and pointing mechanisms often face limitations in simultaneously achieving high speed and high resolution, and their travel range is typically constrained. To overcome these challenges, we propose a novel positioning and pointing mechanism driven by piezoelectric ceramics in this study. This mechanism is capable of achieving both high speed and high resolution by using two driving principles: resonance and stick-slip. This paper will focus on analyzing the stick-slip driving principle. We propose a configuration of the drive module within the positioning and pointing mechanism. By applying a low-frequency sawtooth wave excitation to the piezoelectric ceramics, the mechanism achieves high resolution based on the stick-slip driving principle. First, a simplified dynamic model of the drive module is established. The motion process of the drive module in stick-slip driving is divided into the stick phase and slip phase. With static and transient dynamic analyses conducted for each phase, the relationship between the output shaft angle, resolution, and driving voltage is derived. It is observed that during the stick phase, the output shaft angle and the driving voltage exhibit an approximately linear relationship, while in the slip phase, the output shaft angle and the driving voltage display nonlinearity due to impact forces and vibrations. Finally, a prototype of the positioning and pointing mechanism is designed, and an experimental platform is constructed to test the resolution of the prototype. We construct a prototype of a dual-axis positioning and pointing mechanism composed of multiple drive modules and conduct resolution tests using two control methods: synchronous control and independent control. When synchronous control is used, the output shaft achieves a resolution of 0.38 , while with independent control, the resolution of the output shaft reaches 0.0276 . The research results show that the positioning and pointing mechanism proposed in this study achieves high resolution through stick-slip driving principle, offering a novel approach for the advancement of such mechanisms.

Joint injuries represent a significant clinical challenge with limited regenerative options. Three-dimensional (3D) bioprinting has emerged as a transformative technology, enabling the precise fabrication of patient-specific, anatomically matched, multilayered scaffolds that replicate the complex structure and gradient of natural joint tissues. This review comprehensively summarizes advances in bioprinting techniques, cell sources, and biomaterial formulations, emphasizing cell-laden bioinks composed of biomaterials and viable cells to create functional, bioactive constructs. Beyond basic fabrication, we evaluate the functional performance of bioprinted cartilage, bone, and ligaments, and we discuss strategies for engineering osteochondral interfaces and ligament–bone interfaces to support biomimetic mechanical properties and tissue integration. We further compare major printing modalities, including extrusion-based printing, inkjet, and laser-assisted bioprinting, and we discuss how modality-specific trade-offs in resolution, viscosity window, and cell stress influence construct fidelity and repair outcomes. In addition, we examine biofunctionalization strategies that incorporate growth factors, stem cells, and exosomes to enhance regenerative signaling and matrix remodeling. Notably, 3D bioprinting for joint regeneration is transitioning from bench to bedside, and we detail the current landscape of clinical translation, including commercialized products like Nanochon and active clinical trials for knee and hip repair. However, challenges such as insufficient vascularization and the mechanical performance of the printed constructions remain significant hurdles for clinical translation. Overall, this work underscores the potential of personalized 3D bioprinted scaffolds to advance joint tissue engineering and clarifies key directions for integrating these technologies into clinical practice.