As urban areas expand rapidly, the development of public service facilities has become a critical strategy for optimizing urban spatial structures and addressing the diverse, high-quality living needs of residents. This study presents a referable and evidence-based closed-loop framework for evaluating and optimizing public service facilities within the "15-min community life circle," specifically applied to Nanchang, China. By analyzing the spatial distribution, accessibility, and developmental coordination of 28,082 public service facilities within the six districts and three counties of Nanchang, the research findings reveal that: (1) significant spatial heterogeneity exists in the distribution and accessibility of public service facilities within the study area; (2) the overall coverage efficiency of the 24 categories of public service facilities is low, with notable disparities in coverage among different facility types; and (3) a mismatch exists between the supply of public service facilities and the population distribution. Furthermore, by employing a location allocation model and considering the current developmental context of Nanchang City, we propose targeted optimization strategies for areas experiencing supply-demand mismatches. The findings offer decision support for policymakers in formulating targeted urban renewal strategies and have practical implications for promoting the high-quality development of the 15-min living circle.
Flow diverters (FDs) can induce vascular remodeling in nontarget branches of the circle of Willis (CW), yet the hemodynamic drivers of these changes remain unclear. Using in vitro CW models, flow rate alterations were quantified across both target and contralateral CW branches after FD deployment. Four 3-dimensional-printed CW models were created (standard and hypoplastic variants) and integrated into a physiological pulsatile flow loop. Flow rates and pressures were recorded in all major branches before and after sequential deployment of 3 concentric FDs. Eight experiments were performed across the 4 models to capture anatomy-dependent hemodynamic responses. Across all 4 FD configurations, deployment produced significant flow redistribution both in the covered branch and in remote CW vessels. Covered vessels showed progressive flow reductions of up to 14% after 3 FDs, particularly in hypoplastic anatomies. Importantly, contralateral and collateral pathways also demonstrated measurable redistribution: contralateral anterior cerebral artery flow decreased by up to 4.7%, middle cerebral artery flow increased by 2% to 5%, and posterior cerebral artery flow shifted by 3% to 8% depending on the FD location. Several of these compensatory changes reached statistical significance despite occurring in branches not directly covered by the device, underscoring the CW's sensitivity to localized resistance changes. FD placement produced significant, anatomy-dependent changes in branch flow rate and pressures. Hypoplastic models exhibited more pronounced redistribution patterns than standard CW anatomy, highlighting the role of baseline vessel diameter. These findings support a mechanistic explanation for clinically reported post-treatment vascular remodeling.
Synergistic therapy holds significant potential in cancer diagnosis and treatment, yet faces substantial challenges such as nonspecific drug release and tumor multidrug resistance (MDR). Herein, we report a self-assembled DNA nanoplatform (ZCIS QDs@RD) based on CuInS/ZnS QDs (ZCIS QDs) and rolling circle amplification (RCA) for synergistic photothermal therapy (PTT)/chemodynamic therapy (CDT)/chemotherapy (CT). The nanoplatform achieved selective targeting of breast cancer cells by modifying the multivalent AS1411 aptamer. The hydrothermally synthesized ZCIS QDs exhibited excellent fluorescence properties, allowing for targeted imaging of cancer cells. Moreover, under 808 nm laser irradiation, ZCIS QDs demonstrated both photothermal conversion and peroxidase-like activity, thereby contributing to the synergistic therapeutic effects. Furthermore, the long single-stranded DNA generated via RCA offered high programmability, and its assembled structure (RA) served as an efficient carrier for codelivering doxorubicin (Dox) and antisense oligonucleotides (ASO). Under the action of deoxyribonucleases, controlled disassembly and sustained drug release were achieved, effectively reversing the MDR. Experimental results proved that ZCIS QDs@RD could not only identify cancer cells by fluorescence imaging but also realize PTT/CDT/CT multimode synergistic treatment, which provides a strategy for targeted cancer diagnosis and treatment.
The swift spread of pathogenic bacteria via food, air, and water poses severe risks to human health. Conventional detection methods often suffer from time-consuming operations, bulky instruments, and insufficient sensitivity for on-site screening, highlighting an urgent demand for sensitive and visual platforms. Herein, a detection platform (Cas12a-HRCA) was constructed for sensitive pathogen quantification by integrating hyperbranched rolling circle amplification (HRCA), CRISPR/Cas12a system, copper fluorescence nanoparticles (CuNPs) and smartphone-based signal readout. In this strategy, pathogen target-activated CRISPR/Cas12a precisely regulates HRCA initiation, which exponentially generates AT-TA-rich sequences. These products serve as templates for the self-assembly of the fluorescence CuNPs, achieving integrated rapid signal amplification without requiring sample preprocessing steps. Combined with smartphone-based RGB analysis, the platform enables direct, on-site quantitative readout. Cas12a-HRCA demonstrated exceptional performance for S. aureus, with a detection limit of 1 CFU/mL, high specificity, and 91%-106% reliable recovery in spiked milk samples without pre-enrichment or purification, showcasing great potential for point-of-need food safety monitoring. the detection of various pathogenic bacteria in food, clinical or environmental settings.
Hospice patients with Alzheimer's disease and related dementias (ADRD) are more likely to experience a live discharge. This places increased burden on primary caregivers who may be unprepared for this transition and are more likely to be socially isolated. This study explored primary caregivers' "Circle of Support" (CoS) and how social context influences service utilization patterns, perceived support, and experiences of care transitions following a hospice live discharge. Semi-structured interviews were conducted with 32 caregivers and analyzed using thematic analysis. Caregivers described their CoS, how their CoS functioned (or failed to function) post-hospice, and key caregiver and network attributes affecting support use. Findings show that caregivers reporting no changes in their tasks after discharge described more absent CoS functions. Experiences were also influenced by patient location of care and resources availability, suggesting opportunities for targeted interventions to improve caregivers' experiences and outcomes.
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Early-life sevoflurane exposure is associated with long-term cognitive deficits. Given that hippocampal development relies on precise critical windows, disruption of developmental processes during these periods is likely the origin of these impairments. However, the molecular mechanisms underlying sevoflurane-induced perturbations during critical development periods and their progression to lasting cognitive dysfunction remain elusive. Here, we determined that the first three postnatal weeks are a critical window of vulnerability to early-life sevoflurane exposure. Mechanistically, sevoflurane exposure suppressed the physiological upregulation of activity-regulated cytoskeleton-associated protein (Arc; also known as Arg3.1) during the critical period of hippocampal development, a process driven by glycogen synthase kinase-3 beta (GSK3β)-mediated protein degradation. We demonstrated that transient suppression of Arc via hippocampal injection of Arc antisense oligonucleotide (ASO) during the third postnatal week was sufficient to recapitulate the sevoflurane-induced phenotype, impairing microglial synaptic pruning and causing initial synaptic redundancy. This early pathology subsequently evolved into aberrant microglial phagocytic activation in adolescence and adulthood, resulting in excessive synaptic loss and cognitive deficits. Crucially, restoration of Arc expression specifically during this critical period using a doxycycline (Dox)-inducible Tet-On system successfully reversed this pathological pruning trajectory and prevented long-term cognitive impairment. Our findings highlight that Arc upregulation during this critical period is essential for microglial function and synaptic homeostasis, establishing Arc as a time-sensitive therapeutic target for preventing the developmental neurotoxicity associated with pediatric anesthesia. This diagram illustrates the role of the Arc protein in microglial synaptic pruning and cognitive development under physiological conditions (upper panel, blue; Arc is highly expressed during the critical period) and sevoflurane exposure (lower panel, red; Arc expression during the critical period is downregulated). Under normal conditions, Arc is expressed during the critical period and is localized to synapses, where it facilitates the tagging of redundant synapses for elimination. Synaptic pruning peaks during the critical period, followed by further refinement during adolescence, leading to mature cognitive function in adulthood. Neonatal sevoflurane exposure leads to aberrant activation of GSK3β during the critical period. This promotes Arc degradation, thereby disrupting its synaptic localization. This leads to microglial dysfunction in terms of synaptic engulfment. In adolescence, this disruption leads to excessive microglial phagocytosis and significant synaptic loss, ultimately resulting in cognitive deficits. Graphical elements: GSK3β, green circles; Arc, orange circles; phosphorylation site, pale yellow circle containing the letter "P"; C1q, yellow umbrella shapes.
This research investigates the influence of shell and inner tube geometry modifications on the thermal performance of latent heat thermal energy storage (LHTES) systems employing phase change materials (PCMs), aiming to overcome the low thermal conductivity and weak melting zones commonly observed in conventional configurations. Several shell-and-tube configurations with circular, rectangular, and trapezoidal geometries were investigated numerically. The novelty of the present study lies in the combined optimization of both shell and inner tube trapezoidal geometries to enhance natural convection and improve heat distribution inside the PCM domain. Numerical simulations evaluate melting time, enhancement ratio, energy storage density, and mean power for each case. Results indicate that the conventional Circle-Circle configuration has the longest complete melting time (CMT) of 5440 s. Fully trapezoidal shell-and-tube designs significantly enhance heat transfer, with Trapezoidal-Trapezoidal 03 achieving a remarkable reduction of 23.53%, lowering the CMT to 4160 s. The enhancement ratio analysis shows that Trapezoidal-Trapezoidal 03 achieves a maximum improvement of 18%, whereas other trapezoidal configurations attain enhancements between 4% and 13%. The superior performance of trapezoidal geometries is mainly attributed to improved heat distribution toward the lower PCM region, reduced thermal dead zones, and stronger natural convection circulation. Regarding energy performance, Trapezoidal-Trapezoidal 03 achieves a mean power of 735 W, while Circle-Trapezoidal 01 and 02 exhibit the highest energy storage densities of 206.24 and 207.88 kJ/kg, respectively. These findings demonstrate that the optimal configuration depends on the targeted application, whether prioritizing rapid melting or higher energy storage density. The present results may contribute to the design of more efficient thermal energy storage systems for solar thermal and industrial waste heat recovery applications.
Efficient spatial layout of comprehensive stroke centers (CSCs) is crucial for the timely transport of stroke patients to hospitals for effective treatment following symptom onset. However, limited research has focused on the spatial allocation of CSCs. Therefore, this study aimed to evaluate the spatial distribution and accessibility of CSCs in Liaoning Province, China. The closest-facility analysis and location-allocation model were employed to examine spatial accessibility, urban-rural disparities, and 1-hour coverage of the high-risk population under current and simulated CSC distribution scenarios. Key findings include: (1) CSC accessibility in Liaoning Province varies significantly, with better accessibility in major cities and poorer accessibility in mountainous and rural areas. (2) The existing 34 CSCs were mainly located in urban areas, and only 48.41% of townships and 60.63% of the high-risk population in Liaoning province can access them within 1 h. (3) In the optimization scenario, considering only candidate tertiary hospitals extended coverage to 75.63% of the high-risk populations. Integrating both candidate tertiary and secondary hospitals increased coverage in high-risk populations to 89.78%, effectively increasing the accessibility of CSCs, particularly in rural areas, and reducing the urban-rural accessibility gap. These insights shed light on the spatial disparities of CSCs in Liaoning Province and provide a spatial blueprint for establishing a "1-hour gold rescue circle". While improving geographic accessibility is a prerequisite, future policy should also prioritize the capacity building of candidate hospitals to ensure clinical efficacy.
Cryogenic-temperature friction stir processing (CT-FSP) was performed on AA6xxx sheets at 600 RPM and 500 mm/min using in-process liquid N2 cooling to investigate microstructure, precipitate evolution, and the resulting mechanical response. Multiscale characterization EBSD, SEM/EDS and microhardness tests were conducted. CT-FSP produced a highly refined predominantly equiaxed stir zone (SZ) with average grain sizes of approximately 1.6-1.8 µm at the surface and mid-thickness, and slightly coarser grains (~ 4.4 µm) near the bottom and within the thermomechanically affected zone (TMAZ). Dynamic recrystallization, evidenced by a high fraction of high-angle grain boundaries and low KAM, dominates the SZ. The recrystallization fraction varies laterally and through the thickness due to heterogeneous strain and thermal fields. Second phase particles experience mechanical fragmentation, partial solvus dissolution, and rapid reprecipitation during CT-FSP, yielding a finer and more uniformly dispersed distribution in the upper SZ, while coarser Al-Fe-Si and Mg2Si particles persist near the bottom/TMAZ. Deep-learning-based image segmentation reveals that the mean equivalent-circle diameters of Al-Fe-Si and Mg2Si phases decrease from ~ 0.97 µm and 0.80 µm in the as-received sheet to ~ 0.6-0.8 µm locally after CT-FSP, accompanied by reduced nearest-neighbor spacing in the SZ. This localized particles refinement and redistribution, together with extensive DRX, accounts for the combined SZ softening and TMAZ hardening, establishing a clear microstructure-property linkage in cryogenic FSPed AA6xxx sheet.
Accurate 2D characterization of X-ray tube focal spot dimensions (FS) and detector Point Spread Function (PSF) is essential for radiographic quality assurance, yet traditional methods (pinhole, slit cameras) are either limited to 1D characterization or require impractical setups. This article introduces SCOPE-XR, an open-source Python framework that implements and generalizes a previously established reconstruction technique, providing fully automated 2D estimation of FS distributions and detector PSF from a single radiograph of a basic test object. The software is targeted at medical physicists, researchers, and clinical quality control personnel to streamline and enhance routine acceptance testing. SCOPE-XR processes radiographic images to estimate the shape and dimensions of FS and PSF distributions. The underlying algorithm utilizes automatic circle detection, derivation, pseudo-CT reconstruction and incorporates an oversampling strategy to improve PSF reconstruction accuracy at limited sampling densities. The software was validated against both virtually simulated datasets and experimental clinical acquisitions, demonstrating high fidelity in characterizing source morphology and detector responses. SCOPE-XR is implemented in Python and is cross-platform compatible (Windows, macOS, Linux), requiring minimal computational resources. The software accepts standard radiographic image formats (e.g., [DICOM, TIFF, RAW]) as input and outputs 2D emission profiles, quantitative dimensional metrics, and performance plots. A small dataset of virtual and experimental acquisitions is included as an example for benchmarking and reproducibility. The source code, datasets, and comprehensive documentation are publicly accessible via its public repository: https://doi.org/10.15161/oar.it/hrrqs-cn059. SCOPE-XR provides a practical, fully automated alternative to traditional measurement techniques. Its primary clinical and scientific applications include the streamlined evaluation of imaging system performance during acceptance testing, routine quality control, and system design characterization.
Microenvironmental heterogeneity in cultured cells can compromise cell quality, reduce experimental reproducibility, and weaken the confidence of cell therapeutic efficacy. Although micropatterned cell cultures are more homogeneous, conventional micropatterning methods lack flexibility. We develop a micropatterning technology by denaturing extracellular matrix (ECM) proteins in specific areas through heat inactivation using a high-speed laser via a light-responsive polymer layer. We have successfully seeded human induced pluripotent stem cells (hiPSCs) in flexible patterns and examine their neural induction in circular geometries of varying diameters. Size-dependent and cell-autonomous neural structures are formed on this substrate when hiPSCs differentiate into neural lineages in circles of different diameters. This self-organized pattern results from the mitotic orientation and localization of differentiating cells. Furthermore, teratogenic substances can modulate these patterns. Laser-induced heat inactivation of ECM on culture substrates enables lithography-, hydrogel-, and PDMS-free micropatterning, facilitating on-demand regulation of cell-autonomous tissue formation, the effect of teratogenic substances, and precise tissue engineering in regenerative medicine.
To investigate the CT and MRI features of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, aiming to improve the recognition of this disease by clinicians and radiologists and to reduce misdiagnosis and missed diagnosis. Clinical and imaging data of 6 patients with confirmed SAPHO syndrome hospitalized in our hospital from November 2011 to August 2025 were retrospectively analyzed. The cohort included 4 males and 2 females, aged 26-70 years (mean 44.5 ± 19.2 years). All patients underwent both CT and MRI examinations. The distribution of lesions and the imaging features on CT and MRI were analyzed. The anterior chest wall was involved in all 6 patients, including costosternal joint involvement in 6 (100%) and sternoclavicular joint involvement in 4 (66.7%). The typical "bull head sign" was observed in 4 patients. Among a total of 144 vertebrae examined in the 6 patients, CT detected 34 affected vertebrae (23.6%) and MRI detected 51 affected vertebrae (35.4%), predominantly in the thoracic spine. Characteristic CT signs included the "bright corner sign", "half-circle sign", and "round sign". Characteristic MRI signs included the "kissing sign" (present in 80.0% of continuously involved vertebrae) and bone marrow edema. CT was superior in detecting osteosclerosis, while MRI was superior in detecting bone marrow edema. Bilateral sacroiliac joint involvement was present in 3 cases, and the hip joint was involved in 1 case. Three cases had been misdiagnosed as ankylosing spondylitis, psoriatic arthritis, or spinal metastases. Skeletal lesions of SAPHO syndrome predominantly involve the anterior chest wall (the "bull head sign" is characteristic) and the thoracic spine (with continuous vertebral involvement, showing the "bright corner sign" and "kissing sign"). The combined use of CT and MRI facilitates comprehensive evaluation of lesions, and identification of skin lesions can improve the recognition of this disease.
In vivo confocal microscopy is a valuable tool for evaluating corneal subbasal nerve plexus (SBNP). However, lack of standardised, repeatable, and reliable methods is a challenge, particularly in clinical, multi-centre, and longitudinal settings. To address this, we developed a standardised imaging method using the inferior whorl (IW) region of the SBNP as a reference for imaging a predefined 1.5 mm2 central region of interest (ROI). No systematic differences were observed either between the two operators or between test-retest assessments performed by the same operator. A full 400 μm diameter circle around the IW was imaged in 85% of the mosaics. The inter-operator repeatability for the x- and the y-coordinates when defining the centre of the IW was 0.996 (95% CI [0.991, 0.999]) and 0.997 (95% CI [0.994, 0.999]), respectively. For 61% of the mosaics, the ROI was accurately positioned and fully imaged. By anchoring the ROI to the IW, the approach enables more repeatable and anatomically consistent imaging, supporting improved comparability across examinations. While the method shows promise, further refinement and technical development are required to enhance its reliability and robustness.
Cerebral aneurysms (CAs) are pathological dilations of intracranial arteries with high rupture risk, yet the molecular mechanisms driving their formation remain incompletely understood. The Orexin B/OX2R system, known for regulating arousal and metabolism, has recently been implicated in vascular pathology, but its role in CAs has not been explored. Serum Orexin A and B levels were measured in 38 CA patients and 43 healthy controls. A murine CA model (elastase-induced) was established using wild-type (WT) and OX2R knockout (OX2R-/-) mice, with or without Orexin B treatment (30 μg/kg/day for 7 weeks). Aneurysm size, inflammatory mediators (IL-6, MMP-9, MCP-1, E-selectin), macrophage infiltration (CD68), and SP-1 expression were assessed. In vitro studies using human brain microvascular endothelial cells (HBMVECs) examined Ang II-induced OX2R suppression, monocyte adhesion, and SP-1-mediated signaling following Orexin B treatment and SP-1 overexpression. CA patients and mice exhibited significantly reduced serum Orexin B levels (CA patients: 3.21 ± 0.52 vs. controls: 8.56 ± 1.23 pg/mL, p < 0.01), with no change in Orexin A. OX2R expression was downregulated in the circle of Willis of CA mice. Orexin B administration attenuated aneurysm formation in WT mice (size reduction from 3.72 ± 0.469 mm to 1.93 ± 0.252 mm, p < 0.01) but not in OX2R-/- mice. Orexin B suppressed IL-6, MMP-9, MCP-1, and E-selectin expression, reduced CD68+ macrophage infiltration, and decreased SP-1 levels in WT but not OX2R-/- mice. In HBMVECs, Ang II dose-dependently reduced OX2R expression. Orexin B inhibited Ang II-induced monocyte adhesion and SP-1-mediated pro-inflammatory signaling, effects abolished by OX2R siRNA or SP-1 overexpression. The Orexin B/OX2R axis is dysregulated in CAs, and Orexin B protects against CA formation through OX2R-dependent anti-inflammatory mechanisms involving SP-1 suppression. These findings identify the Orexin B/OX2R/SP-1 pathway as a potential therapeutic target for cerebral aneurysms.
To investigate the effect of Angelica sinensis on thymic cortical regeneration in rapamycin-treated mice and its underlying mechanisms. The chemical components of Angelica sinensis were analyzed using high-resolution liquid chromatography-mass spectrometry (LC-MS) and ultra-performance liquid chromatography (UPLC). Seventy-two 6-8-week-old female BALB/c mice were randomly assigned by weight into six groups (n=12 per group): blank control, model control, normal regeneration, and Angelica sinensis small- (1 g/kg), medium- (2 g/kg), and large-dose (4 g/kg) groups. Except for the blank control group, acute thymic involution was induced in all other groups via intraperitoneal injection of rapamycin (1 mg·kg－1·d－1) for 3 consecutive days. After modeling, the Angelica sinensis-treated groups received oral gavage of corresponding doses for 7 days, while the normal regeneration and blank control groups received an equal volume of saline. Body weight and dorsal hair growth were recorded daily. Forelimb grip strength was measured 2 hours after the last administration. Thymic structure and the spatial distribution of thymic epithelial cells (TECs) and thymocytes were assessed by hematoxylin-eosin (HE) and immunofluorescence staining. Development and homeostasis of T-cell subsets in the thymus and peripheral blood were analyzed by flow cytometry and rapid Wright-Giemsa staining. T-cell receptor excision circles (TRECs) in genomic DNA from peripheral blood mononuclear cells were detected by quantitative PCR (qPCR). The mRNA expression levels of thymic function-related genes, inflammatory factors, and Wnt pathway-related genes were measured by quantitative reverse transcription PCR (qRT-PCR). Potential targets and pathways were screened by integrating network pharmacology prediction and molecular docking. Rapamycin successfully induced acute thymic atrophy. The model control group showed an approximately 50% decrease in thymic index (P<0.01), significantly weakened grip strength (P<0.05), and no obvious hair regeneration. Histologically, the thymic cortical area was reduced, with a blurred corticomedullary junction, disrupted continuity of the cortical TEC (cTEC) cytoplasmic process network, early-stage blockade of thymocyte development, disturbed spatial distribution, and inhibited thymic output. Compared with the normal regeneration group, medium and large doses of Angelica sinensis dose-dependently increased the cortical area, significantly enhanced the density of cortical CK8+ TECs and restored the continuity of their cytoplasmic process network (P<0.01), while upregulating the expression of Foxn1 (P<0.01) and its downstream target gene Dll4. Regarding thymocyte development, Angelica sinensis (large dose) significantly increased the proportion of CD3+ TCRβ+ thymocytes (P<0.05), promoted the balanced differentiation of CD4+CD8+ cells into mature single-positive (SP) thymocytes, and re-established normal spatial localization, manifested as increased density of CD8+ and CD4+CD8+ cells in the cortex and reaggregation of TCRβ+ cells in the medulla. Furthermore, Angelica sinensis (medium dose) significantly reduced the mRNA levels of thymic pro-inflammatory factors TNF-α, TGF-β, and IGFBP5 (P<0.05), thereby improving the local inflammatory microenvironment. For peripheral homeostasis, Angelica sinensis intervention maintained and increased the proportion of peripheral blood CD3+ T cells, elevated the percentage of CD34+ hematopoietic stem cells across all dosage groups (P<0.05), and upregulated the expression of the thymic homing factor Ccl25. Mechanistically, network pharmacology predicted the Wnt pathway as a potential target of Angelica sinensis active components. Experimental validation revealed that Angelica sinensis (medium dose) significantly upregulated Wnt4 mRNA expression, inhibited Gsk3β, and increased CTNNB1 (β-catenin) levels in the thymus (P<0.05), indicating activation of the Wnt/CTNNB1/Foxn1 signaling pathway to drive cTEC cytoskeletal repair and thymic regeneration. Angelica sinensis promotes cortical regeneration and functional recovery after rapamycin-induced acute thymic involution by activating the Wnt/CTNNB1/Foxn1 signaling pathway and improving the thymic inflammatory microenvironment, which collaboratively facilitate cortical thymic epithelial cell cytoskeletal repair and hematopoietic stem cell homing. This suggests its potential benefit for counteracting immune aging. 目的: 探讨当归促进雷帕霉素处理后的小鼠胸腺的皮质再生作用及其机制。方法: 采用高分辨液相色谱-质谱联用（LC-MS）、超高效液相色谱（UPLC）分析当归化学成分。6~8周龄雌性BALB/c小鼠72只，按体重随机分为空白对照组、模型对照组、正常再生组及当归小（1 g/kg）、中（2 g/kg）、大剂量组（4 g/kg），每组12只。除空白对照组外，其余各组通过腹腔注射雷帕霉素（1 mg·kg-1·d-1，连续3 d）建立急性胸腺退化模型。造模后，当归各剂量组连续灌胃给药7 d，正常再生组和空白对照组给予等量等渗氯化钠溶液。实验期间每日记录体重及背部毛发生长情况;于末次给药2 h后测定四肢抓力。采用苏木精-伊红（HE）染色和免疫荧光染色评估胸腺结构、胸腺上皮细胞（TEC）及胸腺细胞的空间分布;流式细胞术和快速瑞特-吉姆萨染色染色分析胸腺及外周血T细胞亚群发育及稳态;定量PCR检测小鼠外周血单个核细胞基因组DNA中T细胞受体切除环（TREC）水平;定量逆转录PCR检测小鼠胸腺功能、炎症因子和Wnt通路相关基因表达水平;结合网络药理学预测及分子对接筛选潜在靶点和通路。结果: 雷帕霉素成功诱导急性胸腺萎缩，模型对照组胸腺指数降低约50%（P<0.01），四肢抓力显著减弱（P<0.05）且未观察到明显毛发再生迹象。组织学显示胸腺皮质面积减少，皮髓质分界模糊，皮质TEC胞突网络连续性破坏，胸腺细胞发育早期受阻，空间分布紊乱，胸腺输出受抑制。与正常再生组比较，当归中、大剂量组能剂量依赖性增加胸腺皮质面积，显著提升皮质CK8+胸腺上皮细胞密度并修复其胞突网络连续性（P<0.01），同时上调Foxn1及其下游靶基因Dll4表达（均P<0.05）。在胸腺细胞发育层面，当归（大剂量）显著提升了CD3+TCRβ+胸腺细胞比例（P<0.05），促进CD4+CD8+细胞向功能成熟的单阳性胸腺细胞均衡分化，并重建了胸腺细胞正常空间定位，表现为皮质CD8+及CD4+CD8+细胞密度增加，TCRβ+细胞重新聚集于髓质区。此外，当归（中剂量）显著降低了胸腺促炎因子TNF-α、TGF-β及IGFBP5的mRNA水平（P<0.05），改善局部炎症微环境。在外周稳态方面，当归能维持并增加外周血CD3+T细胞比例，同时各剂量组均能增加CD34+造血干细胞的比例（P<0.05），并上调胸腺归巢因子Ccl25表达。网络药理学分析结果提示，当归活性成分可能靶向Wnt通路;实验验证发现，当归（中剂量）能显著上调胸腺内Wnt4 mRNA表达，抑制Gsk3β，并提高CTNNB1水平（P<0.05），表明其通过激活Wnt/CTNNB1/Foxn1信号通路驱动皮质TEC骨架修复与胸腺再生。结论: 当归通过激活Wnt/CTNNB1/Foxn1信号通路，并改善胸腺炎症微环境，协同促进皮质胸腺上皮细胞骨架修复与造血干细胞归巢，进而有效促进短期雷帕霉素诱导的急性胸腺退化后的皮质再生与功能恢复，可能具有抗免疫衰老的潜在益处。.
This paper introduces a new method for distributed multi-robot formation control, in which the emphasis is placed on combining audio-visual inter-agent sensing with Bluetooth communication. We recommend a hierarchical control, which would include a local formation controller and centralized control for ESP32-based robots. The scheme is based on a two thread architecture with audio processing and display during video playback without sacrificing synchronous motor output. To dynamically change robot positioning, we've developed an adaptive formation system that uses acoustic signatures and visual landmarks obtained in situ. In a time-division multiple access protocol developed for low-latency between robots, communication is carried out by Bluetooth. Experiments have shown that with a line, wedge, and circle, and keeping the shape to within ±15 cm rms error is possible. When control loop frequencies are maintained above 50 Hz, the device achieves audio packet delivery rates of 92% percent. The distributed sensing reduces individual robot energy costs by approximately 34% compared to traditional architectures, measured at 8.2 W versus 12.5 W per robot for the centralized baseline. The system successfully tolerates temporary sensor occlusions of up to 2 seconds through dead-reckoning supported by acoustic observations; extended occlusions are acknowledged as a limitation that accumulates dead-reckoning drift. Field experiments show that the robot swarms of 3 to 12 units are able to be deployed safely, and that the platform can withstand communication disruptions, short-term sensor occlusions, and dynamic challenges.
Synoptic weather systems play a crucial role in transporting moisture to Antarctica. Climate models project significant changes in these systems, including a wintertime intensification and a summertime poleward shift, with implications for Antarctic ice mass balance. Our analysis of CMIP6 model output shows synoptic moisture fluxes across the Antarctic Circle increasing by 2-6% per decade under high-emission scenarios, accounting for 24% of winter and 93% of summer total moisture transport trends. This increase is mainly associated with enhanced eddy moisture anomalies rather than stronger eddy wind anomalies that are often used to gauge storm track activity. Eddy-driven moisture variability also accounts for a substantial fraction of inter-model uncertainty in future projections. Furthermore, using a large-ensemble approach, we show that differences between reanalysis and multi-model mean externally forced trends could possibly be due to natural climatic variability, while potential model biases cannot be excluded.
Immune checkpoint blockade has revolutionized oncology, yet low response rates and acquired resistance-often driven by inadequate Programmed death-ligand 1 (PD-L1) suppression-remain significant barriers. While degradation-based proteolysis-targeting chimeras offer a promising alternative to traditional antibodies, targeting the intracellular and transcriptional drivers of checkpoint expression remains a challenge. We report a programmable, tumor-responsive DNA hydrogel platform, synthesized via rolling circle amplification, designed for the comprehensive, dual-mode modulation of PD-L1. This modular nucleic acid framework codelivers polyvalent aptamer-based lysosome-targeting chimeras (LYTAC mimics) to induce extracellular PD-L1 degradation and siSMARCAL1 to silence the chromatin-remodeling-driven transcriptional activation of PD-L1. By integrating localized, sequential release within the tumor microenvironment, this system achieves a synergistic "degrade-and-silence" effect that effectively dismantles PD-1/PD-L1-mediated immunosuppression while concurrently triggering immunogenic cell death. In murine melanoma models, the hydrogel significantly suppressed primary tumor growth and prevented postoperative recurrence, eliciting a robust and durable systemic antitumor immune response. Our findings establish a versatile, DNA-based materials strategy for programmable protein degradation and multilevel checkpoint modulation, offering a generalizable approach for enhancing the efficacy of cancer immunotherapy.
BRAF mutations are key oncogenic alterations across multiple malignancies, including melanoma, thyroid carcinoma, colorectal cancer, non-small cell lung cancer, glioma, and hairy cell leukemia. The most prevalent variant, BRAF-V600E, induces constitutive activation of the MAPK signaling pathway, promoting tumor progression and influencing therapeutic responsiveness. Accurate detection of BRAF alterations is therefore essential for molecular classification, prognostic assessment, treatment selection, and resistance surveillance. This review summarizes the molecular heterogeneity of BRAF mutations and critically evaluates current diagnostic methodologies. Conventional approaches such as allele-specific PCR and Sanger sequencing are compared with advanced quantitative platforms, including high-resolution melting analysis, droplet digital PCR, and next-generation sequencing, with emphasis on analytical sensitivity, mutation coverage, and clinical applicability. Emerging technologies such as CRISPR-based assays, rolling circle amplification systems, and nanoparticle-based biosensors and point-of-care diagnostic platforms are also discussed for their potential to enhance ultra-sensitive detection, particularly in liquid biopsy settings. These emerging tools are highlighted for their potential to enable ultra-sensitive, rapid, and decentralized mutation detection, particularly in liquid biopsy settings. Key challenges, including intratumoral heterogeneity, low allele-frequency variants, FFPE-associated artifacts, and clonal evolution under therapeutic pressure, are examined within a translational framework. In addition, we examine critical barriers to clinical implementation, including standardization, cost, and global accessibility of molecular diagnostics, and outline potential solutions through scalable technologies and decentralized testing strategies. We propose that optimal BRAF testing requires a mutation subclass-informed and clinically integrated strategy combining comprehensive baseline profiling with longitudinal molecular monitoring. Future diagnostic paradigms will likely integrate multi-omics data and artificial intelligence (AI)-assisted interpretation to refine precision oncology implementation. Looking forward, we propose that optimal BRAF testing will require integration of multi-omics profiling with AI-assisted interpretation, enabling automated variant classification, real-time clinical decision support, and improved prediction of therapeutic response and resistance.