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To accurately estimate the 6D pose of objects, most methods employ a two-stage algorithm. While such two-stage algorithms achieve high accuracy, they are often slow. Additionally, many approaches utilize encoding-decoding to obtain the 6D pose, with many employing bilinear sampling for decoding. However, bilinear sampling tends to sacrifice the accuracy of precise features. In our research, we propose a novel solution that utilizes implicit representation as a bridge between discrete feature maps and continuous feature maps. We represent the feature map as a coordinate field, where each coordinate pair corresponds to a feature value. These feature values are then used to estimate feature maps of arbitrary scales, replacing upsampling for decoding. We apply the proposed implicit module to a bidirectional fusion feature pyramid network. Based on this implicit module, we propose three network branches: a class estimation branch, a bounding box estimation branch, and the final pose estimation branch. For this pose estimation branch, we propose a miniature dual-stream network, which estimates object surface features and complements the relationship between 2D and 3D. We represent the rotation component using the SVD (Singular Value Decomposition) representation method, resulting in a more accurate object pose. We achieved satisfactory experimental results on the widely used 6D pose estimation benchmark dataset Linemod. This innovative approach provides a more convenient solution for 6D object pose estimation.

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BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex vascular disorder characterized by the progressive dilation of the abdominal aorta, with a high risk of rupture and mortality. Understanding the cellular interactions and molecular mechanisms underlying AAA development is critical for identifying potential therapeutic targets. METHODS: This study utilized datasets GSE197748, GSE164678 and GSE183464 from the GEO database, encompassing bulk and single-cell RNA sequencing data from AAA and control samples. We performed principal component analysis, differential expression analysis, and functional enrichment analysis to identify key pathways involved in AAA. Cell-cell interactions were investigated using CellPhoneDB, focusing on fibroblasts, vascular smooth muscle cells (VSMCs), and macrophages. We further validated our findings using a mouse model of AAA induced by porcine pancreatic enzyme infusion, followed by gene expression analysis and co-immunoprecipitation experiments. RESULTS: Our analysis revealed significant alterations in gene expression profiles between AAA and control samples, with a pronounced immune response and cell adhesion pathways being implicated. Single-cell RNA sequencing data highlighted an increased proportion of pro-inflammatory macrophages, along with changes in the composition of fibroblasts and VSMCs in AAA. CellPhoneDB analysis identified critical ligand-receptor interactions, notably collagen type I alpha 1 chain (COL1A1)/COL1A2-CD18 and thrombospondin 1 (THBS1)-CD3, suggesting complex communication networks between fibroblasts and VSMCs. In vivo experiments confirmed the upregulation of these genes in AAA mice and demonstrated the functional interaction between COL1A1/COL1A2 and CD18. CONCLUSION: The interaction between fibroblasts and VSMCs, mediated by specific ligand-receptor pairs such as COL1A1/COL1A2-CD18 and THBS1-CD3, plays a pivotal role in AAA pathogenesis.

Asunto(s)

Aneurisma de la Aorta Abdominal , Músculo Liso Vascular , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/metabolismo , Animales , Ratones , Análisis de la Célula Individual/métodos , Humanos , Análisis de Secuencia de ARN/métodos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Macrófagos/metabolismo , Progresión de la Enfermedad , Fibroblastos/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Perfilación de la Expresión Génica/métodos , Comunicación Celular/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo

RESUMEN

Color-changing melons are a kind of cucurbit plant that combines ornamental and food. With the aim of increasing the efficiency of harvesting Color-changing melon fruits while reducing the deployment cost of detection models on agricultural equipment, this study presents an improved YOLOv8s network approach that uses model pruning and knowledge distillation techniques. The method first merges Dilated Wise Residual (DWR) and Dilated Reparam Block (DRB) to reconstruct the C2f module in the Backbone for better feature fusion. Next, we designed a multilevel scale fusion feature pyramid network (HS-PAN) to enrich semantic information and strengthen localization information to enhance the detection of Color-changing melon fruits with different maturity levels. Finally, we used Layer-Adaptive Sparsity Pruning and Block-Correlation Knowledge Distillation to simplify the model and recover its accuracy. In the Color-changing melon images dataset, the mAP0.5 of the improved model reaches 96.1%, the detection speed is 9.1% faster than YOLOv8s, the number of Params is reduced from 6.47M to 1.14M, the number of computed FLOPs is reduced from 22.8GFLOPs to 7.5GFLOPs. The model's size has also decreased from 12.64MB to 2.47MB, and the performance of the improved YOLOv8 is significantly more outstanding than other lightweight networks. The experimental results verify the effectiveness of the proposed method in complex scenarios, which provides a reference basis and technical support for the subsequent automatic picking of Color-changing melons.

RESUMEN

Background: Parkinson's disease (PD) is a common degenerative disease caused by abnormal accumulation of α-synuclein. The glymphatic pathway is essential for removing macromolecular proteins including α-synuclein from the brain, which flows into deep cervical lymph nodes (DCLNs) through meningeal lymphatics. As a terminal station for the cerebral lymphatic system drainage, DCLNs can be easily assessed clinically. Objectives: Although the drainage function of the cerebral lymphatic system is impaired in PD, the correlation between DCLNs and PD remains unknown. Design: Single-center retrospective cross-sectional study. Methods: The size of the DCLNs were measured using ultrasound. The Movement Disorder Society Sponsored Revision Unified Parkinson's Disease Rating Scale and other scales were used to assess PD motor and non-motor symptoms. Results: Compared with the healthy control (HC) and the atypical Parkinson's disease (AP) groups, the size of the second and third DCLNs in the Parkinson's disease (PD) group was significantly smaller (P < .05). The width diameter of the third DCLN (DCLN3(y)) was significantly smaller in the PD group than in the AP group (P = .014). DCLN3(y) combined with a variety of clinical features improved the sensitivity of AP identification (sensitivity = .813). Conclusion: DCLNs were able to distinguish HC, PD and AP and were mainly located in Robbins ΙΙA level. PD and AP were associated with different factors that influenced the size of the DCLNs. DCLN3(y) plays an important role in differentiating PD from AP, which, combined with other clinical features, has the ability to distinguish PD from AP; in particular, the sensitivity of AP diagnosis was improved.

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Deep cervical lymph nodes, a potential marker for the diagnosis of PD and AP. Deep cervical lymph nodes (DCLNs) were able to distinguish HC, PD and AP and were mainly located in Robbins ΙΙA level. PD and AP were associated with different factors that influenced the size of the DCLNs. DCLN3(y) plays an important role in differentiating PD from AP, which, combined with other clinical features, has the ability to distinguish PD from AP; in particular, the sensitivity of AP diagnosis was improved. DCLN has potential diagnostic value in differentiating PD from AP.

RESUMEN

Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer's disease. Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular reactive oxygen species level but selectively reduced the expression of apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes, the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysteinyl leukotrienes but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD-mediated reduction of BACE1. The potential mechanism was related to AKT activity, as the protein level of phosphorylated AKT was significantly reduced by silencing of MGST3 and RGS4, and the AKT inhibitor abolished the effect of MGST3/RGS4 on phosphorylated AKT and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream AKT signaling pathway.

Asunto(s)

Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Glutatión Transferasa , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas c-akt , Proteínas RGS , Transducción de Señal , Proteínas RGS/metabolismo , Proteínas RGS/genética , Humanos , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apoptosis , Péptidos beta-Amiloides/metabolismo , Animales

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Vascular calcification is frequently seen in patients with chronic kidney disease (CKD), and significantly increases cardiovascular mortality and morbidity. Sirt7, a NAD+-dependent histone deacetylases, plays a crucial role in cardiovascular disease. However, the role of Sirt7 in vascular calcification remains largely unknown. Using in vitro and in vivo models of vascular calcification, this study showed that Sirt7 expression was significantly reduced in calcified arteries from mice administered with high dose of vitamin D3 (vD3). We found that knockdown or inhibition of Sirt7 promoted vascular smooth muscle cell (VSMC), aortic ring and vascular calcification in mice, whereas overexpression of Sirt7 had opposite effects. Intriguingly, this protective effect of Sirt7 on vascular calcification is dependent on its deacetylase activity. Unexpectedly, Sirt7 did not alter the osteogenic transition of VSMCs. However, our RNA-seq and subsequent studies demonstrated that knockdown of Sirt7 in VSMCs resulted in increased intracellular reactive oxygen species (ROS) accumulation, and induced an Nrf-2 mediated oxidative stress response. Treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly attenuated the inhibitory effect of Sirt7 on VSMC calcification. Furthermore, we found that knockdown of Sirt7 delayed cell cycle progression and accelerated cellular senescence of VSMCs. Taken together, our results indicate that Sirt7 regulates vascular calcification at least in part through modulation of ROS and cellular senescence of VSMCs. Sirt7 may be a potential therapeutic target for vascular calcification.

Asunto(s)

Senescencia Celular , Músculo Liso Vascular , Miocitos del Músculo Liso , Estrés Oxidativo , Especies Reactivas de Oxígeno , Sirtuinas , Calcificación Vascular , Animales , Calcificación Vascular/patología , Calcificación Vascular/metabolismo , Calcificación Vascular/genética , Especies Reactivas de Oxígeno/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratones , Sirtuinas/metabolismo , Sirtuinas/genética , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Masculino , Colecalciferol/farmacología , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Ratones Endogámicos C57BL , Células Cultivadas

RESUMEN

The elevated levels of lactate in tumor tissue play a pivotal role in fostering an immunosuppressive microenvironment. Therefore, efficiently reducing lactate levels to reprogram tumor immune microenvironment (TIM) is considered a crucial step for boosted immunotherapy. Here, a high-lactate-metabolizing photosynthetic bacteria (LAB-1) is selectively screened for TIM reprogramming, which then improves the efficacy of tumor immunotherapy. The culture medium for LAB-1 screening is initially developed through an orthogonal experiment, simulating the tumor microenvironment (TME) and utilizing lactate as the sole organic carbon source. As demonstrated in a murine 4T1 model, LAB-1 colonizes the TME selectively, resulting in a significant reduction in lactate levels and a subsequent increase in pH values within the tumor tissue. Furthermore, single-cell RNA sequencing analysis reveals that LAB-1 effectively reprograms the TIM, thereby enhancing the effectiveness of antitumor immune therapy. This approach of utilizing lactate-consuming bacteria represents a potent tool for augmenting tumor immunotherapy efficiency.

RESUMEN

This study delves into the factors influencing the willingness of rural land transfers in different terrain areas, aiming to promote the improvement of land transfer institutions and accelerate the process of scale farming. Based on rural survey data from Anhui and Qinghai provinces in China, this research uses geographical detector and Binary Logistic Model to explore the differential factors affecting the willingness of farmers to participate in land contract transfer in the first and third terrain areas of China. The study examines four dimensions, including individual characteristics, family endowments, social support strategies, and geographical environment. The findings reveal the following: (1) By comparing the mean values, standard deviations, and coefficients of variation of the data from both provinces, it is evident that the indicators of individual characteristics, family endowments, social support strategies, and geographical environment differ significantly between the two provinces. This indicates substantial disparities in the basic attributes of farmers and their living environments. (2) The single-factor explanatory power significantly influencing farmers' willingness to engage in land transfer varies considerably and is statistically significant at the 1% level. The types of interaction between two factors mainly include dual-factor enhancement, nonlinear enhancement, single-factor nonlinear attenuation, and nonlinear attenuation. (3) There are commonalities and differences in the factors that significantly influence farmers' willingness to participate in land transfer in the two provinces. Common factors influencing farmers' land transfer willingness in both provinces include: the educational level of household heads, the health status of household heads, the number of family laborers, the arable land area, the differentiation of agricultural management objectives, the proportion of agricultural operating income, labor service economy, and relocation policies. Factors showing different influences include: the age of household heads, school-age children, the number of family members engaged in different occupations, the proportion of income from off-farm employment, minimum guarantee policies credit support, location distance, and terrain undulation. Therefore, in formulating land transfer policies, the government should prioritize significant driving factors influencing farmers' decision-making behavior in different regions. It is essential to develop and implement land transfer policies tailored to local conditions with the primary goal of safeguarding the rights and interests of the principal stakeholders, thus achieving sustainable land utilization.

Asunto(s)

Agricultura , Agricultores , Población Rural , China , Humanos , Encuestas y Cuestionarios , Agricultores/psicología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Factores Socioeconómicos

RESUMEN

Color-changing melon is an ornamental and edible fruit. Aiming at the problems of slow detection speed and high deployment cost for Color-changing melon in intelligent agriculture equipment, this study proposes a lightweight detection model YOLOv8-CML.Firstly, a lightweight Faster-Block is introduced to reduce the number of memory accesses while reducing redundant computation, and a lighter C2f structure is obtained. Then, the lightweight C2f module fusing EMA module is constructed in Backbone to collect multi-scale spatial information more efficiently and reduce the interference of complex background on the recognition effect. Next, the idea of shared parameters is utilized to redesign the detection head to simplify the model further. Finally, the α-IoU loss function is adopted better to measure the overlap between the predicted and real frames using the α hyperparameter, improving the recognition accuracy. The experimental results show that compared to the YOLOv8n model, the parametric and computational ratios of the improved YOLOv8-CML model decreased by 42.9% and 51.8%, respectively. In addition, the model size is only 3.7 MB, and the inference speed is improved by 6.9%, while mAP@0.5, accuracy, and FPS are also improved. Our proposed model provides a vital reference for deploying Color-changing melon picking robots.

RESUMEN

Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral ß-amyloid protein (Aß) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of ß-amyloid converting enzyme 1 (BACE1) and Aß. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 ß (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment.

Asunto(s)

Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Proteínas de Unión al ARN , Proteínas tau , Animales , Proteínas tau/metabolismo , Proteínas tau/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Ratones , Fosforilación , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/genética , Humanos , Ratones Transgénicos , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Células Cultivadas , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/genética

RESUMEN

Labile organic matter (OM) immobilized by secondary iron (Fe) minerals from chemodenitrification may be an effective way to immobilize organic carbon (OC). However, the underlying mechanisms of coupled chemodenitrification and OC sequestration are poorly understood. Here, OM immobilization by secondary Fe minerals from chemodenitrification was investigated at different C/Fe ratios. Kinetics of Fe(II) oxidation and nitrite reduction rates decreased with increasing C/Fe ratios. Despite efficient sequestration, the immobilization efficiency of OM by secondary minerals varied with the C/Fe ratios. Higher C/Fe ratios were conducive to the formation of ferrihydrite and lepidocrocite, with defects and nanopores. Three contributions, including inner-core Fe-O and edge- and corner-shared Fe-Fe interactions, constituted the local coordination environment of mineral-organic composites. Microscopic analysis at the molecular scale uncovered that labile OM was more likely to combine with secondary minerals with poor crystallinity to enhance its stability, and OM distributed within nanopores and defects had a higher oxidation state. After chemodenitrification, high molecular weight substances and substances high in unsaturation or O/C ratios including phenols, polycyclic aromatics, and carboxylic compounds exhibited a stronger affinity to Fe minerals in the treatments with lower C/Fe ratios. Collectively, labile OM immobilization can occur during chemodenitrification. The findings on OM sequestration coupled with chemodenitrification have significant implications for understanding the long-term cycling of Fe, C, and N, providing a potential strategy for OM immobilization in anoxic soils and sediments.

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Hierro , Minerales , Minerales/química , Hierro/química , Oxidación-Reducción , Carbono/química , Cinética

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Despite the exciting promise of cancer immunotherapy in the clinic, immune checkpoint blockade therapy and T cell-based therapies are often associated with low response rates, intrinsic and adaptive immune resistance, and systemic side effects. CRISPR-Cas-based genome editing appears to be an effective strategy to overcome these unmet clinical needs. As a safer delivery platform for the CRISPR-Cas system, non-viral nanoformulations have been recently explored to target tumor cells and immune cells, aiming to improve cancer immunotherapy on a gene level. In this review, we summarized the efforts of non-viral vector-based CRISPR-Cas-mediated genome editing in tumor cells and immune cells for cancer immunotherapy. Their design rationale and specific applications were highlighted.

Asunto(s)

Sistemas CRISPR-Cas , Edición Génica , Inmunoterapia , Neoplasias , Edición Génica/métodos , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/genética , Inmunoterapia/métodos , Animales , Vectores Genéticos

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In conventional clinical disease diagnosis and screening based on biomarker detection, most analysis samples are collected from serum, blood. However, these invasive collection methods require specific instruments, professionals, and may lead to infection risks. Additionally, the diagnosis process suffers from untimely results. The identification of skin-related biomarkers plays an unprecedented role in early disease diagnosis. More importantly, these skin-mediated approaches for collecting biomarker-containing biofluid samples are noninvasive or minimally invasive, which is more preferable for point-of-care testing (POCT). Therefore, skin-based biomarker detection patches have been promoted, owing to their unique advantages, such as simple fabrication, desirable transdermal properties and no requirements for professional medical staff. Currently, the skin biomarkers extracted from sweat, interstitial fluid (ISF) and wound exudate, are achieved with wearable sweat patches, transdermal MN patches, and wound patches, respectively. In this review, we detail these three types of skin patches in biofluids collection and diseases-related biomarkers identification. Patch classification and the corresponding manufacturing as well as detection strategies are also summarized. The remaining challenges in clinical applications and current issues in accurate detection are discussed for further advancement of this technology (Scheme 1).

Asunto(s)

Biomarcadores , Técnicas Biosensibles , Técnicas Analíticas Microfluídicas , Piel , Humanos , Biomarcadores/sangre , Biomarcadores/análisis , Técnicas Biosensibles/métodos , Técnicas Biosensibles/instrumentación , Líquidos Corporales/química , Diseño de Equipo , Líquido Extracelular/química , Pruebas en el Punto de Atención , Piel/química , Piel/patología , Sudor/química , Técnicas Analíticas Microfluídicas/métodos , Parche Transdérmico

RESUMEN

Effectively addressing retinal issues represents a pivotal aspect of blindness-related diseases. Novel approaches involving reducing inflammation and rebalancing the immune response are paramount in the treatment of these conditions. This study delves into the potential of a nanogel system comprising polyethylenimine-benzene boric acid-hyaluronic acid (PEI-PBA-HA). We have evaluated the collaborative impact of cerium oxide nanozyme and chemokine CX3CL1 protein for targeted immunomodulation and retinal protection in uveitis models. Our nanogel system specifically targets the posterior segment of the eyes. The synergistic effect in this area reduces oxidative stress and hampers the activation of microglia, thereby alleviating the pathological immune microenvironment. This multifaceted drug delivery system disrupts the cycle of oxidative stress, inflammation, and immune response, suppressing initial immune cells and limiting local retinal structural damage induced by excessive immune reactions. Our research sheds light on interactions within retinal target cells, providing a promising avenue for the development of efficient and innovative drug delivery platforms.

Asunto(s)

Cerio , Quimiocina CX3CL1 , Nanogeles , Uveítis , Animales , Cerio/química , Cerio/farmacología , Uveítis/tratamiento farmacológico , Nanogeles/química , Quimiocina CX3CL1/metabolismo , Ratas , Retina/efectos de los fármacos , Retina/metabolismo , Inmunomodulación/efectos de los fármacos , Modelos Animales de Enfermedad , Polietileneimina/química , Estrés Oxidativo/efectos de los fármacos , Ácido Hialurónico/química , Masculino , Polietilenglicoles

RESUMEN

INTRODUCTION: Sympathetic hyperinnervation plays an important role in modulating the vascular smooth muscle cell (VSMC) phenotype and vascular diseases, but its role in abdominal aortic aneurysm (AAA) is still unknown. OBJECTIVES: This study aimed to investigate the role of sympathetic hyperinnervation in promoting AAA development and the underlying mechanism involved. METHODS: Western blotting and immunochemical staining were used to detect sympathetic hyperinnervation. We performed sympathetic denervation through coeliac ganglionectomy (CGX) and 6-OHDA administration to understand the role of sympathetic hyperinnervation in AAA and investigated the underlying mechanisms through transcriptome and functional studies. Sema4D knockout (Sema4D-/-) mice were utilized to determine the involvement of Sema4D in inducing sympathetic hyperinnervation and AAA development. RESULTS: We observed sympathetic hyperinnervation, the most important form of sympathetic neural remodeling, in both mouse AAA models and AAA patients. Elimination of sympathetic hyperinnervation by CGX or 6-OHDA significantly inhibited AAA development and progression. We further revealed that sympathetic hyperinnervation promoted VSMC phenotypic switching in AAA by releasing extracellular ATP (eATP) and activating eATP-P2rx4-p38 signaling. Moreover, single-cell RNA sequencing revealed that Sema4D secreted by osteoclast-like cells induces sympathetic nerve diffusion and hyperinnervation through binding to Plxnb1. We consistently observed that AAA progression was significantly ameliorated in Sema4D-deficient mice. CONCLUSIONS: Sympathetic hyperinnervation driven by osteoclast-like cell-derived Sema4D promotes VSMC phenotypic switching and accelerates pathological aneurysm progression by activating the eATP/P2rx4/p38 pathway. Inhibition of sympathetic hyperinnervation emerges as a potential novel therapeutic strategy for preventing and treating AAA.

RESUMEN

BACKGROUND: MRG002 is a novel HER2-targeted antibody-drug conjugate being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2-positive urothelial carcinoma patients. METHODS: This is an open-label, single-arm, multicenter phase II study. Eligibility criteria included: histologically confirmed HER2 IHC 2 + or 3 + UC, prior received ≥ 1 standard treatment. Patients in this study received MRG002 every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST 1.1. RESULTS: As of February 24, 2023, a total of 43 patients were enrolled. The median age was 60. 9 patients were dosed at 2.6 mg/kg and 34 patients were dosed at 2.2 mg/kg. At baseline, most patients (29/43) received ≥ 2 lines of treatment and 35 (81.4%) patients had prior ICI therapy. FISH test was performed in 41 patients and 9 (22.0%) were positive. By the cut-off date, 41 patients were evaluable and the ORR was 53% (95%CI：38.9%-67.5%), with 6.9% CR, and the DCR was 83.7% (95%CI：70.0%-91.9%). The median PFS and OS for the 43 patients were 7.0 months (95%CI：5.4-NE) and 14.9 months (95%CI：11.9-NE), respectively. The ORR was 77.8% in 9 patients with positive HER2 FISH results. Most common treatment-related AEs were anemia (51.2%), alopecia (44.2%) and neutropenia (39.5%); most were grade 1 or 2. CONCLUSION: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients. MRG002 at 2.2 mg/kg was well tolerated with a manageable toxicity.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Inmunoconjugados , Receptor ErbB-2 , Humanos , Femenino , Masculino , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Anciano , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Adulto , Anciano de 80 o más Años , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario

RESUMEN

BACKGROUND: Serum lactate dehydrogenase to albumin ratio (LAR) is associated with poor outcomes in malignancy and pneumonia. However, there are few studies suggesting that LAR is associated with the occurrence of acute kidney injury (AKI) in patients with sepsis, which was investigated in this study. METHODS: We conducted a retrospective cohort study based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary outcome was the occurrence of AKI within 2 days and 7 days. Multivariable logistic regression models were used to calculate odds ratios to validate the association between LAR and AKI, in-hospital mortality, RRT use, and recovery of renal function, respectively. RESULTS: A total of 4010 participants were included in this study. The median age of the participants was 63.5 years and the median LAR was 10.5. After adjusting for confounding variables, patients in the highest LAR quartile had a higher risk of AKI than those in the lowest LAR quartile within 2 days and 7 days, with odds ratios of 1.37 (95% confidence interval [CI]: 1.23-1.52) and 1.95 (95% CI: 1.72-2.22), respectively. The adjusted odds of AKI within 2 and 7 days were 1.16 (95% CI: 1.12-1.20) and 1.29 (95% CI: 1.24-1.35) for each 1 unit increase in LAR(log2), respectively. CONCLUSION: This study demonstrated that elevated LAR was associated with poor prognosis in patients with sepsis. The risk of AKI and in-hospital mortality increased, the need for RRT increased, and the chance of recovery of renal function decreased with the increase of LAR.

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Lesión Renal Aguda , Mortalidad Hospitalaria , Sepsis , Humanos , Lesión Renal Aguda/sangre , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/diagnóstico , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Femenino , Sepsis/complicaciones , Sepsis/sangre , Anciano , L-Lactato Deshidrogenasa/sangre , Biomarcadores/sangre , Factores de Riesgo , Albúmina Sérica Humana/análisis , Terapia de Reemplazo Renal

RESUMEN

Cold atmospheric plasma (CAP) is a unique form of physical plasma that has shown great potential for cancer therapy. CAP uses ionized gas to induce lethal oxidative stress on cancer cells; however, the efficacy of CAP therapy continues to be improved. Here, we report an injectable hydrogel-mediated approach to enhance the anti-tumor efficacy of CAP by regulating the phosphorylation of eIF2α. We discovered that reactive oxygen and nitrogen species (ROS/RNS), two main anti-tumor components in CAP, can lead to lethal oxidative stress on tumor cells. Elevated oxidative stress subsequently induces eIF2α phosphorylation, a pathognomonic marker of immunogenic cell death (ICD). Trehalose, a natural disaccharide sugar, can further enhance CAP-induced ICD by elevating the phosphorylation of eIF2α. Moreover, injectable hydrogel-mediated delivery of CAP/trehalose treatment promoted dendritic cell (DC) maturation, initiating tumor-specific T-cell mediated anti-tumor immune responses. The combination therapy also supported the polarization of tumor-associated macrophages to an M1-like phenotype, reversing the immunosuppressive tumor microenvironment and promoting tumor antigen presentation to T cells. In combination with immune checkpoint inhibitors (i.e., anti-programmed cell death protein 1 antibody, aPD1), CAP/trehalose therapy further inhibited tumor growth. Importantly, our findings also indicated that this hydrogel-mediated local combination therapy engaged the host systemic innate and adaptive immune systems to impair the growth of distant tumors.

Asunto(s)

Gases em Plasma , Trehalosa , Trehalosa/química , Trehalosa/farmacología , Animales , Ratones , Línea Celular Tumoral , Humanos , Células Dendríticas/efectos de los fármacos , Ratones Endogámicos C57BL , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Hidrogeles/química , Microambiente Tumoral/efectos de los fármacos , Femenino , Muerte Celular Inmunogénica/efectos de los fármacos , Fosforilación/efectos de los fármacos

RESUMEN

Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.

Asunto(s)

Interleucina-10 , Infarto del Miocardio , Adulto , Humanos , Interleucina-10/genética , Optogenética , Infarto del Miocardio/terapia , Nervio Vago , Miocitos Cardíacos

RESUMEN

Geological bodies are important sources of greenhouse gas (GHG) emissions. Organic-rich oil shale in sedimentary basins is a good gas source rock, the GHG in which will be released into the atmosphere during crushing to affect climate change. Quantitative calculations of GHG emissions during oil shale crushing were carried out on oil shales from the Yaojie (YJ) and Fushun (FS) mining areas in China. Organic geochemistry, X-ray diffraction, and pore structure analysis experiments, as well as the relationship between storage time and GHG emissions, were analyzed to investigate the main controlling factors of GHG release in different types of oil shales. The results showed that the CH4 and CO2 released from the YJ oil shale were 0.002-0.145 mL/g and 0.011-0.054 mL/g, respectively; the CH4 and CO2 released from the FS oil shale were 0.0001-0.0008 mL/g and 0.002-0.045 mL/g, respectively. Residual CH4 release was closely related to total organic carbon (TOC) and maturity: the CH4 released from the organic-rich and mature YJ oil shale was much higher than that of the FS oil shale, which is relatively organic-lean and immature. The control factors of the released CO2 vary in different regions: CO2 released from the YJ oil shale was somewhat affected by the TOC, while that released from the FS oil shale was mainly controlled by carbonate minerals and their contributing pores. The results of pore structure and organic maceral analyses indicated that both organic and inorganic pores of the YJ oil shale are occupied by asphaltenes, forming a key gas preservation mechanism of residual CH4 and CO2 as solutes dissolved in asphaltenes. In addition, CO2 has a greater absorptive capacity than CH4 and is therefore more difficult to release during the same crushing time. As oil shale is stored for longer periods, residual CH4 will be preferentially released to the atmosphere, while residual CO2 will be released in large quantities during crushing.