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A bstract We propose a systematic theoretical framework for the topological amplitudes of the heavy meson decays and their SU( N ) decomposition. In the framework, the topologies are expressed in invariant tensors and classified into tree- and penguin-operator-induced diagrams according to which four-quark operators, tree or penguin, being inserted into their effective weak vertexes. The number of possible topologies contributing to one type of decay can be counted by permutations and combinations. The Wigner-Eckhart theorem ensures the topological amplitudes under flavor symmetry are the same for different decay channels. By decomposing the four-quark operators into irreducible representations of SU( N ) group, one can get the SU( N ) irreducible amplitudes. Taking the D → PP decay ( P denoting a pseudoscalar meson) with SU(3) F symmetry as an example, we present our framework in detail. The linear correlation of topologies in the SU(3) F limit is clarified in group theory. It is found there are only nine independent topologies in all tree- and penguin-operator-induced diagrams contributing to the D → PP decays in the Standard Model. If a large quark-loop diagram, named T LP , is assumed, the large ∆ A CP and the very different D 0 → K + K − and D 0 → π + π − branching fractions can be explained with a normal U -spin breaking. Moreover, our framework provides a simple way to analyze the SU( N ) breaking effects. The linear SU(3) F breaking and the high order U -spin breaking in charm decays are re-investigated in our framework, which are consistent with literature. Analogous to the degeneracy and splitting of energy levels, we propose the concepts of degeneracy and splitting of topologies to describe the flavor symmetry breaking effects in decay. As applications, we analyze the strange-less D decays in SU(3) F symmetry breaking into Isospin symmetry and the charm-less B decays in SU(4) F symmetry breaking into SU(3) F symmetry.

A bstract The dynamical studies on the non-leptonic weak decays of charmed baryons are always challenging, due to the large non-perturbative contributions at the charm scale. In this work, we develop the final-state rescattering mechanism to study the two-body non-leptonic decays of charmed baryons. The final-state interaction is a physical picture of long-distance effects. Instead of using the Cutkosky rule to calculate the hadronic triangle diagrams which can only provide the imaginary part of decay amplitudes, we point out that the loop integral is more appropriate, as both the real parts and the imaginary parts of amplitudes can be calculated completely. In this way, it can be obtained for the non-trivial strong phases which are essential to calculate CP violations. With the physical picture of long-distance effects and the reasonable method of calculations, it is amazingly achieved that all the nine existing experimental data of branching fractions for the Λ c + decays into an octet light baryon and a vector meson can be explained by only one parameter of the model. Besides, the decay asymmetries and CP violations are not sensitive to the model parameter, since the dependence on the parameter is mainly cancelled in the ratios, so that the theoretical uncertainties on these observables are lowered down.

Cancer immunotherapy is exploited for the treatment of disease by modulating the immune system. Since the conventional in vivo animal and 2D in vitro models insufficiently recapitulate the complex tumor immune microenvironment (TIME) of the original tumor. In addition, due to the involvement of the immune system in cancer immunotherapy, more physiomimetic cancer models, such as patient-derived organoids (PDOs), are required to evaluate the efficacy of immunotherapy agents. On the other hand, the dynamic interactions between the neoplastic cells and non-neoplastic host components in the TIME can promote carcinogenesis, tumor metastasis, cancer progression, and drug resistance of cancer cells. Indeed, tumor organoid models can properly recapitulate the TIME by preserving endogenous stromal components including various immune cells, or by adding exogenous immune cells, cancer-associated fibroblasts (CAFs), vasculature, and other components. Therefore, organoid culture platforms could model immunotherapy responses and facilitate the immunotherapy preclinical testing. Here, we discuss the various organoid culture approaches for the modeling of TIME and the applications of complex tumor organoids in testing cancer immunotherapeutics and personalized cancer immunotherapy.

Background Gonadotropin-releasing hormone receptor (GnRHR) is expressed in several malignant tumors and inhibits the proliferation and metastasis of cancer cells, but its role in triple-negative breast cancers (TNBCs) is unclear. This study investigated the biological effects of GnRHR and their influence on TNBC prognosis. Methods The GSE21653 database was used to obtain information about GnRHR expression and clinicopathological factors in patients with TNBC. GnRHR was activated in cultured MDA-MB-231 and MDA-MB-468 cells by leuprolide acetate and antagonized by elagolix sodium. Cell proliferation was assessed by the cell counting kit-8 and colony formation assays. Cell metastasis was detected by the wound healing assay and Transwell assay. Apoptosis and the cell cycle were investigated by flow cytometry. GnRHR protein expression was determined by western blotting. Results GnRHR mRNA expression was significantly higher in patients with TNBC than in hormone receptor+/human epidermal growth factor receptor (HER)2– and HER2+ patients with breast cancer. Patients with high GnRHR expression had significantly better disease-free survival than those with lower expression. Activated GnRHR significantly inhibited cell proliferation and metastasis, increased apoptosis, and enhanced GnRHR protein expression levels. Conclusion GnRHR inhibits TNBC proliferation and metastasis, suggesting it could be targeted for TNBC treatment.

Artificial intelligence has been successfully applied in various fields, one of which is computer vision. In this study, a deep neural network (DNN) was adopted for Facial emotion recognition (FER). One of the objectives in this study is to identify the critical facial features on which the DNN model focuses for FER. In particular, we utilized a convolutional neural network (CNN), the combination of squeeze-and-excitation network and the residual neural network, for the task of FER. We utilized AffectNet and the Real-World Affective Faces Database (RAF-DB) as the facial expression databases that provide learning samples for the CNN. The feature maps were extracted from the residual blocks for further analysis. Our analysis shows that the features around the nose and mouth are critical facial landmarks for the neural networks. Cross-database validations were conducted between the databases. The network model trained on AffectNet achieved 77.37% accuracy when validated on the RAF-DB, while the network model pretrained on AffectNet and then transfer learned on the RAF-DB results in validation accuracy of 83.37%. The outcomes of this study would improve the understanding of neural networks and assist with improving computer vision accuracy.

Objectives DNA N6‐methyladenine (N6‐mA) demethylase Alkbh1 participates in regulating osteogenic differentiation of mesenchymal stem cell (MSCs) and vascular calcification. However, the role of Alkbh1 in bone metabolism remains unclear. Materials and Methods Bone marrow mesenchymal stem cells (BMSCs)‐specific Alkbh1 knockout mice were used to investigate the role of Alkbh1 in bone metabolism. Western blot, qRT‐PCR, and immunofluorescent staining were used to evaluate the expression of Alkbh1 or optineurin (optn). Micro‐CT, histomorphometric analysis, and calcein double‐labeling assay were used to evaluate bone phenotypes. Cell staining and qRT‐PCR were used to evaluate the osteogenic or adipogenic differentiation of BMSCs. Dot blotting was used to detect the level of N6‐mA in genomic DNA. Chromatin immunoprecipitation (Chip) assays were used to identify critical targets of Alkbh1. Alkbh1 adeno‐associated virus was used to overexpress Alkbh1 in aged mice. Results Alkbh1 expression in BMSCs declined during aging. Knockout of Alkbh1 promoted adipogenic differentiation of BMSCs while inhibited osteogenic differentiation. BMSC‐specific Alkbh1 knockout mice exhibited reduced bone mass and increased marrow adiposity. Mechanistically, we identified optn as the downstream target through which Alkbh1‐mediated DNA m6A modification regulated BMSCs fate. Overexpression of Alkbh1 attenuated bone loss and marrow fat accumulation in aged mice. Conclusions Our findings demonstrated that Alkbh1 regulated BMSCs fate and bone‐fat balance during skeletal aging and provided a potential target for the treatment of osteoporosis. Our findings revealed that DNA N6‐methyladenine demethylase Alkbh1 regulates bone marrow mesenchymal stem cell fate during aging. Loss of Alkbh1 inhibited bone formation and promoted marrow fat accumulation. Mechanistically, we identified optn as the downstream target through which Alkbh1‐mediated DNA m6A modification regulated BMSCs fate.

Background The growing use of silica nanoparticles (SiNPs) in many fields raises human toxicity concerns. We studied the toxicity of SiNP-20 (particle diameter 20 nm) and SiNP-100 (100 nm) and the underlying mechanisms with a focus on the endothelium both in vitro and in vivo. Methods The study was conducted in cultured human umbilical vein endothelial cells (HUVECs) and adult female Balb/c mice using several techniques. Results In vitro, both SiNP-20 and SiNP-100 decreased the viability and damaged the plasma membrane of cultured HUVECs. The nanoparticles also inhibited HUVECs migration and tube formation in a concentration-dependent manner. Both SiNPs induced significant calcium mobilization and generation of reactive oxygen species (ROS), increased the phosphorylation of vascular endothelial (VE)-cadherin at the site of tyrosine 731 residue (pY731-VEC), decreased the expression of VE-cadherin expression, disrupted the junctional VE-cadherin continuity and induced F-actin re-assembly in HUVECs. The injuries were reversed by blocking Ca 2+ release activated Ca 2+ (CRAC) channels with YM58483 or by eliminating ROS with N-acetyl cysteine (NAC). In vivo, both SiNP-20 and SiNP-100 (i.v.) induced multiple organ injuries of Balb/c mice in a dose (range 7–35 mg/kg), particle size, and exposure time (4–72 h)-dependent manner. Heart injuries included coronary endothelial damage, erythrocyte adhesion to coronary intima and coronary coagulation. Abdominal aorta injury exhibited intimal neoplasm formation. Lung injuries were smaller pulmonary vein coagulation, bronchiolar epithelial edema and lumen oozing and narrowing. Liver injuries included multifocal necrosis and smaller hepatic vein congestion and coagulation. Kidney injuries involved glomerular congestion and swelling. Macrophage infiltration occurred in all of the observed organ tissues after SiNPs exposure. SiNPs also decreased VE-cadherin expression and altered VE-cadherin spatial distribution in multiple organ tissues in vivo. The largest SiNP (SiNP-100) and longest exposure time exerted the greatest toxicity both in vitro and in vivo. Conclusions SiNPs, administrated in vivo, induced multiple organ injuries, including endothelial damage, intravascular coagulation, and secondary inflammation. The injuries are likely caused by upstream Ca 2+ -ROS signaling and downstream VE-cadherin phosphorylation and destruction and F-actin remodeling. These changes led to endothelial barrier disruption and triggering of the contact coagulation pathway.

Selective uptake and elution of trace amounts of hazardous radioactive 90 Sr from large-scale high-level liquid waste (HLW) is crucial for sustainable development. Here, we propose a site differentiation strategy, based on the presence of distinct selective metal capture sites (concavity site and tweezer site) within the giant polyoxoniobate (PONb) nanoclusters of an all-inorganic PONb framework (FZU-1). Through this strategy, FZU-1 can not only effectively remove 98.9% of Sr²⁺ from simulated nuclear liquid waste, performing best among the reported Sr adsorbents, but also achieve desorption of adsorbed Sr²⁺ ions by selectively loading Na⁺ ions, thus enabling the recycling of FZU-1. Based on the well-defined single-crystal structures and theoretical studies, it can be revealed that the rapid and selective uptake of Sr²⁺ is attributed to the strong binding energy between the Sr²⁺ ions and the concavity sites. The effective elution of Sr²⁺, on the other hand, stems from the preferential binding of Na⁺ ions at the tweezer sites, elevating the cluster’s electrostatic potential and indirectly facilitating the elution of Sr²⁺ ions. The exceptional stability of FZU-1, along with its rapid and selective Sr²⁺ capture and elution capabilities, positions it as a promising candidate for large-scale nuclear waste treatment and groundwater remediation applications. Here, the authors propose a site differentiation strategy in ion exchange, that is, functional materials with different adsorption sites for specific metal ions can achieve efficient uptake and elution of specific ions (e.g., Sr 2+ ion in this work).

BACKGROUNDAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease.METHODSTwenty-seven patients with CC with stage III-IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections.RESULTSTILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9-22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response.CONCLUSIONTIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. \"Hot\" inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT04443296.FUNDINGNational Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

In the field of AGV, a path planning algorithm is always a heated area. However, traditional path planning algorithms have many disadvantages. To solve these problems, this paper proposes a fusion algorithm that combines the kinematical constraint A* algorithm and the following dynamic window approach algorithm. The kinematical constraint A* algorithm can plan the global path. Firstly, the node optimization can reduce the number of child nodes. Secondly, improving the heuristic function can increase efficiency of path planning. Thirdly, the secondary redundancy can reduce the number of redundant nodes. Finally, the B spline curve can make the global path conform to the dynamic characteristics of AGV. The following DWA algorithm can be dynamic path planning and allow the AGV to avoidance moving obstacle. The optimization heuristic function of the local path is closer to the global optimal path. The simulation results show that, compared with the fusion algorithm of traditional A* algorithm and traditional DWA algorithm, the fusion algorithm reduces the length of path by 3.6%, time of path by 6.7% and the number of turns of final path by 25%.