Kindlin-2 promotes Src-mediated tyrosine phosphorylation of androgen receptor and contributes to breast cancer progression

Androgen receptor (AR) signaling plays important roles in breast cancer progression. We show here that Kindlin-2, a focal adhesion protein, is critically involved in the promotion of AR signaling and breast cancer progression. Kindlin-2 physically associates with AR and Src through its two neighboring domains, namely F1 and F0 domains, resulting in formation of a Kindlin-2-AR-Src supramolecular complex and consequently facilitating Src-mediated AR Tyr-534 phosphorylation and signaling. Depletion of Kindlin-2 was sufficient to suppress Src-mediated AR Tyr-534 phosphorylation and signaling, resulting in diminished breast cancer cell proliferation and migration. Re-expression of wild-type Kindlin-2, but not AR-binding-defective or Src-binding-defective mutant forms of Kindlin-2, in Kindlin-2-deficient cells restored AR Tyr-534 phosphorylation, signaling, breast cancer cell proliferation and migration. Furthermore, re-introduction of phosphor-mimic mutant AR-Y534D, but not wild-type AR reversed Kindlin-2 deficiency-induced inhibition of AR signaling and breast cancer progression. Finally, using a genetic knockout strategy, we show that ablation of Kindlin-2 from mammary tumors in mouse significantly reduced AR Tyr-534 phosphorylation, breast tumor progression and metastasis in vivo. Our results suggest a critical role of Kindlin-2 in promoting breast cancer progression and shed light on the molecular mechanism through which it functions in this process.Subject terms: Cell signalling, Breast cancer     

DeepMHADTA: Prediction of Drug-Target Binding Affinity Using Multi-Head Self-Attention and Convolutional Neural Network

Drug-target interactions provide insight into the drug-side effects and drug repositioning. However, wet-lab biochemical experiments are time-consuming and labor-intensive, and are insufficient to meet the pressing demand for drug research and development. With the rapid advancement of deep learning, computational methods are increasingly applied to screen drug-target interactions. Many methods consider this problem as a binary classification task (binding or not), but ignore the quantitative binding affinity. In this paper, we propose a new end-to-end deep learning method called DeepMHADTA, which uses the multi-head self-attention mechanism in a deep residual network to predict drug-target binding affinity. On two benchmark datasets, our method outperformed several current state-of-the-art methods in terms of multiple performance measures, including mean square error (MSE), consistency index (CI), rm2, and PR curve area (AUPR). The results demonstrated that our method achieved better performance in predicting the drug–target binding affinity.     

本溪关门山国家森林公园游客行为特征

研究游客行为特征对于旅游资源的开发、管理以及旅游目的地的可持续发展具有重要的作用。以本溪关门山国家森林公园为研究对象,通过问卷调查的方法对游客的人口统计学特征、地域结构特征、一般行为特征、消费特征及感知特征进行了研究。结果表明:关门山国家森林公园的游客以较高学历的男性中青年为主;客源主要来自本省辽宁,并以沈阳、本溪和大连的游客为主,客源地理集中度指数为35.71;旅游的主要目的是观赏枫叶,出游时间大部分集中在每年"十一"黄金周期间,且半数以上为当日往返的短程游览者;游客偏好与家人一起出游的旅行方式,所选择的交通工具主要为自驾车和旅游专车;游客的消费结构不平衡,主要集中于景区门票和交通费,占总消费的56.7%;游客对景区的喜好度依次为龙门峡景区月台子景区小黄山景区夹砬子景区鸣翠谷景区。总的来说,游客满意度较高,有89.1%的游客愿意重游此地,游客最不满意的地方主要表现在景区卫生方面。基于调查研究结果,对关门山国家森林公园的开发建设和可持续发展提供了相关建议。     

长期施用稀土对小麦植株中稀土元素含量及分布的影响

在我国施用稀土时间最长的黑龙江花园农场,研究了连续１２ａ叶面喷施稀土对小麦植株及土壤中稀土元素总含量和分布模式的影响。结果表明：连续１２ａ叶施稀土没有造成土壤中元素含量及分布模式的变化;对小麦拔节始期（喷施稀土７ｄ）后叶部的影响较大,Ｌａ,Ｃｅ最明显增高,叶部稀土元素分布模式与“常乐”稀土中的相一致,与土壤中稀土元素分布模式不同,而在小麦拔节始期的根部、小麦成熟期的根、茎、叶、壳等部位稀土元素分布     

高温对水稻叶片蛋白质表达的影响

为明确高温对耐热性不同水稻品种叶片蛋白质表达的影响,以耐热性不同的2个籼稻品种双桂1号(不耐热)和黄华占(耐热)为材料,分别于苗期、减数分裂期及抽穗(始穗后0—10d)和灌浆早期(始穗后11—20d)进行高温处理,之后取材并采用双向凝胶电泳技术研究高温对不同水稻品种叶片蛋白质表达的影响。结果表明,高温胁迫导致叶片中蛋白质的变化呈4种状况:新蛋白质的产生,一些蛋白质表达量上调,一些蛋白质的表达被抑制,一些蛋白质表达量下调。蛋白质表达变化在两品种以及4个处理时期的表现不同,总体表现为在热敏感品种中表达谱发生变化的蛋白质总数高于耐热品种。质谱分析表明,差异蛋白质主要涉及光合作用和信号转导,该类蛋白质在热敏感品种中表现为不表达或表达量下降,而在耐热品种则表现为有新诱导的蛋白质的产生或表达量上调,表明参与光合作用和信号转导的蛋白质在水稻耐热机制中发挥了重要作用。     

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.