The Role of Cell Cycle Regulators in Cell Survival—Dual Functions of Cyclin-Dependent Kinase 20 and p21Cip1/Waf1

The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21^Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.     

PI3K/AKT/GSK3β信号通路参与腺苷A1R介导异丙酚对缺血再灌注损伤大鼠的脑保护作用

目的：探讨PI3K/AKT/GSK-3β信号通路参与异丙酚对缺血再灌注损伤大鼠的脑保护作用及机制。方法：健康雄性SD大鼠72只，所有大鼠参照Zea Longa法建立局灶性脑缺血再灌注损伤的模型。随机分成6组（n=12），A-假手术组，B-模型组（MCAO），C-异丙酚组，D-异丙酚+腺苷A1R拮抗剂组（DPCPX），E-异丙酚组+PI3K特异性抑制剂（LY294002），F-异丙酚+GSK-3β抑制剂组（SB216763），观察大鼠术后24 h神经功能评分情况；LDF监测插栓前后脑血流变化；采用TTC染色法检测各组大鼠的脑梗死体积；用HE染色方法观察大鼠脑组织形态学改变；免疫组织化学法检测Bcl-2阳性细胞表达；采用TUNEL检测各组大脑脑皮质缺血周围神经元凋亡细胞的百分率。结果：与A组比较，B、C、D、E及F组大鼠行为学、脑梗死体积、细胞凋亡率、Bcl-2蛋白表达量均增加（P<0.05）；与C组比较，B、D、E组大鼠行为学评分，脑梗死体积及细胞凋亡率均明显增加，Bcl-2蛋白表达量均明显减少（P<0.01），F组Bcl-2蛋白表达量却增加，细胞凋亡率降低（P<0.05），行为学评分减少、梗死体积减少（P<0.05）。 结论：腺苷A1R介导的异丙酚对缺血再灌注损伤大鼠的神经保护作用可能与PI3K/AKT/GSK-3β信号转导通路有关。     

A novel multi-focus image fusion method based on distributed compressed sensing

Multi-focus image fusion aims to produce an all-in-focus image by merging multiple partially focused images of the same scene. The main work is identifying the focused region and then composing all the focused regions. In this paper, a novel efficient multi-focus image fusion method based on distributed compressed sensing (DCS) is proposed. Firstly, the low-frequency and high-frequency images are obtained by comparing the variance of the source images, which are further utilized to get the low-frequency and high-frequency dictionaries. Secondly, DCS using joint sparsity model-1 (JSM-1) is applied to reconstruct the precise high-frequency images. Thirdly, the decision map is obtained based on all the high-frequency images and then improved by the morphological processing. Finally, the focused pixels are chosen from the source images through the decision map. Experimental results indicate that the proposed DCS-based method can be competitive with or even outperform some state-of-the-art methods in terms of both visual and quantitative metric evaluations.     

Targeting Casein Kinase 1 (CK1) in Hematological Cancers

The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.     

Aptamer/Peptide-Functionalized Genome-Editing System for Effective Immune Restoration through Reversal of PD-L1-Mediated Cancer Immunosuppression

Effective reversal of tumor immunosuppression is of critical importance in cancer therapy. A multifunctional delivery vector that can effectively deliver CRISPR-Cas9 plasmid for β-catenin knockout to reverse tumor immunosuppression is constructed. The multi-functionalized delivery vector is decorated with aptamer-conjugated hyaluronic acid and peptide-conjugated hyaluronic acid to combine the tumor cell/nuclear targeting function of AS1411 with the cell penetrating/nuclear translocation function of TAT-NLS. Due to the significantly enhanced plasmid enrichment in malignant cell nuclei, the genome editing system can induce effective β-catenin knockout and suppress Wnt/β-catenin pathway, resulting in notably downregulated proteins involved in tumor progression and immunosuppression. Programmed death-ligand 1 (PD-L1) downregulation in edited tumor cells not only releases the PD-1/PD-L1 brake to improve the cancer killing capability of CD8⁺ T cells, but also enhances antitumor immune responses of immune cells. This provides a facile strategy to reverse tumor immunosuppression and to restore immunosurveillance and activate anti-tumor immunity.     

Thermodynamic and Surface Properties of Aqueous 1-Dodecyl-3-Methylimidazolium Chloride [C12mim][Cl] Solution in the Presence of a Series of Inorganic Salts

The micellization behavior of amphiphiles is a well-analyzed physicochemical phenomenon, which can be easily influenced by various parameters such as pressure, temperature, and the presence of different additives. Inorganic salts are able to affect the thermodynamic and surface properties of amphiphiles significantly. The effect of a series of salts as additives namely lithium chloride (LiCl), potassium chloride (KCl), sodium chloride (NaCl), sodium bromide (NaBr), and sodium iodide (NaI) on interfacial chemical characteristics of the surface-active ionic liquid (SAIL) 1-dodecyl-3-methylimidazolium chloride [C₁₂mim][Cl] in aqueous solution were examined through conductance, surface tension, fluorescence, ¹H NMR, and dynamic light scattering measurements. The interfacial and thermodynamic parameters of all investigated SAIL-salt systems were evaluated from surface tension and conductance measurements, respectively. A detailed analysis of the microenvironment of the micelles and the size of the micelles was done using ¹H NMR and dynamic light scattering measurements.     

舰船燃气轮机高压涡轮动叶多维热耦合设计方法

针对舰船燃气轮机复杂高效冷却叶片设计,基于压力修正算法建立冷却叶片一维管网设计方法;通过快速求解可压缩边界层微分方程获得叶片外换热边界,基于参数化的叶片网格生成方法,采用全隐式有限体积的固体导热求解方法,构建了冷却叶片的耦合传热模型,开发了耦合传热计算程序。对某高压涡轮动叶进行多维热耦合设计,确定冷却流路及冷气分布,通过三维气热耦合计算验证了设计方案的可行性,通过对比分析验证了多维热耦合设计方法对主要流通单元的流量、压力误差小于5%,具备较高的工程应用价值。