靶向紧密连接蛋白6的药物在癌症治疗中的研究进展

紧密连接蛋白6(Claudin6,CLDN6)是紧密连接蛋白(Claudins,CLDNs)家族的一员,在卵巢癌、睾丸癌、子宫颈内膜癌、肝癌和肺腺癌等多种癌症中特异性高表达,而在成人正常组织中几乎不表达。其能够激活多条通路参与肿瘤发生的多个过程,包括促进肿瘤生长、迁移和侵袭,且促进肿瘤化疗耐药。近年来,CLDN6作为癌症治疗的新靶点引起了研究人员的广泛关注,针对CLDN6靶点开发了多种类型的抗癌药物,包括抗体偶联药物(antibody-drug conjugate,ADC)、单克隆抗体、双特异性抗体和嵌合抗原受体T细胞免疫疗法(chimeric antigen receptor T-cell immunotherapy,CAR-T)。本文简要概述了CLDN6的蛋白结构、表达分布以及在肿瘤中的功能,并对其作为药靶开发的抗癌药物研发现状和研发思路进行了综述。     

Do Geographically Isolated Grasslands Follow the Principle of Island Biogeography in a Landscape Scale? Taking Poyang Lake Grassland as an Example

As one of the basic theories of biodiversity conservation, island biogeography has been widely accepted in the past decades. Originally, island biogeography was put forward and applied in oceanic environments. But later on, it was found out that the application was not only limited to oceanic islands, but also in terrestrial environments with relatively isolated conditions. In terms of biodiversity level, island biogeography generally focuses on a small scale, such as species diversity and genetic diversity. The studies of biodiversity on a large-scale based on island biogeography, such as ecosystem and landscape scales, were seldomly conducted. Taking Poyang Lake, the largest fresh water lake in China as case study area, 30 grasslands were randomly selected to study whether island biogeography can be applied to grasslands at a landscape level from three island attributes (area, distance and shape), and the most important ecological variable (flooding) in Poyang Lake. The results showed that in general, grasslands have the property of an island, and follow the basic principle of island biogeography. We found the area and flooding duration were the two most important determinants of landscape diversity. There was a significant positive correlation between the grassland area and the landscape diversity, which could be well expressed by logarithmic function model (R² = 0.73). There was a negative correlation between flooding duration and landscape diversity, which could be described by an inverse model (R² = 0.206). The distance to mainland and the shape of grassland were correlated with landscape diversity, but the fitting result of the models was not as good as expected. The possible reason could be that Poyang Lake is a seasonal lake, the water level varies with hydrological conditions, so that the grasslands are not strongly isolated and their shape is not stable enough required by island biogeography. Furthermore, it indicates that besides area, distance and shape attributes, flooding strongly affects the biodiversity of grassland vegetation, and should not be ignored when applying island biogeography theory to Poyang Lake. This study is expected to be a supplement for island biogeography in terrestrial environments, and the results are expected to benefit for the biodiversity conservation in Poyang Lake.     

Spatial phylogenetics of the Chinese angiosperm flora provides insights into endemism and conservation

The flora of China is well known for its high diversity and endemism. Identifying centers of endemism and designating conservation priorities are essential goals for biodiversity studies.However, there is no comprehensive study from a rigorous phylogenetic perspective to understand patterns of diversity and endemism and to guide biodiversity conservation in China. We conducted a spatial phylogenetic analysis of the Chinese angiosperm flora at the generic level to identify centers of neo-and pale...     

植物雌激素的作用机制

流行病学研究表明,膳食中摄入适量的植物雌激素尤其大豆及谷类食品者,患激素依赖型癌症如乳腺癌、前列腺癌以及骨质疏松的概率较低。因而,植物雌激素潜在的抗癌、抗氧化及对心血管和骨质的保护作用近年来备受人们的关注,但是目前关于植物雌激素作用的机制尚未完全阐明。该文介绍近年来有关植物雌激素作用机制方面的研究进展。     

Synonymous codon usage bias and overexpression of a synthetic gene encoding Interferon α2b in yeast

To achieve higher level expression of Interferon α2b (IFN-α2b) in methylotrophic yeast (Pichia pastoris), a cDNA fragment coding for the mature IFN-α2b was designed and synthesized based on the synonymous codon bias of P. pastoris and optimized G+C content. The synthetic IFN-α2b was inserted into the secreted expression vector pPICZαA, and then integrated into P. pastoris GS115 genome by electroporation. Multi-copy integrants in the Mut⁺ recombinant P. pastoris strain were screened by high concentrations of Zeocin. 120 hours culturing allowed expression of the IFN-α2b transformant up to 810 mg/L as detected by SDS-PAGE and quantitative methods. In addition, Western blot analysis showed that the recombinant proteins had immunogenicity. The significant antiviral activity of the recombinant IFN-α2b protein was verified by WISH/ VSV system, which was 3.3×10⁵ IU/mL. Foundation items: The National ‘973’ Basic Research Program (2002CB111302); The National Natural Science Foundation of China (30370807)     

VEGF siRNA降低人肝癌细胞株SMMC7721的致瘤性

本研究应用RNA干扰（RNAi）技术高效抑制VEGF的表达,明显降低了人肝癌细胞株SMMC7721的致瘤性。化学合成针对人VEGF基因的siRNA,体外瞬时转染人肝癌细胞株SMMC7721,RT-PCR和Elisa法检测表明VEGFsiRNA实验组与对照组相比,细胞内VEGFmRNA表达下降了76．16％,VEGF分泌蛋白表达则下降了96．28％,而MTT法结果显示VEGFsiRNA对SMMC7721细胞增殖没有明显作用。体内实验中,不同时间对荷SMMC7721细胞瘤裸小鼠进行siRNA直接瘤内注射,同时测量瘤体积,最后取瘤块进行组织切片观察并进行分子生物学分析,结果显示,与对照组相比,VEGFsiRNA实验组肿瘤体积明显缩小,瘤内出现细胞坏死,同时肿瘤组织中VEGFmRNA和蛋白表达水平均明显降低。     

Magnetic investigation of two helical frameworks derived from mixed ligands

Although the 2,2′-biphenyldicarboxylate ligand (2,2′-dpa) has been widely used to construct metal-organic frameworks (MOFs) with helical sub-structure, the effect of the helical arrangement of spin carriers on the magnetic properties remains rarely scarce. In this article, two unique magnetic metal-organic supramolecular frameworks with different structural features, [Cu₂(dpa)₂(H₂O)₂(4,4′-dpdo)_0.5]_n (1) and [Ni(H₂O)₄(dpa)] · (4,4′-dpdo)(H₂O) (2) (dpdo = 4,4′-dipyridine-N,N′-dioxide), have been isolated from the direct reaction of H₂dpa with their corresponding salts in the presence of dpdo. In complex 1, the Cu-dpa double-helical chains, which are bridged by long flexible μ₂-dpdo ligands to give rise to a regular 6³ covalent layer, exhibit strong antiferromagnetic coupling interactions. Whereas the 1D [Ni(dpa)]_n helical chains in complex 2 exhibit weak antiferromagnetic coupling interactions. Rich hydrogen bonds between perpendicular 1D [Ni(dpa)]_n helical chains and quasi-1D (dpdo)_n chains result in an intricate 3D supramolecular network.     

Triage protein fold prediction

We have constructed, in a completely automated fashion, a new structure template library for threading that represents 358 distinct SCOP folds where each model is mathematically represented as a Hidden Markov model (HMM). Because the large number of models in the library can potentially dilute the prediction measure, a new triage method for fold prediction is employed. In the first step of the triage method, the most probable structural class is predicted using a set of manually constructed, high-level, generalized structural HMMs that represent seven general protein structural classes: all-alpha, all-beta, alpha/beta, alpha+beta, irregular small metal-binding, transmembrane beta-barrel, and transmembrane alpha-helical. In the second step, only those fold models belonging to the determined structural class are selected for the final fold prediction. This triage method gave more predictions as well as more correct predictions compared with a simple prediction method that lacks the initial classification step. Two different schemes of assigning Bayesian model priors are presented and discussed.     

TaTPP-7A positively feedback regulates grain filling and wheat grain yield through T6P-SnRK1 signalling pathway and sugar–ABA interaction

Grain size and filling are two key determinants of grain thousand-kernel weight (TKW) and crop yield, therefore they have undergone strong selection since cereal was domesticated. Genetic dissection of the two traits will improve yield potential in crops. A quantitative trait locus significantly associated with wheat grain TKW was detected on chromosome 7AS flanked by a simple sequence repeat marker of Wmc17 in Chinese wheat 262 mini-core collection by genome-wide association study. Combined with the bulked segregant RNA-sequencing (BSR-seq) analysis of an F₂ genetic segregation population with extremely different TKW traits, a candidate trehalose-6-phosphate phosphatase gene located at 135.0 Mb (CS V1.0), designated as TaTPP-7A, was identified. This gene was specifically expressed in developing grains and strongly influenced grain filling and size. Overexpression (OE) of TaTPP-7A in wheat enhanced grain TKW and wheat yield greatly. Detailed analysis revealed that OE of TaTPP-7A significantly increased the expression levels of starch synthesis- and senescence-related genes involved in abscisic acid (ABA) and ethylene pathways. Moreover, most of the sucrose metabolism and starch regulation-related genes were potentially regulated by SnRK1. In addition, TaTPP-7A is a crucial domestication- and breeding-targeted gene and it feedback regulates sucrose lysis, flux, and utilization in the grain endosperm mainly through the T6P-SnRK1 pathway and sugar–ABA interaction. Thus, we confirmed the T6P signalling pathway as the central regulatory system for sucrose allocation and source–sink interactions in wheat grains and propose that the trehalose pathway components have great potential to increase yields in cereal crops.     

Spermidine promotes nucleus pulposus autophagy as a protective mechanism against apoptosis and ameliorates disc degeneration

Spermidine has therapeutic effects in many diseases including as heart diastolic function, myopathic defects and neurodegenerative disorders via autophagy activation. Autophagy has been found to mitigate cell apoptosis in intervertebral disc degeneration (IDD). Accordingly, we theorize that spermidine may have beneficial effects on IDD via autophagy stimulation. In this study, spermidine's effect on IDD was evaluated in tert‐butyl hydroperoxide (TBHP)‐treated nucleus pulposus cells of SD rats in vitro as well as in a puncture‐induced rat IDD model. We found that autophagy was actuated by spermidine in nucleus pulposus cells. In addition, spermidine treatment weakened the apoptotic effects of TBHP in nucleus pulposus cells. Spermidine increased the expression of anabolic proteins including Collagen‐II and aggrecan and decreased the expression of catabolic proteins including MMP13 and Adamts‐5. Additionally, autophagy blockade using 3‐MA reversed the beneficial impact of spermidine against nucleus pulposus cell apoptosis. Autophagy was thus important for spermidine's therapeutic effect on IDD. Spermidine‐treated rats had an accentuated T2‐weighted signal and a diminished histological degenerative grade than vehicle‐treated rats, showing that spermidine inhibited intervertebral disc degeneration in vivo. Thus, spermidine protects nucleus pulposus cells against apoptosis through autophagy activation and improves disc, which may be beneficial for the treatment of IDD.