维生素D_3及其类似物调控细胞生长分化的可能机制

维生素Ｄ3 是一种脂溶性维生素 ,其活性形式是 1α ,2 5 (ＯＨ) 2 Ｄ3 。它除了分布于传统的靶组织如肠、成骨细胞、肾远曲小管外 ,亦分布于许多非经典的靶组织细胞中 ,如造血组织、神经肌肉组织、生殖细胞以及免疫细胞等 ,这强烈提示 1α ,2 5 (ＯＨ) 2 Ｄ3 具有更多的其它生物效应[1] 。现已清楚 ,1α ,2 5 (ＯＨ) 2 Ｄ3除了能调节钙磷代谢和免疫系统的功能外 ,还能调控多种组织来源的正常细胞和肿瘤细胞的生长和分化 ,主要表现为抑制细胞的增殖和促进细胞分化[2～ 4] 。然而其分子机制并不完全清楚。本文就维生素Ｄ3 及其类似物调节细胞…     

1α,25(OH)_2D_3抑制前列腺癌机制研究进展

1α,25(OH)_2D_3是一种类固醇激素,在抑制前列腺癌发生和发展中具重要作用。1α,25(OH)_2D_3抑制前列腺癌涉及多方面的分子过程,包括G1/S细胞周期阻滞、促癌细胞凋亡、抗血管生成和阻止癌细胞迁移等。本文将从维生素D_3合成代谢羟化酶表达调控、VDR基因多态性、雄激素及受体调控、抗炎因子表达调控、胰岛素样生长因子及相关结合蛋白表达调控等方面阐述了近年来1α,25(OH)_2D_3抑制前列腺癌分子机制的研究进展,为维生素D_3预防和治疗前列腺癌的应用提供了参考。     

1,25-二羟维生素D3的生物学效应

1,25-二羟维生素D3是维生素D3的活性形式,其生物学效应是由基因组与非基因组两种机制介导的。维生素D3除了具有钙磷代谢调节作用外,还具有其他更为广泛的生物学效应。1,25-二羟维生素D3能够抑制多种类型细胞的增殖,诱导细胞的凋亡和分化,调节机体免疫系统功能,保护中枢神经系统,以及保护基因等。     

维生素D_3联合5-氟尿嘧啶对人食管癌Eca-109细胞移植瘤VDR表达的影响

探讨维生素D3、5-氟尿嘧啶单独与联合使用对人食管癌Eca-109细胞移植瘤维生素D受体(vitamin Dreceptor,VDR)的作用.随机分为对照组(C)、预处理组(PT)、维生素D3组(V)、5-氟尿嘧啶组(F)、预处理+5-氟尿嘧啶组(PT+F)、维生素D3+5-氟尿嘧啶组(V+F).体外培养人食管癌Eca-109细胞,BALB/c裸鼠皮下荷瘤,2.5μg/kg1,25-(OH)2维生素D3、25 mg/kg 5-氟尿嘧啶单独与联合腹腔注射,观察瘤体生长情况,逆转录聚合酶链反应(RT-PCR)和蛋白质印迹技术(Western blot)检测裸鼠瘤体组织VDR mRNA与蛋白的表达.研究发现1,25-(OH)2维生素D3、5-氟尿嘧啶均能抑制裸鼠移植瘤的生长,PT、V、F、PT+F、V+F组瘤体体积与C组比较差异有统计学意义(P<0.05);RT-PCR与Western blot结果显示经1,25-(OH)2维生素D3单独与联合5-氟尿嘧啶使用后瘤体组织中VDR mRNA和蛋白表达升高,且联合用药更为显著(P<0.05).结果表明1,25-(OH)2维生素D3、5-氟尿嘧啶均能抑制人食管癌Eca-1...     

LRP16与 ERα相互作用增强ERα介导的转录活性

LRP16是一个雌激素（E2）通过受体α（ERα）诱导表达的靶基因,LRP16不仅促进人乳腺癌MCF-7细胞的增殖,而且促进细胞的侵袭生长,但对LRP16作用的分子机制尚不清楚.首先,检测到LRP16表达缺陷明显削弱了MCF-7细胞对E2的反应性增殖能力;采用Northern 印迹与Western印迹法,进一步检测到抑制LRP16表达,明显损害了ERα靶基因对E2诱导上调的反应性,这些基因包括了cyclin D1, c-myc, c-fos,MTA3, pS2和维甲酸受体α基因（RARα）等;以上结果提示,LRP16参与了ERα介导的信号途径.将ERα模式启动子报告基因3×ERE-TATA-luc,ERα以及LRP16表达载体共转染MCF-7与HeLa细胞.结果发现,LRP16增强了ERα对报告基因的转录激活,并呈现对LRP16的剂量依赖性;进而采用GST-pull down以及免疫共沉淀方法证实了LRP16与ERα之间的直接相互作用,该作用不依赖于E2的存在,但可被E2增强;采用哺乳动物双杂交方法进一步证实了ERα与LRP16相互作用位点存在于A/B区的激活功能域-１（AF1）.以上结果表明,LRP16是ERα的一个共激活因子,通过相互作用,LRP16增强了ERα介导转录活性.该研究为LRP16促进ERα阳性乳腺癌细胞增殖与侵袭生长提供了合理的分子解释.     

对维生素D有了新看法

目前大量研究结果表明,维生素 D 系统的功能比早期的认识更复杂。早期对维生素 D 的作用和作用机制的解释已日益与新发现的事实不符。本文作者根据最近的一些研究结果提出了对维生素 D 系统的新看法:1.细胞粘附蛋白或1,25-(OH)_2D_(?)受体不仅限于骨和小肠这经典的靶组织还存在于其他组织中,例如     

阿法骨化醇的药理与临床评价

阿法骨化醇是目前研制出的较理想的活性维生素D的衍生物制剂,与维生素D结合蛋白的亲和力强,在肝脏经肝微粒体羟基化酶作用后形成具有活性的1α,25-（OH）z,分布于肠道及骨等靶组织内与受体结合而表现出促进肠道吸收钙、促进骨形成、抑制甲状旁腺激素（PTH）过剩分泌等代谢调节作用。现临床常用于治疗骨质疏松症,改善慢性肾功能不全,甲状旁腺机能减退,抗维生素D的佝偻病和骨软化病等。本文就阿法骨化醇的药理与临床评价作简要综述。     

整联蛋白信号与银屑病发病发子机制

整联蛋白可激活酪氨酸激酶和维持生长因子的生物活性,实现细胞外基质－整联蛋白－细胞内的信号转导功能,调节细胞生长、分化、粘附等生理功能;在病理状态下,如银屑病整联蛋白表达异常,可介导角质形成细胞的过度增生、异常分化甚至炎症的发生。本文综述调节细胞基本行为的整联蛋白信号转导及其与银屑病分子发病机制的关系。     

生理性低氧通过HIF1α上调PLOD2参与绒毛外滋养细胞分化

生理性低氧在胎盘发育及滋养细胞分化中具有重要作用。HIF1α是响应低氧诱导的关键因子之一,但生理性低氧通过HIF1α影响胎盘发育的具体分子机制尚不明确。该研究首先通过生物信息学方法分析了HIF1α的下游靶基因和绒毛外滋养细胞分化过程中的差异表达基因,并筛选出两者交集基因作为HIF1α调控绒毛外滋养细胞分化的潜在靶标基因。实验验证发现,生理性低氧条件下(8% O_2),HIF1α和其下游靶基因PLOD2、HPCAL1、SLC16A3、FAM174B、SYDE1均被诱导上调表达,而NREP和CD4表达下调。过表达HIF1α后,上述靶基因被调控并呈现与生理性低氧诱导相同的表达模式。通过体外Transwell侵袭、细胞划痕和绒毛外植体实验发现,敲低靶基因PLOD2后可显著抑制滋养细胞的侵袭、迁移和外植体外延水平,并能进一步阻碍滋养细胞的细胞骨架重塑及滋养细胞上皮–间质转换过程。该研究初步发现,生理性低氧可以诱导HIF1α上调,并进一步介导其下游靶基因PLOD2等的选择性表达,促进EVT分化。     

VD通过VDR下调β-catenin磷酸化水平抑制胃癌细胞增殖

为探讨维生素D(vitamin D, VD)及维生素D受体(vitamin D receptor, VDR)对胃癌细胞增殖的作用及分子机制,该研究首先通过免疫荧光实验观察胃癌细胞SGC-7901和MKN-45中VDR的表达水平,进一步利用shRNA干扰慢病毒转染两种胃癌细胞,嘌呤霉素筛选建立shVDR稳定株,应用CCK8及细胞集落形成实验,流式细胞学实验, Western blot实验检测VD/VDR在两种胃癌细胞恶性表型增殖及细胞周期中的作用;最后再次应用Western blot实验检测VD/VDR对胃癌细胞中β-catenin磷酸化表达水平的影响。结果表明两种胃癌细胞均表达VDR;在配体骨化三醇(1α,25(OH)_2D_3)存在的情况下,胃癌细胞的增殖和集落形成受到明显抑制,同时抑制β-catenin的磷酸化水平,但对细胞周期分布及细胞周期蛋白Cyclin D1无明显作用。下调VDR的表达水平后, VD对β-catenin磷酸化表达水平无明显影响。证实VDR通过下调β-catenin的磷酸化水平,发挥抑制胃癌细胞增殖的作用。     

Anthropology and genetics of the caucasus peoples and the problem of the origin of the caucasoids

The electrophoretical polymorphisms of some blood proteins were studied in the Talysh population of Pirasora situated in South-East Azerbaidjan. We calculated the gene frequencies of these polymorphisms and determined the genetic distances between the Talyshes and some Iranian populations of North, Central and South Iran, Afghans, and three populations of Azerbaijan. The Talyshes are very close to Iranians of Shiraz, whereas they are distant from the Azerbaijanians. Anthropological investigations showed that the Caucasoids and Mongoloids lived in the Aragvi Basin since the Eneolithic period. This was stated by Alexeev (1974), who emphasized the mixture of the Caucasus populations from ancient times on. We calculated the genetic distances between the Caucasus populations and numerous populations of other geographic regions, considering 28 alleles of 12 loci of blood group, serum protein and red cell enzyme polymorphisms and constructed the dendrogram of these populations. The position of the Caucasus populations in the dendrogram corresponds on principle to the earlier anthropological observations. The clustering of the Caucasoid populations corresponds completely with anthropological and historical data, and supports our earlier hypothesis (Nazarova 1999) concerning the differentiation of Caucasoids, Northern Mongoloids and Amerinds from the populations, which inhabitated Asia in palaeolithic times.     

On the structure and dynamics of the complex of the nucleosome and the linker histone

Several different models of the linker histone (LH)–nucleosome complex have been proposed, but none of them has unambiguously revealed the position and binding sites of the LH on the nucleosome. Using Brownian dynamics-based docking together with normal mode analysis of the nucleosome to account for the flexibility of two flanking 10 bp long linker DNAs (L-DNA), we identified binding modes of the H5-LH globular domain (GH5) to the nucleosome. For a wide range of nucleosomal conformations with the L-DNA ends less than 65 Å apart, one dominant binding mode was identified for GH5 and found to be consistent with fluorescence recovery after photobleaching (FRAP) experiments. GH5 binds asymmetrically with respect to the nucleosomal dyad axis, fitting between the nucleosomal DNA and one of the L-DNAs. For greater distances between L-DNA ends, docking of GH5 to the L-DNA that is more restrained and less open becomes favored. These results suggest a selection mechanism by which GH5 preferentially binds one of the L-DNAs and thereby affects DNA dynamics and accessibility and contributes to formation of a particular chromatin fiber structure. The two binding modes identified would, respectively, favor a tight zigzag chromatin structure or a loose solenoid chromatin fiber.     

Kinematics and dynamics of the temporomandibular joint and of the movements of the mandible

In order to analyze the complicated movements of the mandible as the open-closing movement and the protrusio are, it is useful to evaluate the basic kinematic principles and reduce them to simple technical constructions. Both the open-closing movement and the protrusio could be reduced to 4-bar links, which were used to simulate the movements with help of a computer. Besides, the polodes and the curves of points in the muscular attachments could be constructed. The 2 entirely different 4-bar links have 3 things in common: The resting system - cranium, the moving system - mandibula, and 1 of the 2 arms connecting these 2 systems - the ligamentum laterale. As this ligament is taut during movements it can be considered a "guiding ligament" representing 1 of the 3 determining components of the mandibular movements. The other of the 2 arms has no anatomical equivalent; this arm, however, is "replaced" by the 2 other determining components of the mandibular movements: the joint and the muscles. The curves, which the Caput mandibulae describes, are practically identical for the open-closing movement and the protrusio despite of the different 4-bar links and these curves exactly correspond to the Discus articularis, taut by the upper part of the M. pterygoideus lateralis. The muscles do not only just move the mandibula, but they are also the component, which can choose between the different mandibular movements. By means of the curves, which points in the muscular attachments describe, the function of the masticatory muscles could be analyzed exactly.     

Biophysics and Structure of the Patch and the Gigaseal

Interpreting channel behavior in patches requires an understanding of patch structure and dynamics, especially in studies of mechanosensitive channels. High resolution optical studies show that patch formation occurs via blebbing that disrupts normal membrane structure and redistributes in situ components including ion channels. There is a 1-2 μm region of the seal below the patch where proteins are excluded and this may consist of extracted lipids that form the gigaseal. Patch domes often have complex geometries with inhomogeneous stresses due to the membrane-glass adhesion energy (E_a), cytoskeletal forces, and possible lipid subdomains. The resting tension in the patch dome ranges from 1-4 mN/m, a significant fraction of the lytic tension of a bilayer (∼10 mN/m). Thus, all patch experiments are conducted under substantial, and uneven, resting tension that may alter the kinetics of many channels. E_a seems dominated by van der Waals attraction overlaid with a normally repulsive Coulombic force. High ionic strength pipette saline increased E_a and, surprisingly, increased cytoskeletal rigidity in cell-attached patches. Low pH pipette saline also increased E_a and reduced the seal selectivity for cations, presumably by neutralizing the membrane surface charge. The seal is a negatively charged, cation selective, space with a resistance of ∼7 gigohm/μm in 100 mM KCl, and the high resistivity of the space may result from the presence of high viscosity glycoproteins. Patches creep up the pipette over time with voltage independent and voltage dependent components. Voltage-independent creep is expected from the capillary attraction of E_a and the flow of fresh lipids from the cell. Voltage-dependent creep seems to arise from electroosmosis in the seal. Neutralization of negative charges on the seal membrane with low pH decreased the creep rate and reversed the direction of creep at positive pipette potentials.     

Serology and systematics of the Ebenales and the Theales

The systematic position ofthe Ebenaceae, Sapotaceae, Styracaceae, Ochnaceae, Stachyuraceae, Dipterocarpaceae, Clusiaceae and Hypericaceae has been investigated using serological comparisons of sets of antigenic determinants. The results show that the Sytracaceae and Sapotaceae are undoubtedly more closely associated with the Actinidiaeceae and Theaceae, respectively, than with each other. We found no corresponding determinants betnween antigen systems from the Ebenaceae and systems from any other family whose relations to this family have been proposed. As discovered previously, investigations of antigen systems from the Ochnaceae, Dipterocarpaceae, Stachyuraceae, Clusiaceae and Hypericaceae are against the idea of a natural order “Theales” in which these families, or at least some of them, are combined with the Theaceae and Actinidiaceae. This paper completes our previous investigations which largely support a superorder Ericanae sensu Ehrendorfer and Takhtajan. We propose to include the Actinidiaceae and Theaceae in this superorder, assigning them a central position laong with the Sapotaceae and Sytracaeae on one side and the Primulales and Ericales on the other. Another most interesting finding is that there are corresponding determinants between antigen systems from the members of the Ericanae and representatives of the Polemoniaceae and Loasaceae.     

人类基因组及后基因组研究进展及其应用与开发研究现状

人类对自身基因组的研究,随着人类基因组工作草图的绘制完成和对基因功能研究的深入已加快进入了实质性、关键性的开发利用阶段。本文概述了人类基因组及后基因组的研究进展及依此开展基因治疗及基因（组）药物研制等应用开发研究的现状。     

Comparison of the Effects of Flexion and Extension of the Thumb and Fingers on the Position and Cross-Sectional Area of the Median Nerve

Objective

To assess the separate effects of thumb and finger extension/flexion on median nerve position and cross-sectional area.

Methods

Ultrasonography was used to assess median nerve transverse position and cross-sectional area within the carpal tunnel at rest and its movement during volitional flexion of the individual digits of the hand. Both wrists of 165 normal subjects (11 men, 4 women, mean age, 28.6, range, 22 to 38) were studied.

Results

Thumb flexion resulted in transverse movement of the median nerve in radial direction (1.2±0.6 mm), whereas flexion of the fingers produced transverse movement in ulnar direction, which was most pronounced during flexion of the index and middle fingers (3.2±0.9 and 3.1±1.0 mm, respectively). Lesser but still statistically significant movements were noted with flexion of the ring finger (2.0±0.8 mm) and little finger (1.2±0.5 mm). Flexion of the thumb or individual fingers did not change median nerve cross-sectional area (8.5±1.1 mm²).

Conclusions

Volitional flexion of the thumb and individual fingers, particularly the index and middle fingers, produced significant transverse movement of the median nerve within the carpal tunnel but did not alter the cross-sectional area of the nerve. The importance of these findings on the understanding of the pathogenesis of the carpal tunnel syndrome and its treatment remains to be investigated.     

Schistosoma haematobium: the effect of Astiban on the cell composition and ultrastructure of the vitelline gland and the ultrastructure of the tegument and gastrodermis

Treatment of Schistosoma haematobium (Nigerian strain) in hamsters with a single dose of 40 mg/kg of Astiban caused a reduction in the number of S1, S2, and S3 vitelline cells and an increase in S4 cells. Following seven daily doses of the drug, a marked reduction in S1 cells and a complete loss of S2 and S3 cells occurred such that 95% of the cells were S4 cells, all of which were structurally abnormal. Coagulation and disintegration of the protein granules of the vitelline droplets occurred with increase in lipid droplets, swelling of the nuclear membrane and an increase in cytosegresomes. Blebbing of the tegument in both sexes occurred following a single treatment and vacuolation of the basal infolds and alterations to the mitochondria also resulted, but severe erosion of the tegument was rare even following repeated drug treatment. Damage to the gastrodermis was severe with the development of autophagic vacuoles containing whorls of myelin and sequestered portions of damaged tissue. The degree of damage increased with the number of drug treatments.     

On the Microanatomy of the Brain and the Innervation and Homologues of the Cephalic Appendages of Hesionidae and Syllidae (Polychaeta)

Abstract Earlier papers dealing with the anatomy of the hesionids and syllids were studied. Thereby it was found that information about the structure of the central nervous system was meagre. As a result, the anterior end appendages, especially the large, laterloventral ones of the Syllidae, have been differently interpreted. This prompted a re-investigation. The circum-oesophageal connectives, the brain commissures and the innervation of the alimentary canal and the cephalic appendages of a number of hesionid and syllid species were studied. The results, summarized in schematic diagrams, were compared with corresponding observations in other polychaete families. Among other things, it was concluded that not only the latero-ventral cephalic appendages of the hesionids but also those of the syllids are homologous with the palps of the nereids and of many other “errant” and “sedentary” families.