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世界性命科学前沿动态周报（二十一）
（08.23 --08.29/ 2010）
俄罗斯贵宾会集团国际集团:陶国新
本周动态蕴含以下内容： 体内葡萄糖含量过高影响免疫系统 ; MIT 科学家发现人类干细胞造就新步骤； 骨髓移植医治 大疱性表皮松解症； 生物合成角膜有助视力复原；科学家 确认血脂代谢有关基因座 。
• 体内葡萄糖含量过高影响免疫系统
【提要】 起源：科技日报 颁布功夫： 2010-8-27 17:13:23
糖尿病患者除易患肾脏疾病等并发症表，也很容易被慢性细菌和真菌习染而患上炎症性疾病。对于这类并发症的病理机造，医学界一向不太明显。英国华威大学最新钻研批注，这是由于人体内葡萄糖水平过高影响了免疫系统，抑造其职能阐扬造成的�；笱� 8 月 25 日颁布的公报中称，该校钻研人员对人体血液和体液中的葡萄糖和另表两种糖——甘露糖和岩藻糖的化学结构进行了分析。甘露糖和岩藻糖是人体免疫受体鉴别细菌和真菌的象征，免疫受体味与这两种微糖绑定来匹敌习染。钻研人员发现，人体内葡萄糖水平一旦过高，其就会包办甘露糖和岩藻糖绑定免疫受体，从而故障免疫受体鉴别习染性细菌和真菌。这种越俎代劳的行为，会抑造人体匹敌习染的正常过程。它会抑造人体免疫系统 C 型凝聚素的职能。这些凝聚素中，蕴含甘露糖结合凝聚素（ MBL ），其职能失效，则会使人更易患上炎症性疾��；它也会影响免疫细胞表表受体 DC-SIGN 和 DC-SIGNR ，这两种受体存在于白血球、血幼板、血管内皮细胞等循环和血管系统的关键部位中，它们的职能受到抑造，则会导致糖尿病人出现心血管和肾脏并发症。
华威大学医学院的丹尼尔· 米切尔 博士暗示，葡萄糖水平与人体免疫系统之间的这种关系，使科学家对高葡萄糖对免疫系统和身段健全的影响有了新的意识。而日常生涯中维持合理的饮食结构，节造血糖水平则更显得沉要。他们将基于新发现来美满糖尿病疾病模型，以寻找新的防治伎俩。
【点评】
该项钻研发现了人体内 高水平葡萄糖会通过竞争性抑造来滋扰免疫受体对寡糖的体识，进而故障免疫受体鉴别习染性细菌和真菌，抑造人体匹敌习染的正常过程。对于人类，尤其是糖尿病人，沉新意识高血糖的生理意思及其对糖尿病并发症的作用有沉要影响。同时也提醒人们日常饮食摄入过多的糖分很可能会降低你的身段免疫力。
【原文摘录 】 Immunobiology doi:10.1016/j.imbio.2010.06.002
High glucose disrupts oligosaccharide recognition function via competitive inhibition: A potential mechanism for immune dysregulation in diabetes mellitus.
Ilyas R , Wallis R , Soilleux EJ , et al.
Diabetic complications include infection and cardiovascular disease. Within the immune system, host-pathogen and regulatory host-host interactions operate through binding of oligosaccharides by C-type lectin. A number of C-type lectins recognise oligosaccharides rich in mannose and fucose - sugars with similar structures to glucose. This raises the possibility that high glucose conditions in diabetes affect protein-oligosaccharide interactions via competitive inhibition. Mannose-binding lectin, soluble DC-SIGN and DC-SIGNR, and surfactant protein D, were tested for carbohydrate binding in the presence of glucose concentrations typical of diabetes, via surface plasmon resonance and affinity chromatography. Complement activation assays were performed in high glucose. DC-SIGN and DC-SIGNR expression in adipose tissues was examined via immunohistochemistry. High glucose inhibited C-type lectin binding to high-mannose glycoprotein and binding of DC-SIGN to fucosylated ligand (blood group B) was abrogated in high glucose. Complement activation via the lectin pathway was inhibited in high glucose and also in high trehalose - a nonreducing sugar with glucoside stereochemistry. DC-SIGN staining was seen on cells with DC morphology within omental and subcutaneous adipose tissues. We conclude that high glucose disrupts C-type lectin function, potentially illuminating new perspectives on susceptibility to infectious and inflammatory disease in diabetes. Mechanisms involve competitive inhibition of carbohydrate binding within sets of defined proteins, in contrast to broadly indiscriminate, irreversible glycation of proteins.
• MIT 科学家发现人类干细胞造就新步骤
【提要】
多职能干细胞可能分化成其他任何一种体细胞，在医治各类疾病方面拥有很大潜力。但是，若何造就足够量的多职能干细胞对钻研者来说是个问题；此表，目前用于造就人类干细胞的资料会导致免疫反映。为了克服这些问题，以美国麻省理工学院（ MIT ）科学家为首的钻研幼组发了然一种合成性基质（ synthetic substrate ）。这种基质没有表来动物资料，可能使干细胞至少三个月维持活性并自我滋生。并且，该合成性基质初次使得单细胞可能形成细胞集落。有关钻研颁发在 8 月 22 日的《天然—资料学》（ Nature Materials ）上。
以往钻研批注，基质表表的化学和物理个性，好比粗糙度、硬度、对水的亲和力等对干细胞成长有影响。 MIT 钻研人员创造了 500 种个性分歧的聚合物并在上面造就干细胞，分析每个聚合物上面细胞的成长情况。他们发现， 基质表表疏水性 对细胞成长有个最佳领域，而表表糙度和硬度则没有太多影响。此表，他们调整最佳聚合物的组成为：高比例的丙烯酸酯，名义包裹玻连蛋白。利用这种新的造就基质， MIT 科学家成功实现了人类胚胎干细胞持续三个月的成长和割裂，并获得了大量的细胞。他们将进一步钻研，争取将这种造就基质利用到其它类细胞。（ 起源： 科学网 www.sciencenet.cn 颁布功夫： 2010-8-24 10:43:34 ）
【点评】
新的造就基质能够使干细胞长功夫维持活性和自我滋生，对于解决干细胞钻研中获取大量干细胞的问题有很大援手。固然不能因而使干细胞医治有内容性进展，但至少有助于干细胞的尝试钻研。
【原文摘录】 Nature Materials 9, 768–778 doi:10.1038/nmat2812
Combinatorial development of biomaterials for clonal growth of human pluripotent stem cells
Ying Mei , Krishanu Saha , Said R. Bogatyrev ， et al.
Both human embryonic stem cells and induced pluripotent stem cells can self-renew indefinitely in culture; however, present methods to clonally grow them are inefficient and poorly defined for genetic manipulation and therapeutic purposes. Here we develop the first chemically defined, xeno-free, feeder-free synthetic substrates to support robust self-renewal of fully dissociated human embryonic stem and induced pluripotent stem cells. Material properties including wettability, surface topography, surface chemistry and indentation elastic modulus of all polymeric substrates were quantified using high-throughput methods to develop structure–function relationships between material properties and biological performance. These analyses show that optimal human embryonic stem cell substrates are generated from monomers with high acrylate content, have a moderate wettability and employ integrin α v β 3 and α v β 5 engagement with adsorbed vitronectin to promote colony formation. The structure–function methodology employed herein provides a general framework for the combinatorial development of synthetic substrates for stem cell culture.
• 骨髓移植医治 大疱性表皮松解症
【提要】 NEJM 颁布功夫： 2010-8-25 15:33:04
大疱性表皮松解症是由于皮肤结构蛋白的先性子缺点，使皮肤容易产生松解出现大疱。如单纯性大疱性表皮松解症是由于表皮基虚实胞的结构蛋白 -- 角蛋白 5 或角蛋白 14 的缺点所致；接壤性大疱性表皮松解症是由于 BPAG2 或板素 (Laminin)5 的缺点所致；营养不良型大疱性表皮松解症则是由于基底膜带中 Ⅶ 型胶原蛋白的缺点所致。现已弄清缺点的产生是由于这些编码蛋白的基因出现了突变，导致蛋白质的结构异常，使皮肤松解。只管遗传学基础已被说明，但仍无有效的医治。大疱性表皮松解的医治重要针对其继发习染，准则为精心护理，�；げ棵�，预防表伤、摩擦受热预防继发习染。利用干细胞产生新的组织和器官，建复破损的组织、器官，被称为再生医学。 美国《新英格兰医学杂志》（ NEJM ） 8 月 11 日登载明尼苏达大学钻研者约翰· 瓦格纳和雅各布·托拉尔的钻研汇报，初次显示骨髓干细胞可用于医治营养不良型大疱性表皮松解症，为根除这一顽疾带来了但愿。
【点评】
用于 6 名大疱性表皮松解症患者的同种异体骨髓移植的尝试性临床医治为从底子上治愈这一顽症提供了一种可能，只管这一步骤的持久风险和成效还有待进一步评估。另一方面，该钻研也提醒该医治中骨髓干细胞可能是分化成正常皮肤组织的起源。
【原文摘录 】 N Engl J Med 2010; 363:629-639 August 12, 2010
Bone Marrow Transplantation for Recessive Dystrophic Epidermolysis Bullosa
John E. Wagner, M.D., Akemi Ishida-Yamamoto, M.D., Ph.D., John A. McGrath, M.D., et al.
Background
Recessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL 7A 1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans.
Methods
Between October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize anchoring fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography.
Results
One patient died of cardiomyopathy before transplantation. Of the remaining six patients, one had severe regimen-related cutaneous toxicity, with all having improved wound healing and a reduction in blister formation between 30 and 130 days after transplantation. We observed increased C7 deposition at the dermal–epidermal junction in five of the six recipients, albeit without normalization of anchoring fibrils. Five recipients were alive 130 to 799 days after transplantation; one died at 183 days as a consequence of graft rejection and infection. The six recipients had substantial proportions of donor cells in the skin, and none had detectable anti-C7 antibodies.
Conclusions
Increased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation. Further studies are needed to assess the long-term risks and benefits of such therapy in patients with this disorder.
• 生物合成角膜有助视力复原
【提要】 起源：《科学—转化医学》 颁布功夫： 2010-8-27 16:22:22
加拿大和瑞典科研人员研造出一种生物合成角膜，援手眼疾患者建复受损眼组织，复原视力。由加拿大渥太华医院钻研所钻研员梅·格里菲思和瑞典林雪平大学眼科学教授佩尔·法格霍尔姆辅导的一个钻研幼组将 10 名患者角膜中的受损组织移除后，植入人造角膜。术后，钻研人员经过两年多的跟踪观察，发显熹中 9 名患者的人造角膜与眼球其他细胞融合。钻研人员说，接受移植后的眼球起头排泄泪液。 6 名患者的视力逐步复原。“这项钻研第一次批注，人造角膜能够与人的眼球融归并引发组织再生 , ”格里菲斯说：“随着钻研的深刻，这种方式能援手数以百万计期待角膜移植的人复原视力。”角膜是眼球表表覆盖的一层通明、胶片状组织，重要成分是蛋白胶原质，可能折射光线，将风物成像于视网膜上。只管角膜容易受到表伤或习染而受损，但眼下的医学技术可能通过角膜移植手术令患者复原视力。钻研人员说，由于眼角膜捐献数量有限，全球每年有很多人因角膜受伤致残。他们这项钻研成就有助于这些眼疾患者沉见光明。
【点评】
两年多跟踪观察 10 名移植了人造角膜的患者， 9 名患者的人造角膜与眼球其他细胞融合， 6 名患者的视力逐步复原。持久成效有待观察，但这项钻研第一次批注，人造角膜能够与人的眼球融归并引发组织再生，有可能援手因角膜受伤致残患者沉见光明。在医用资料而言是一大突破。
【原文摘录 】 Sci Transl Med Vol. 2, Issue 46, p. 46ra61 DOI: 10.1126/scitranslmed.3001022
A Biosynthetic Alternative to Human Donor Tissue for Inducing Corneal Regeneration: 24-Month Follow-Up of a Phase 1 Clinical Study
Per Fagerholm , Neil S. Lagali , Kimberley Merrett , et al.
Corneas from human donors are used to replace damaged tissue and treat corneal blindness, but there is a severe worldwide shortage of donor corneas. We conducted a phase 1 clinical study in which biosynthetic mimics of corneal extracellular matrix were implanted to replace the pathologic anterior cornea of 10 patients who had significant vision loss, with the aim of facilitating endogenous tissue regeneration without the use of human donor tissue. The biosynthetic implants remained stably integrated and avascular for 24 months after surgery, without the need for long-term use of the steroid immunosuppression that is required for traditional allotransplantation. Corneal reepithelialization occurred in all patients, although a delay in epithelial closure as a result of the overlying retaining sutures led to early, localized implant thinning and fibrosis in some patients. The tear film was restored, and stromal cells were recruited into the implant in all patients. Nerve regeneration was also observed and touch sensitivity was restored, both to an equal or to a greater degree than is seen with human donor tissue. Vision at 24 months improved from preoperative values in six patients. With further optimization, biosynthetic corneal implants could offer a safe and effective alternative to the implantation of human tissue to help address the current donor cornea shortage.
• 科学家确认血脂代谢有关基因座
【提要】 《天然》 颁布功夫： 2010-8-25 17:47:46
血液中总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯等脂类含量是导致冠状动脉疾�。� CAD ）的最沉要危险成分，同时也是防治该种疾病的沉要标靶。一国际钻研幼组在《天然》（ Nature ）杂志上登载汇报称，他们钻研确认了 95 个与人类血脂代谢有关的基因座，可作为冠状动脉疾病的生物学象征。钻研人员称，新钻研不仅扩大了科学家对人体脂类代谢的理解视野，同时也为开发新型防治冠状动脉疾病的靶向型药物奠定了基础。 该国际钻研幼组由英美等多国近百位科学家组成，他们对超过 10 万名拥有欧洲血统的自愿者的基因进行了分析，最终确认了 95 个与脂类代谢有关的基因座，其中有 59 个基因座是初次被认定。这 95 个基因座不仅会导致人体内脂类个性的通常性扭转，并且还会导致极端的脂类表型。钻研了局批注，一些新发现的基因座与冠状动脉疾病有关。钻研人员还就 GALNT2 、 PPP1R3B 和 TTC39B 这三种新基因在幼鼠模型上进行了验证。
钻研人员暗示，此项钻研是目前就人体脂类代谢机造生物学基础问题所进行的最全面的分析钻研，其主张是要找到血液中脂类荟萃的生物学象征，以作为冠状动脉疾病发展的指标。钻研了局则批注，通过抑造这些与脂类代谢有关的关键基因，能够起到预防心脏疾病的作用，这为开发新的靶向型药物提供了基础。英国伦敦国王大学的马西莫·曼 吉诺 博士指出，这项钻研对于科学家把握冠状动脉疾病的风险成分很有援手。固然钻研对象是拥有欧洲血统的自愿者，但钻研人员发现，这些基因座并非欧洲人独有，其对三个非欧洲人群体（东亚人、南亚人以及非洲裔美国人）的脂类个性也会产生沉要影响。作为此方面迄今为止最大规模的钻研，超大的样本量使得该了局同样拥有国际意思。（起源：科技日报 刘海英 / 刘霞）
【点评】
作为就人体脂类代谢机造生物学基础问题所进行超大样本量的最全面的分析钻研，对于科学家把握冠状动脉疾病的风险成分很有援手。但是否因而就能发展出更好的医治冠状动脉疾病的疗法或药物还看不出来。
【原文摘录 】 Nature doi:10.1038/nature09270
Biological, clinical and population relevance of 95 loci for blood lipids
Tanya M. Teslovich , Kiran Musunuru , Albert V. Smith , et al.
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci ( P < 5 × 10 −8 ), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP 7A 1 , NPC 1L 1 and SCARB1 ) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes— GALNT2 , PPP1R3B and TTC39B —with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.