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| 1 | Driving gene-engineered T cell immunotherapy of cancer显示文摘妄想的抗原受体(汽车) 设计基因的 T 房间治疗保持潜力与终末期癌在病人的生活有有意义的差别。为十年,癌症治疗基于生物物理的参数,与到 debulk 的外科的切除术,由放射和化疗列在后面指向很快成长的肿瘤房间,当时主要 sparing 静止正常纸巾。一突破与 allogeneic 骨头髓发生了与白血病为病人移植,它提供了一有时药品治疗。为稳固的肿瘤的采纳房间治疗的地与发现被建立渗入肿瘤的淋巴细胞能与变形黑瘤被扩展并且使用到对待和甚至痊愈病人。肿瘤特定的 T 房间受体(TCR ) 被识别并且设计了进耐心的外部血淋巴细胞,它也被发现治疗肿瘤。然而,这些被耐心的 HLA 限制限制。紧随来汽车的产生,把抗体的优美识别与一个 T 房间的受动器功能相结合。为与先进 B 房间恶意的多重表格对待病人的指向 CD19 的汽车的来临取得了大成功,与多达 95% 反应率。然而,到稳固的肿瘤的适用的汽车治疗刚开始了,但是已经,某些因素被弄明白:肿瘤目标具有最大的重要性让临床医生不做伤害;并且稳固的肿瘤与 hematologic 相比对汽车治疗不同地作出回应。这里,我们考察临床的设计基因的 T 房间免疫疗法,它的成功,挑战,和未来的状态。 | Laura A Johnson Carl H June | 2017 | Cell Research2017,27,1: | 37 |
| 2 | An integrated approach for increasing breeding efficiency in apple and peach in Europe显示文摘Despite the availability of whole genome sequences of apple and peach,there has been a considerable gap between genomics and breeding.To bridge the gap,the European Union funded the FruitBreedomics project(March 2011 to August 2015)involving 28 research institutes and private companies.Three complementary approaches were pursued:(i)tool and software development,(ii)deciphering genetic control of main horticultural traits taking into account allelic diversity and(iii)developing plant materials,tools and methodologies for breeders.Decisive breakthroughs were made including the making available of ready-to-go DNA diagnostic tests for Marker Assisted Breeding,development of new,dense SNP arrays in apple and peach,new phenotypic methods for some complex traits,software for gene/QTL discovery on breeding germplasm via Pedigree Based Analysis(PBA).This resulted in the discovery of highly predictive molecular markers for traits of horticultural interest via PBA and via Genome Wide Association Studies(GWAS)on several European genebank collections.FruitBreedomics also developed pre-breeding plant materials in which multiple sources of resistance were pyramided and software that can support breeders in their selection activities.Through FruitBreedomics,significant progresses were made in the field of apple and peach breeding,genetics,genomics and bioinformatics of which advantage will be made by breeders,germplasm curators and scientists.A major part of the data collected during the project has been stored in the FruitBreedomics database and has been made available to the public.This review covers the scientific discoveries made in this major endeavour,and perspective in the apple and peach breeding and genomics in Europe and beyond. | Francois Laurens Maria JoséAranzana Pere Arus Daniele Bassi Marco Bink Joan Bonany Andrea Caprera Luca Corelli-Grappadelli Evelyne Costes Charles-Eric Durel Jehan-Baptiste Mauroux Hélène Muranty Nelson Nazzicari Thierry Pascal Andrea Patocchi Andreas Peil Bénédicte Quilot-Turion Laura Rossini Alessandra Stella Michela Troggio Riccardo Velasco Eric van de Weg | 2018 | Horticulture Research2018,5,1: | 10 |
| 3 | 国际抗癫痫联盟心理工作组循证建议:成人和儿童癫痫患者的心理治疗显示文摘社会心理因素和癫痫治疗可能对癫痫患者及其家庭的健康相关生活质量(Health-related quality of life,HRQOL)产生显著影响,临床上广泛关注心理评估和治疗在改善HRQOL和癫痫共病中的作用。因此,国际抗癫痫联盟(ILAE)委托心理工作组,基于其最近对癫痫患者心理治疗的Cochrane回顾证据的评估,制定了相关临床建议。近期关于癫痫患者心理治疗随机对照试验的Cochrane回顾是本文的主要证据来源。为提供具有实用意义的指导,我们根据美国神经病学学会证据水平系统以及推荐分级、评估、开发和评价系统对研究设计进行评级。本文是儿童和成人心理学家、神经病学家、精神病学家和神经精神病学家进行国际合作的顶点。ILAE执行委员会审查并批准了这一进程和结论。心理干预的最强证据被确定为最常见的心理健康问题,包括抑郁症、神经认知障碍和药物依从性。针对提高HRQOL和依从性以及减少共病症状(焦虑、抑郁)的心理干预应纳入癫痫综合护理中。一系列的心理策略(如认知行为疗法和正念疗法)为提升癫痫患者生活质量带来希望,也给癫痫临床工作者提供了治疗癫痫共病、应对挑战的临床建议。 | Rosa Michaelis Venus Tang Laura H Goldstein 肖英凤(译) 童馨(审) 慕洁(审) | 2019 | 癫痫杂志2019,5,4: | 9 |
| 4 | Targeting collagen expression in alcoholic liver disease显示文摘Alcoholic liver disease(ALD)is a leading cause of liver disease and liver-related deaths globally,particularly in developed nations.Liver fibrosis is a consequence of ALD and other chronic liver insults,which can progress to cirrhosis and hepatocellular carcinoma if left un-treated.Liver fibrosis is characterized by accumulation of excess extracellular matrix components,including typeⅠcollagen,which disrupts liver microcirculation and leads to injury.To date,there is no therapy for the treatment of liver fibrosis;thus treatments that either prevent the accumulation of typeⅠcollagen or hasten its degradation are desirable.The focus of this review is to examine the regulation of typeⅠcollagen in fibrogenic cells of the liver and to discuss current advances in therapeutics to eliminate excessive collagen deposition. | Kyle J Thompson Iain H McKillop Laura W Schrum | 2011 | World Journal of Gastroenterology2011,17,20: | 7 |
| 5 | Chronic stress sensitizes rats to pancreatitis induced by cerulein:Role of TNF-α显示文摘AIM:To investigate chronic stress as a susceptibility factor for developing pancreatitis,as well as tumor necrosis factor-α (TNF-α) as a putative sensitizer.METHODS:Rat pancreatic acini were used to analyze the influence of TNF-α on submaximal (50 pmol/L) cholecystokinin (CCK) stimulation.Chronic restraint (4 h every day for 21 d) was used to evaluate the effects of submaximal (0.2 μg/kg per hour) cerulein stimulation on chronically stressed rats.RESULTS:In vitro exposure of pancreatic acini toTNF-α disorganized the actin cytoskeleton.This was further increased by TNF-α/CCK treatment,which additionally reduced amylase secretion,and increased trypsin and nuclear factor-κB activities in a protein-kinase-C δ and ε-dependent manner.TNF-α/CCK also enhanced caspases' activity and lactate dehydrogenase release,induced ATP loss,and augmented the ADP/ATP ratio.In vivo,rats under chronic restraint exhibited elevated serum and pancreatic TNF-α levels.Serum,pancreatic,and lung inflammatory parameters,as well as caspases' activity in pancreatic and lung tissue,were substantially enhanced in stressed/cerulein-treated rats,which also experienced tissues' ATP loss and greater ADP/ATP ratios.Histological examination revealed that stressed/cerulein-treated animals developed abundant pancreatic and lung edema,hemorrhage and leukocyte infiltrate,and pancreatic necrosis.Pancreatitis severity was greatly decreased by treating animals with an anti-TNF-αantibody,which diminished all inflammatory parameters,histopathological scores,and apoptotic/necrotic markers in stressed/cerulein-treated rats.CONCLUSION:In rats,chronic stress increases susceptibility for developing pancreatitis,which involves TNF-α sensitization of pancreatic acinar cells to undergo injury by physiological cerulein stimulation. | Marcelo G Binker Andres A Binker-Cosen Daniel Richards Herbert Y Gaisano Rodica H de Cosen Laura I Cosen-Binker | 2010 | World Journal of Gastroenterology2010,16,44: | 7 |
| 6 | Counter-regulatory phosphatases TNAP and NPP1 temporally regulate tooth root cementogenesis显示文摘Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone.Biomineralization is regulated by the ratio of inorganic phosphate(Pi) to mineral inhibitor pyrophosphate(PPi), where local Piand PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase(TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1(NPP1). The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enpp1 null mouse increased acellular cementum, with little effect on cellular cementum.Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enpp1 gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPienvironment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPihave little effect on cellular cementum formation, though matrix mineralization is affected. | Laura E Zweifler Mudita K Patel Francisco H Nociti Jr Helen F Wimer Jose L Milln Martha J Somerman Brian L Foster | 2015 | International Journal of Oral Science2015,7,1: | 5 |
| 7 | Approach to medical therapy in perianal Crohn’s disease显示文摘Perianal Crohn’s disease remains a challenging condition to treat and can have a substantial negative impact on quality of life.It often requires combined surgical and medical interventions.Anti-tumor necrosis factor(anti-TNF)therapy,including infliximab and adalimumab,remain preferred medical therapies for perianal Crohn’s disease.Infliximab has been shown to be efficacious in improving fistula closure rates in randomized controlled trials.Clinicians can be faced with a number of questions relating to the optimal use of anti-TNF therapy in perianal Crohn’s disease.Specific issues include evaluation for the presence of perianal sepsis,the treatment target of therapy,the ideal time to commence treatment,whether additional medical therapy should be used in conjunction with anti-TNF therapy,and the duration of treatment.This article will discuss key studies which can assist clinicians in addressing these matters when they are considering or have already commenced anti-TNF therapy for the treatment of perianal Crohn’s disease.It will also discuss current evidence regarding the use of vedolizumab and ustekinumab in patients who are failing to achieve a response to anti-TNF therapy for perianal Crohn’s disease.Lastly,new therapies such as local injection of mesenchymal stem cell therapy will be discussed. | Abhinav Vasudevan David H Bruining Edward V Loftus Jr William Faubion Eric C Ehman Laura Raffals | 2021 | World Journal of Gastroenterology2021,27,25: | 4 |
| 8 | Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety-related behavior in mice显示文摘Epigenetic 基因规定畸形包括精神分裂症和消沉在各种各样的 neuropsychiatric 混乱,以及在心情和焦虑的规定被含有。另外, epigenetic 机制涉及精神病学的药的行动。当前的 anxiolytic 药有新药的重要缺点,和开发被保证。二蛋白质, G9a (也作为 EHMT2 或 KMT1C 知道) 并且 GLP (象 G9a 一样蛋白质,也作为 EHMT1 或 KMT1D 知道) ,它甲醇化物离氨酸 9 histone H3 (H3K9 ) ,能正在答应 anxiolytic 目标。G9a 的出生后的基因大美人减少焦虑相关的行为,与由过去常对待焦虑(amitriptyline, imipramine 和 paroxetine ) 的一些药的 G9a 层次的减小一致。相反地,在有 GLP haplodeficiency 的老鼠有增加的像焦虑的行为。我们寻求了决定是否 G9a/GLP, UNC0642 和 A-366 的二个药理学禁止者,将有类似的效果到基因 G9a/GLP 不足。当予成年老鼠以时,我们发现有任何一个化合物的 G9a/GLP 抑制减少了像焦虑的行为,与在大脑的减少的 H3K9 methylation 一起。相反,到这些的暴露从胚胎的白天加重(E9.5 ) 9.5 增加了像焦虑的行为直到出生并且减少在成人生活的社会相互作用,当 H3K9 methylation 在在成年老鼠的大脑的正常层次时。这些调查结果增强 G9a/GLP 在大脑开发的不同阶段在像焦虑的行为上有不同效果的基因证据,并且建议指向这条 histone methyltransferase 小径能为开发新 anxiolytic 药是有用的。这些数据也建议在 utero 的抗抑郁剂暴露能在成人生活有否定效果,并且这些效果的进一步的调查被保证。 | Dong-yao WANG Joel KOSOWAN James SAMSOM Laura LEUNG Kai-lai ZHANG Ying-xiang LI Yan XIONG Jian JIN Arturas PETRONIS Gabriel OH Albert H C WONG | 2018 | Acta Pharmacologica Sinica2018,39,5: | 4 |
| 9 | Proximal gastric response to small intestinal nutrients is abnormal in mechanically ventilated critically ill patients显示文摘瞄准:在非常有病的病人决定近似的胃的反应到小肠的营养素。方法:近似胃的活动性在 13 个非常有病的病人被测量(49.3 +/- 4.7 年) 并且 12 个健康志愿者(27.7 +/- 2.9 年) 用一种 barostat 技术。记录在基线被执行,在 60-min 期间 intra 十二指肠的注入保证(2 kcal/min ) ,并且为跟随注入的 2 h。最小的扩张压力(MDP ) , intra 袋子体积和底的波浪活动是坚定的。结果:MDP 在病人是更高的(11.7 +/- 1.1 对 7.8 +/- 0.7 毫米汞柱;P <
0.01 ) 。基线 intra 袋子体积在 2 个组是类似的。在健康题目,一“双性人形式”近似胃的体积反应被观察。在病人,近似胃的体积的起始的增加小、推迟,但是最后到达了类似于健康题目的最大的体积。在健康题目,近似胃的体积很快在滋养的注入以后回到了基线水平(中部 18 min ) 。相反,到基线的体积的恢复在非常有病的病人被推迟(中部 106 min ) 。在 6 个病人,体积没在滋养的注入以后回到基线水平 2 小时。在病人,底的体积波浪是不太经常的(P <
0.05 ) 并且有的更低的振幅(P <
0.001 ) ,与健康题目相比。结论:在重病,对小肠的滋养的刺激的近似胃的马达回答是反常的。 | Nam Q Nguyen Robert J Fraser Marianne Chapman Laura K Bryant Richard H Holloway Rosalie Vozzo Christine Feinle-Bisset | 2006 | World Journal of Gastroenterology2006,12,27: | 3 |
| 10 | Comparative transcriptomics of Central Asian Vitis vinifera accessions reveals distinct defense strategies against powdery mildew显示文摘Grape powdery mildew(PM),caused by the biotrophic ascomycete Erysiphe necator,is a devastating fungal disease that affects most Vitis vinifera cultivars.We have previously identified a panel of V.vinifera accessions from Central Asia with partial resistance to PM that possess a Ren1-like local haplotype.In this study,we show that in addition to the typical Ren1-associated late post-penetration resistance,these accessions display a range of different levels of disease development suggesting that alternative alleles or additional genes contribute to determining the outcome of the interaction with the pathogen.To identify potential Ren1-dependent transcriptional responses and functions associated with the different levels of resistance,we sequenced and analyzed the transcriptomes of these Central Asian accessions at two time points of PM infection.Transcriptomes were compared to identify constitutive differences and PM-inducible responses that may underlie their disease resistant phenotype.Responses to E.necator in all resistant accessions were characterized by an early up-regulation of 13 genes,most encoding putative defense functions,and a late down-regulation of 32 genes,enriched in transcriptional regulators and protein kinases.Potential Ren1-dependent responses included a hotspot of co-regulated genes on chromosome 18.We also identified 81 genes whose expression levels and dynamics correlated with the phenotypic differences between the most resistant accessions‘Karadzhandahal’,DVIT3351.27,and O34-16 and the other genotypes.This study provides a first exploration of the functions associated with varying levels of partial resistance to PM in V.vinifera accessions that can be exploited as sources of genetic resistance in grape breeding programs. | Katherine C H Amrine Barbara Blanco-Ulate Summaira Riaz Dániel Pap Laura Jones Rosa Figueroa-Balderas M Andrew Walker Dario Cantu | 2015 | Horticulture Research2015,2,1: | 3 |
| 11 | Proximal gastric motility in critically ill patients with type 2 diabetes mellitus显示文摘AIM: To investigate the proximal gastric motor response to duodenal nutrients in critically ill patients with long- standing type 2 diabetes mellitus. METHODS: Proximal gastric motility was assessed (using a barostat) in 10 critically ill patients with type 2 diabetes mellitus (59 ± 3 years) during two 60-min duodenal infusions of Ensure? (1 and 2 kcal/min), in random order, separated by 2 h fasting. Data were compared with 15 non-diabetic critically ill patients (48 ± 5 years) and 10 healthy volunteers (28 ± 3 years). RESULTS: Baseline proximal gastric volumes were similar between the three groups. In diabetic patients, proximal gastric relaxation during 1 kcal/min nutrient infusion was similar to non-diabetic patients and healthy controls. In contrast, relaxation during 2 kcal/ min infusion was initially reduced in diabetic patients (P < 0.05) but increased to a level similar to healthy humans, unlike non-diabetic patients where relaxation was impaired throughout the infusion. Duodenal nutrient stimulation reduced the fundic wave frequency in a dose-dependent fashion in both the critically ill diabetic patients and healthy subjects, but not in critically ill patients without diabetes. Fundic wave frequency in diabetic patients and healthy subjects was greater than in non-diabetic patients. CONCLUSION: In patients with diabetes mellitus, proximal gastric motility is less disturbed than non- diabetic patients during critical illness, suggesting that these patients may not be at greater risk of delayed gastric emptying. | Nam Q Nguyen Robert J Fraser Laura K Bryant Marianne Chapman Richard H Holloway | 2007 | World Journal of Gastroenterology2007,13,2: | 3 |
| 12 | CD4+ T cells and natural killer cells: Biomarkers for hepatic fibrosis in human immunodeficiency virus/hepatitis C virus-coinfected patients显示文摘AIM To characterize peripheral blood natural killer(NK) cells phenotypes by flow cytometry as potential biomarker of liver fibrosis in human immunodeficiency virus(HIV)/hepatitis C virus(HCV) coinfected patients.METHODS Peripheral mononuclear cells from 24 HIV/HCV(HBVnegative) coinfected and 5 HIV/HCV/HBV seronegative individuals were evaluated. HIV/HCV coinfected patients were divided in to groups: G1, patients with METAVIR F0-F2 and G2, patients with METAVIR F3-F4. NK surface cell staining was performed with: AntiCD3(APC/Cy7), anti-CD56(PE/Cy5), anti-CD57(APC), anti-CD25(PE), anti-CD69(FITC), anti-NKp30(PE), antiNKp46(PE/Cy7), anti-NKG2D(APC), anti-DNAM(FITC); anti-CD62L(PE/Cy7), anti-CCR7(PE), anti-TRAIL(PE), anti-Fas L(PE), anti CD94(FITC). Flow cytometry data acquisition was performed on BD FACSCanto, analyzed using Flow Jo software. Frequency of fluorescence was analyzed for all single markers. Clinical records were reviewed, and epidemiological and clinical data were obtained.RESULTS Samples from 11 patients were included in G1 and from 13 in G2. All patients were on ARV, with undetectable HIV viral load. Liver fibrosis was evaluated by transient elastography in 90% of the patients and with biopsy in 10% of the patients. Mean HCV viral load was(6.18 ± 0.7 log10). Even though, no major significant differences were observed between G1 and G2 regarding NK surface markers, it was found that patients with higher liver fibrosis presented statistically lower percentage of NK cells than individual with low to mild fibrosis and healthy controls(G2: 5.4% ± 2.3%, G1: 12.6% ± 8.2%, P = 0.002 and healthy controls 12.2% ± 2.7%, P = 0.008). It was also found that individuals with higher liver fibrosis presented lower CD4 LT count than those from G1(G2: 521 ± 312 cells/μL, G1: 770 ± 205 cells/μL; P = 0.035).CONCLUSION Higher levels of liver fibrosis were associated with lower percentage of NK cells and LTCD4+ count; and they may serve as noninvasive biomarkers of liver damage. | Natalia Laufer Diego Ojeda María Laura Polo Ana Martinez Héctor Pérez Gabriela Turk Pedro Cahn Norberto Walter Zwirner Jorge Quarleri | 2017 | World Journal of Hepatology2017,9,25: | 2 |
| 13 | Phospholipid Scramblase 1 regulates Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells显示文摘像使用费的受体(TLR9 ) 9 在 plasmacytoid 的内涵体察觉到微生物引起的 DNA 树枝状的房间(pDCs ) 和扳机 MyD88 依赖的类型我干扰素(IFN ) 回答。更好在 pDCs 理解 TLR9 生物学,我们建立了酵母为交往 TLR9 蛋白质的鉴定的二混血儿的图书馆。这里,我们报导那 IFN 可诱导的蛋白质, phospholipid scramblase 1 (PLSCR1 ) ,在 pDCs 与 TLR9 交往。由在人的 pDC 的 siRNA 的 PLSCR1 表示击倒房间线导致了 IFN-α 的 60-70% 减小;回答列在后面 CpG-ODN (oligodeoxynucleotide ) 刺激。从生产的 PLSCR1 缺乏的老鼠的主要 pDCs 响应 CpG-ODN 从野类型的老鼠比 pDCs 降低类型 1 IFN 的数量,疱疹单一的病毒和流行性感冒 A 病毒。后面的 CpG -- 刺激,有在和 CpG 的早内涵体的 TLR9 的低得多的数量 -- 在从 PLSCR1 缺乏的老鼠的 pDCs 的 A。我们的学习证明 PLSCR1 是在 pDC 的类型起一个重要作用的交往 TLR9 蛋白质由调整 TLR9 trafficking 到 endosomal 分隔空间的 1 IFN 回答。 | Amjad H Talukder Musheng Bao Tae Whan Kim Valeria Facchinetti Shino Hanabuchi Laura Bover Tomasz Zal Yong-Jun Liu | 2012 | Cell Research2012,22,7: | 2 |
| 14 | T S Internal Monitoring Mechanisms and CEO Turnover: Along-term Perspective 显示文摘 | Mark R H Robert P Laura | 2001 | The Journal of Fi- nance2001,,6: | 1 |
| 15 | Free cupric ion concentration and Cu speciation in a eutrophic lake显示文摘 | XUE H B LAURA S | 1993 | Limnol Oceanogr1993,38,6: | 1 |
| 16 | Effect of Glass Fiber and Maleated Ethylene-Propylene Rubber Content on the Impact Fracture Parameters of Nylon 6显示文摘 | D M Laura H Keskkula J W Barlow D R Paul | 2001 | Polymer2001,42,: | 1 |
| 17 | Exercise Training in Patients With Severe Congestive Heart Failure: Enhancing Peak Aerobic Capacity While Minimizing the Increase in Ventricular Wall Stress显示文摘 | Laura Demopoulos Rachel Bijou Icilma Fergus Margaret Jones Joel Strom Thierry H LeJemtel | 1997 | Journal of the American College of Cardiology1997,,3: | 1 |
| 18 | Mycobacterium bovis BCG-Induced Granuloma Formation Depends on Gamma Interferon and CD40 Ligand but Does Not Require CD28显示文摘 | Laura H Wes Markofski Anja Bock | 2001 | Infect Immun2001,69,4: | 1 |
| 19 | Regulation of Retinal Cone Bipolar Cell Differentiation and Photopic Vision by the CVC Homeobox Gene Vsx1显示文摘 | Akihira Ohtoshi Steven W Wang Hidetaka Maeda Shannon M Saszik Laura J Frishman William H Klein Richard R Behringer | 2004 | Current Biology2004,,6: | 1 |
| 20 | Effect of Glass Fiber Surface Chemistry on the Mechanical Properties of Glass Fiber Reinforced, Rubber-toughened Nylon 6 显示文摘 | D M Laura H Keskkula J W Barlow D R Paul | 2002 | Polymer2002,43,: | 1 |