BACKGROUND & AIMS: :Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.

背景与目标： ：人类有两个谷氨酰胺酶基因，GLS（GLS1）和GLS2，每个都有两个替代转录物：GLS的肾脏同种型（KGA）和谷氨酰胺酶C（GAC），肝脏同种型（LGA）和谷氨酰胺酶B（GAB）适用于GLS2。初始命中化合物（Z）-5-（（（1-（4-溴苯基）-2,5-二甲基-1H-吡咯-3-基）亚甲基）噻唑烷-2,4-二酮（2），噻唑烷-2通过对KGA筛选40000种化合物的高通量筛选获得了4-4-二酮。随后，合成了一系列噻唑烷-2,4-二酮衍生物。发现其中大多数可抑制KGA和GAC的活性相当，对GAB的抑制作用较弱，并且对GLS1的选择性比对GLS2的中等。研究了化学结构，活性和选择性之间的关系。发现获得的先导化合物（1）提供体外细胞活性以抑制细胞生长，克隆形成和细胞谷氨酸生成；（2）通过药代动力学研究显示血浆中高浓度暴露；（3）减小肿瘤大小小鼠体内异种移植人胰腺AsPC-1癌细胞的表达。

BACKGROUND & AIMS: BACKGROUND:Outcome in stroke trials is often based on a 3-month modified Rankin scale (mRS). How 3-month mRS relates to longer-term outcomes will depend on late recovery, delayed stroke-related deaths, recurrent strokes, and nonstroke deaths. We evaluated 3-month mRS and death/disability at 1 and 5 years in a population-based cohort study. METHODS AND RESULTS:In 3-month survivors of ischemic stroke (Oxford Vascular Study; 2002-2014), we related 3-month mRS to disability (defined as mRS >2) at 1 and 5 years and/or death rates (age/sex adjusted). Accrual of disability and index-stroke-related and nonstroke deaths in each poststroke year was categorized according to 3-month mRS. Among 1606 patients with acute ischemic stroke, 181 died within 3 months, but 126 index-stroke-related deaths and 320 other deaths occurred during the subsequent 4866 patient-years of follow-up up to 5 years. Although 69/126 (54.8%) post-3-month index-stroke-related deaths occurred after 1 year, mRS>2 at 1 year strongly predicted these deaths (adjusted hazard ratio=21.94, 95%CI 7.88-61.09, P<0.0001). Consequently, a 3-month mRS >2 was a strong independent predictor of death at both 1 year (adjusted hazard ratio=6.67, 95%CI 4.16-10.69, P<0.0001) and 5 years (adjusted hazard ratio=2.93, 95%CI 2.38-3.60, P<0.0001). Although mRS improved by ≥1 point from 3 months to 1 year in 317/1266 (25.0%) patients with 3-month mRS ≥1, improvement in mRS after 1 year was limited (improvement by ≥1 point: 91/858 [10.6%]; improvement to mRS ≤2: 13/353 [3.7%]). CONCLUSIONS:Our results reaffirm use of the 3-month mRS outcome in stroke trials. Although later recovery does occur, extending follow-up to 1 year would capture most long-term stroke-related disability. However, administrative mortality follow-up beyond 1 year has the potential to demonstrate translation of early disability gains into additional reductions in long-term mortality without much erosion by non-stroke-related deaths.

背景与目标： 背景：中风试验的结果通常基于3个月的改良兰金量表（mRS）。 3个月的mRS与长期结果的关系将取决于晚期康复，中风相关的延迟死亡，中风复发和非中风死亡。在一项基于人群的队列研究中，我们评估了3个月的mRS和1年和5年时的死亡/残疾。
方法和结果：在3个月的缺血性中风幸存者中（牛津血管研究; 2002-2014），我们将3个月的mRS与1岁和5岁时的残疾（定义为mRS> 2）和/或死亡率（年龄/性别调整）。根据每个月的3个月mRS对残疾的累积以及与卒中相关的卒中和非卒中死亡进行分类。在1606例急性缺血性中风患者中，有3个月内有181例死亡，但在随后的4866个患者年的随访中（长达5年）发生了126例与中风相关的死亡，还有320例其他死亡。尽管1年后发生69/126（54.8％）的3个月后与指数卒中相关的死亡，但1年时的mRS> 2强烈预测了这些死亡（调整后的危险比= 21.94，95％CI 7.88-61.09，P < 0.0001）。因此，在1年（调整后的危险比= 6.67，95％CI 4.16-10.69，P <0.0001）和5年（调整后的危险比= 2.93，95％）下，三个月的mRS> 2是死亡的强有力的独立预测因子。 CI 2.38-3.60，P <0.0001）。尽管317/1266（35.0％）3个月mRS≥1的患者在3个月至1年间mRS改善了≥1点，但1年后mRS的改善是有限的（≥1点的改善：91/858 [10.6 ％]； mRS≤2的改善：13/353 [3.7％]）。
结论：我们的研究结果重申了在卒中试验中使用3个月的mRS结果。尽管确实会出现稍后的康复，但将随访延长至1年将捕获大多数与中风相关的长期残疾。但是，对1年以上的行政死亡率进行随访，有可能证明将早期残疾的增加转化为长期死亡率的进一步降低，而不会因非中风相关的死亡而受到很大的侵蚀。

BACKGROUND & AIMS: :Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.

背景与目标： ：胃蛋白酶是天冬氨酸蛋白酶，参与宿主细胞血红蛋白的降解，被疟原虫用作食物来源。纤溶酶作为药物靶标非常有前途，特别是与抑制也与血红蛋白分解代谢有关的falcipains结合使用时。在这篇综述中，我们鉴于对过渡态模拟物作为潜在的潜在铅化合物的发展感兴趣，讨论了纤溶酶I-IV的机制。概述了针对纤溶酶II的抑制剂的开发以及相关的晶体结构，以便对该领域进行概述。计算技术的应用，特别是通过线性相互作用能法的结合亲和力预测，在疟疾纤溶酶抑制剂的开发中已经取得了很大的成功，并进行了详细的讨论。均相建模和分子对接在当前的抑制剂设计项目中非常有用，并且分析了这些方法与结合自由能计算的结合。

BACKGROUND & AIMS: :The purpose of this study was to evaluate the outcome of patients who underwent glenoid bone grafting and implantation of a reverse design prosthesis in 1 or 2 stages for the treatment of glenoid bone loss and rotator cuff insufficiency. Indications for the reverse prosthesis in this series included cuff tear arthropathy and revision arthroplasty. Nine patients were reviewed clinically and radiographically with a minimum 2-year follow-up (range, 24-41 months). Despite a low postoperative functional score (mean Constant score, 53 points [range, 22-79 points]), most patients were satisfied with their results primarily because of pain relief. (The mean pain score increased from 3 points preoperatively to 12.5 points postoperatively.) Radiographic evaluation did not demonstrate component loosening or evidence of graft failure. Six patients had radiographic evidence of an inferior scapular notch, which may be of concern in the future. Early results of this procedure are encouraging, but further clinical and radiologic assessment is necessary.

背景与目标： ：本研究的目的是评估接受关节盂骨移植并在1或2个阶段植入反向设计假体以治疗关节盂骨丢失和肩袖功能不全的患者的预后。本系列反向假体的适应症包括袖套撕裂性关节炎和翻修置换术。对9例患者进行了临床和影像学检查，至少随访2年（范围24-41个月）。尽管术后功能评分较低（平均恒定评分为53分[范围，22-79分]），但大多数患者对他们的结果感到满意的主要原因是疼痛减轻。 （平均疼痛评分从术前的3分增加到术后的12.5分。）影像学评估未显示组件松动或移植失败的迹象。六例患者的放射学证据显示肩s骨下凹，将来可能会引起关注。该方法的早期结果令人鼓舞，但需要进一步的临床和放射学评估。

BACKGROUND & AIMS: :The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI50 values in the submicromolar (0.033-0.630 μM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI50 values of 0.063 and 0.033 μM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling.

背景与目标： ：7-氮杂茚并异喹啉是细胞毒性拓扑异构酶I（Top1）抑制剂。以前报道的代表带有一个3-硝基基团。本报告记录了潜在的具有遗传毒性的3-硝基被3-氯和3-氟取代基取代，从而导致在人类癌细胞培养中具有高Top1抑制活性和强细胞毒性的化合物，并降低了动物模型的致死率。一些新的Top1抑制剂还具有对酪氨酰DNA磷酸二酯酶1（TDP1）和酪氨酰DNA磷酸二酯酶2（TDP2）的中等抑制活性，这两种酶都参与了由Top1抑制剂引起的DNA损伤修复，并且它们产生的DNA明显更多。在癌细胞中的损伤要比正常细胞中的损伤大。 18种新化合物的细胞毒性平均图中点（MGM）GI50值在亚微摩尔（0.033-0.630μM）范围内。化合物16b和17b在人类癌细胞培养物中最有效，其MGM GI50值分别为0.063和0.033μM。通过分子建模研究了与Top1和TDP1可能的结合模式。

BACKGROUND & AIMS: :We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.

背景与目标： ：我们最近报道了八氢吡咯并[1,2-a]吡嗪A作为凋亡蛋白（IAP）拮抗剂抑制剂的先导化合物的发现。为了开发具有良好PK谱的IAP拮抗剂，我们基于A与细胞的共晶体结构分析，设计了新颖的三环化合物，八氢-1H-环丙[4,5]吡咯并[1,2-a]吡嗪1和2。 IAP-1（cIAP-1）。额外的环丙烷部分用于封闭化合物A的预测代谢位点，而不会损害对cIAP的结合亲和力。经由中间体4a和5b'立体选择性地合成化合物1和2，所述中间体通过乙酯3a和甲硅烷基醚3b'的Simmons-Smith环丙烷化获得。与A相比，化合物1和2在MDA-MB-231乳腺癌细胞中显示出强大的生长抑制作用，并改善了代谢稳定性。化合物2在剂量方面具有显着的体内PD效应，从而增加了肿瘤坏死因子-αmRNA的表达。

BACKGROUND & AIMS: :A series of 1-methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (3a-k and 4a-u) were designed, synthesized, and evaluated for their inhibitory efficacy towards the two hMAO isoforms. Most of the derivatives were found to be potent and selective hMAO-B inhibitors. In particular, derivative 3g showed greater hMAO-B affinity than selective inhibitor selegiline coupled with high selectivity index (SI=145). The most selective hMAO-B inhibitor was the 3-methyl analogue 3f with an SI higher than 909.

背景与目标： ：设计，合成了一系列1-甲基-3,5-二苯基-4,5-二氢-1H-吡唑（3a-k和4a-u），并评估了它们对两种hMAO同工型的抑制作用。发现大多数衍生物是有效的和选择性的hMAO-B抑制剂。特别是，衍生物3g与选择性抑制剂司来吉兰相比具有更高的hMAO-B亲和力，并具有高选择性指数（SI = 145）。最具选择性的hMAO-B抑制剂是3-甲基类似物3f，SI高于909。

BACKGROUND & AIMS: :Walking outdoors is often difficult or impossible for many seniors and people with disabilities during winter. We present a novel approach for conducting winter accessibility evaluations of commonly used pedestrian facilities, including sidewalks, street crossings, curb ramps (curb cuts and dropped curbs), outdoor stairs and ramps, building and transit entrances, bus stops, and driveways. A total of 183 individuals, aged 18-85 completed our survey. The results show that cold weather itself had little impact on the frequency of outdoor excursions among middle-aged and older adults while the presence of snow and/or ice on the ground noticeably kept people, especially older adults at home. The survey found that the key elements decreasing winter accessibility were icy sidewalks and puddles at street crossings and curb ramps. While communities have recognized the need to improve snow and ice removal, little attention has been paid to curb ramp design which is especially ineffective in winter when the bottom of the ramps pool with rain, snow, and ice, making it hazardous and inaccessible to nearly all users. We conclude that investigations of alternative designs of curb ramp are needed.

背景与目标： ：在冬天，对于许多老年人和残疾人来说，户外散步通常很困难或不可能。我们提出了一种新颖的方法，用于对常用的行人设施进行冬季可达性评估，包括人行道，人行横道，路缘坡道（路缘削减和掉落的路缘），室外楼梯和坡道，建筑物和公交入口，公交车站和车道。共有183位年龄在18-85岁之间的人完成了我们的调查。结果表明，寒冷的天气本身对中年和老年人的户外旅行的频率几乎没有影响，而地面上积雪和/或冰的存在则使人们尤其是老年人更加留在家里。调查发现，影响冬季通行能力的关键因素是人行横道，路口和路缘坡道上的水坑。尽管社区已经认识到需要改善除冰和除冰的必要性，但很少有人关注遏制坡道的设计，这种设计在冬季坡道池底部积有雨，雪和冰的情况下尤其无效，这使得它几乎是危险的并且难以接近所有用户。我们得出结论，需要研究路缘坡道的替代设计。

BACKGROUND & AIMS: :Purine-binding proteins are of critical importance to all living organisms. Approximately 13% of the human genome is devoted to coding for purine-binding proteins. Given their importance, purine-binding proteins are attractive targets for chemotherapeutic intervention against a variety of disease states, particularly cancer. Modern computational and biophysical techniques, combined together in a structure-based drug design approach, aid immensely in the discovery of inhibitors of these targets. This review covers the process of modern structure-based drug design and gives examples of its use in discovery and development of drugs that target purine-binding proteins. The targets reviewed are human purine nucleoside phosphorylase, human epidermal growth factor receptor kinase, and human kinesin spindle protein.

背景与目标： ：嘌呤结合蛋白对所有生物至关重要。人类基因组中约有13％专门用于编码嘌呤结合蛋白。鉴于其重要性，嘌呤结合蛋白是针对多种疾病尤其是癌症的化学疗法干预的有吸引力的靶标。现代的计算和生物物理技术，结合以基于结构的药物设计方法，极大地帮助发现了这些靶标的抑制剂。这篇综述涵盖了基于现代结构的药物设计过程，并举例说明了其在发现和开发针对嘌呤结合蛋白的药物中的应用。审查的目标是人嘌呤核苷磷酸化酶，人表皮生长因子受体激酶和人驱动蛋白纺锤体蛋白。

BACKGROUND & AIMS: :The purpose of the present research is to establish a novel nanosizing technique starting from wet nano-milling, named "dry nanosuspension" technique for poorly water-soluble drugs. The spray freeze-drying (SFD) method was applied instead of the spray-drying one previously developed. Drug particles were milled in the aqueous solution of dispersing agents using an oscillating beads-milling apparatus. The milled nanosuspension was sprayed to the surface of liquid nitrogen, and the resultant iced droplets were freeze-dried to obtain the powdery product. The loading ratio of a dispersing agent was investigated to enhance its redispersing property. Dry nanosuspension, which could be spontaneously dispersed into original nanosuspension in water, was obtained by SFD process. It was assumed that self dispersion property would be attributed to its structure with porous network, in which the primary milled drug crystals were embedded. Such unique structure contributed greatly to immediate release behaviors of the drug in gastrointestinal buffered media. These pharmaceutical properties were enhanced by increasing the ratio of the dispersing agent to the drug and the solid content in suspension to be sprayed. The present technique via wet milling and spray freeze-drying processes would be a novel dissolution-enhanced technology for poorly water-soluble drugs.

背景与目标： ：本研究的目的是建立一种从湿法纳米研磨开始的新型纳米技术，该技术被称为“干纳米悬浮”技术，用于水溶性差的药物。应用喷雾冷冻干燥（SFD）方法代替先前开发的喷雾干燥方法。使用振荡珠磨设备在分散剂的水溶液中研磨药物颗粒。将研磨后的纳米悬浮液喷雾至液氮表面，并将所得的冰滴冷冻干燥，以获得粉状产物。为了提高分散剂的再分散性，对分散剂的负载率进行了研究。通过SFD工艺获得了可以自发分散在水中的纳米悬浮液的干燥纳米悬浮液。假定自分散性归因于其具有多孔网络的结构，其中嵌入了原始研磨的药物晶体。这种独特的结构极大地促进了药物在胃肠缓冲介质中的立即释放行为。通过增加分散剂与药物的比例和待喷雾悬浮液中的固体含量，可以提高这些药物的性能。通过湿磨和喷雾冷冻干燥方法的本技术将是用于水溶性差的药物的新型溶解增强技术。

BACKGROUND & AIMS: BACKGROUND:Word sense disambiguation (WSD) is critical in the biomedical domain for improving the precision of natural language processing (NLP), text mining, and information retrieval systems because ambiguous words negatively impact accurate access to literature containing biomolecular entities, such as genes, proteins, cells, diseases, and other important entities. Automated techniques have been developed that address the WSD problem for a number of text processing situations, but the problem is still a challenging one. Supervised WSD machine learning (ML) methods have been applied in the biomedical domain and have shown promising results, but the results typically incorporate a number of confounding factors, and it is problematic to truly understand the effectiveness and generalizability of the methods because these factors interact with each other and affect the final results. Thus, there is a need to explicitly address the factors and to systematically quantify their effects on performance. RESULTS:Experiments were designed to measure the effect of "sample size" (i.e. size of the datasets), "sense distribution" (i.e. the distribution of the different meanings of the ambiguous word) and "degree of difficulty" (i.e. the measure of the distances between the meanings of the senses of an ambiguous word) on the performance of WSD classifiers. Support Vector Machine (SVM) classifiers were applied to an automatically generated data set containing four ambiguous biomedical abbreviations: BPD, BSA, PCA, and RSV, which were chosen because of varying degrees of differences in their respective senses. Results showed that: 1) increasing the sample size generally reduced the error rate, but this was limited mainly to well-separated senses (i.e. cases where the distances between the senses were large); in difficult cases an unusually large increase in sample size was needed to increase performance slightly, which was impractical, 2) the sense distribution did not have an effect on performance when the senses were separable, 3) when there was a majority sense of over 90%, the WSD classifier was not better than use of the simple majority sense, 4) error rates were proportional to the similarity of senses, and 5) there was no statistical difference between results when using a 5-fold or 10-fold cross-validation method. Other issues that impact performance are also enumerated. CONCLUSION:Several different independent aspects affect performance when using ML techniques for WSD. We found that combining them into one single result obscures understanding of the underlying methods. Although we studied only four abbreviations, we utilized a well-established statistical method that guarantees the results are likely to be generalizable for abbreviations with similar characteristics. The results of our experiments show that in order to understand the performance of these ML methods it is critical that papers report on the baseline performance, the distribution and sample size of the senses in the datasets, and the standard deviation or confidence intervals. In addition, papers should also characterize the difficulty of the WSD task, the WSD situations addressed and not addressed, as well as the ML methods and features used. This should lead to an improved understanding of the generalizablility and the limitations of the methodology.

背景与目标： 背景：字词歧义消除（WSD）在生物医学领域对于提高自然语言处理（NLP），文本挖掘和信息检索系统的精度至关重要，因为模棱两可的单词会对准确访问包含生物分子实体（例如基因）的文献产生负面影响蛋白质，细胞，疾病和其他重要实体。已经开发出自动技术来解决许多文本处理情况下的WSD问题，但是该问题仍然是一个具有挑战性的问题。有监督的WSD机器学习（ML）方法已应用于生物医学领域，并显示出令人鼓舞的结果，但是结果通常包含许多混杂因素，并且由于这些因素相互作用，真正了解这些方法的有效性和可推广性是有问题的彼此影响最终结果。因此，需要明确解决这些因素并系统地量化其对性能的影响。
结果：设计了实验来测量“样本量”（即数据集的大小），“感官分布”（即歧义词的不同含义的分布）和“难易程度”（即歧义词的含义之间的距离）对WSD分类器的性能。支持向量机（SVM）分类器应用于自动生成的数据集，该数据集包含四个歧义生物医学缩写：BPD，BSA，PCA和RSV，这是由于它们各自含义上的差异程度不同而选择的。结果表明：1）增加样本大小通常会降低错误率，但这主要限于良好分离的感官（即，感官之间的距离较大的情况）；在困难的情况下，需要极大地增加样本数量以略微提高性能，这是不切实际的； 2）当感官可分离时，感官分布对性能没有影响； 3）当多数感官超过90时％，WSD分类器并不比使用简单多数感官更好； 4）错误率与各种感官的相似性成正比； 5）当使用5倍或10倍交叉比对时，结果之间没有统计学差异验证方法。还列举了影响性能的其他问题。
结论：将ML技术用于WSD时，有几个不同的独立方面会影响性能。我们发现将它们组合成一个单一的结果会模糊对基本方法的理解。尽管我们仅研究了四个缩写，但我们使用了一种完善的统计方法，该方法可以保证结果对于具有相似特征的缩写很可能是可推广的。我们的实验结果表明，为了了解这些ML方法的性能，至关重要的是，论文要报告基线性能，数据集中感官的分布和样本大小以及标准偏差或置信区间。此外，论文还应描述WSD任务的难度，WSD解决和未解决的WSD情况以及所使用的ML方法和功能。这应该导致人们对通用性和方法的局限性有了更好的了解。

BACKGROUND & AIMS: :Lubrication mechanisms and contact mechanics have been analysed in a new generation of 'cushion form' bearings for artificial hip joints, which comprise low elastic modulus layers on the articulating surfaces. Comparisons have been made with 'hard' bearings used in existing prostheses and also with the natural hip joint. Lubricating film thicknesses are enhanced by larger contact areas and lower contact pressures. For a fixed contact area, simultaneous changes in layer thickness and radial clearance have been shown to have a small effect on elastohydrodynamic film thickness. Hard bearings designed with the same contact area as the cushion bearings produced a similar film thickness, but lubricant film thickness is not optimized in current designs. The main advantage of using a cushion bearing with low elastic modulus layers was found to be associated with microelastohydrodynamic lubrication. Careful selection of the elastic modulus is important in order to ensure that this lubrication regime was effective. Low elastic modulus layers may also produce local deformations, which enhance squeeze film action. The elastic modulus of the material should not be lower than necessary to produce effective microelastohydrodynamic lubrication, as a further reduction in modulus only increases the strain distribution in the material. A lubricant film thickness of 0.3 microns has been predicted for a cushion hip prosthesis with a femoral head diameter of 32 mm and radius of contact zone of 16 mm, using a 2 mm thick layer with an elastic modulus of 20 MPa.

背景与目标： ：已经在新一代用于人工髋关节的“缓冲形式”轴承中分析了润滑机理和接触机理，该轴承在关节表面上包括低弹性模量层。与现有假肢中使用的“硬”轴承以及自然髋关节进行了比较。较大的接触面积和较低的接触压力会增加润滑膜的厚度。对于固定的接触面积，层厚度和径向间隙的同时变化已显示出对弹性流体动力膜厚度的影响很小。设计为与缓冲轴承接触面积相同的硬轴承可产生相似的薄膜厚度，但目前的设计并未优化润滑剂薄膜的厚度。发现使用具有低弹性模量层的缓冲轴承的主要优点与微弹性流体动力润滑有关。仔细选择弹性模量很重要，以确保这种润滑方式有效。低弹性模量层也可能产生局部变形，从而增强挤压膜的作用。材料的弹性模量不应低于产生有效的微弹性流体动力润滑所需的弹性模量，因为模量的进一步降低只会增加材料中的应变分布。对于具有2 mm厚的弹性模量为20 MPa的股骨头直径为32 mm，接触区域半径为16 mm的坐垫髋关节假体，预测的润滑膜厚度为0.3微米。

BACKGROUND & AIMS: BACKGROUND:Annually, about 30% of the persons of 65 years and older falls at least once and 15% falls at least twice. Falls often result in serious injuries, such as fractures. Therefore, the prevention of accidental falls is necessary. The aim is to describe the design of a study that evaluates the efficacy and cost-effectiveness of a multidisciplinary assessment and treatment of multiple fall risk factors in independently living older persons with a high risk of falling. METHODS/DESIGN:The study is designed as a randomised controlled trial (RCT) with an economic evaluation. Independently living persons of 65 years and older who recently experienced a fall are interviewed in their homes and screened for risk of recurrent falling using a validated fall risk profile. Persons at low risk of recurrent falling are excluded from the RCT. Persons who have a high risk of recurrent falling are blindly randomised into an intervention (n = 100) or usual care (n = 100) group. The intervention consists of a multidisciplinary assessment and treatment of multifactorial fall risk factors. The transmural multidisciplinary approach entails close cooperation between geriatrician, primary care physician, physical therapist and occupational therapist and can be extended with other specialists if relevant. A fall calendar is used to record falls during one year of follow-up. Primary outcomes are time to first and second falls. Three, six and twelve months after the home visit, questionnaires for economic evaluation are completed. After one year, during a second home visit, the secondary outcome measures are reassessed and the adherence to the interventions is evaluated. Data will be analysed according to the intention-to-treat principle and also an on-treatment analysis will be performed. DISCUSSION:Strengths of this study are the selection of persons at high risk of recurrent falling followed by a multidisciplinary intervention, its transmural character and the evaluation of adherence. If proven effective, implementation of our multidisciplinary assessment followed by treatment of fall risk factors will reduce the incidence of falls. TRIAL REGISTRATION:Current Controlled Trials ISRCTN11546541.

背景与目标： 背景：每年，年龄在65岁以上的人中至少有30％跌倒一次，而15％的人跌倒至少两次。跌倒通常会导致严重的伤害，例如骨折。因此，防止意外跌倒是必要的。目的是描述一项研究的设计，该研究评估多学科评估和多种跌倒危险因素的治疗的多学科评估和治疗的有效性和成本效益，这些老人独立生活在有跌倒高风险的老年人中。
方法/设计：本研究设计为具有经济评估的随机对照试验（RCT）。最近经历过跌倒的65岁及65岁以上的独立生活者在他们的家中接受采访，并使用经过验证的跌倒风险图来筛查反复跌倒的风险。反复跌倒风险低的人不包括在RCT中。反复跌倒风险高的人被盲目随机分为干预组（n = 100）或常规护理组（n = 100）。干预措施包括多学科评估和多因素跌倒危险因素的治疗。跨壁的多学科方法需要老年医生，初级保健医师，物理治疗师和职业治疗师之间的密切合作，并且可以在相关专家的陪同下进行扩展。秋季日历用于记录随访一年中的秋季。主要结果是第一次和第二次跌倒的时间。进行家访后的三个，六个和十二个月，完成了经济评估问卷。一年后，在第二次家庭访视期间，将重新评估次要结局指标，并评估对干预措施的依从性。将根据意向性治疗原则对数据进行分析，并进行治疗中分析。
讨论：本研究的优势在于选择高风险反复跌倒的人，然后进行多学科干预，其透壁性和依从性评估。如果证明有效，实施我们的多学科评估再治疗跌倒危险因素，将减少跌倒的发生率。
试用注册：电流控制试验ISRCTN11546541。

BACKGROUND & AIMS: :Lys-gingipain (Kgp) is a major cysteine proteinase produced by the oral anaerobic bacterium Porphyromonas gingivalis, and has been implicated as a major pathogen in the development and progression of advanced adult periodontitis. This enzyme is believed to act as a major virulence factor of the disease, yet there exist no convenient and sensitive substrates for analyzing its biological activity. For a better understanding of the importance of this enzyme in the organism, there is an urgent need for specific substrates. Here we designed and synthesized two peptide 4-methyl-coumaryl-7-amides (MCA), carbobenzoxy (Z)-His-Glu-Lys-MCA, and Z-Glu-Lys-MCA, and tested their possible use as sensitive substrates for Kgp with limited specificity. Both substrates exhibited greater k(cat)/K(m) values than the best known Kgp substrates described so far. Both substrates were resistant to Arg-gingipain, another pathogenic cysteine proteinase from P. gingivalis, as well as trypsin and cathepsins B, L, and H. The levels of Kgp in various microorganisms and human cells were determined with Z-His-Glu-Lys-MCA. Little or no Kgp-like activity was detected in either other microorganisms or human cells tested. These results indicate that the present substrates are a valuable and fast tool for routine assays and for mechanistic studies on Kgp.

背景与目标： ：Lys-gingipain（Kgp）是由口腔厌氧细菌齿龈卟啉单胞菌（Porphyromonas gingivalis）产生的一种主要的半胱氨酸蛋白酶，已被认为是晚期成人牙周炎的发展和进展的主要病原体。该酶被认为是该疾病的主要毒力因子，但是尚不存在方便而敏感的底物来分析其生物活性。为了更好地理解这种酶在生物体中的重要性，迫切需要特定的底物。在这里，我们设计并合成了两种肽4-甲基-香豆基-7-酰胺（MCA），碳苯并（Z）-His-Glu-Lys-MCA和Z-Glu-Lys-MCA，并测试了它们可用作敏感底物的可能性对Kgp的特异性有限。两种底材都比迄今描述的最知名的Kgp底材具有更大的k（cat）/ K（m）值。两种底物均对齿龈假单胞菌的另一种致病性半胱氨酸蛋白酶Arg-gingipain以及胰蛋白酶和组织蛋白酶B，L和H均具有抗性。Z-His-Glu- Lys-MCA。在测试的其他微生物或人类细胞中几乎未检测到Kgp样活性。这些结果表明，本发明的底物是用于常规测定和关于Kgp的机理研究的有价值且快速的工具。

BACKGROUND & AIMS: :Computational protein design can be used to select sequences that are compatible with a fixed-backbone template. This strategy has been used in numerous instances to engineer novel proteins. However, the fixed-backbone assumption severely restricts the sequence space that is accessible via design. For challenging problems, such as the design of functional proteins, this may not be acceptable. Here, we present a method for introducing backbone flexibility into protein design calculations and apply it to the design of diverse helical BH3 ligands that bind to the anti-apoptotic protein Bcl-xL, a member of the Bcl-2 protein family. We demonstrate how normal mode analysis can be used to sample different BH3 backbones, and show that this leads to a larger and more diverse set of low-energy solutions than can be achieved using a native high-resolution Bcl-xL complex crystal structure as a template. We tested several of the designed solutions experimentally and found that this approach worked well when normal mode calculations were used to deform a native BH3 helix structure, but less well when they were used to deform an idealized helix. A subsequent round of design and testing identified a likely source of the problem as inadequate sampling of the helix pitch. In all, we tested 17 designed BH3 peptide sequences, including several point mutants. Of these, eight bound well to Bcl-xL and four others showed weak but detectable binding. The successful designs showed a diversity of sequences that would have been difficult or impossible to achieve using only a fixed backbone. Thus, introducing backbone flexibility via normal mode analysis effectively broadened the set of sequences identified by computational design, and provided insight into positions important for binding Bcl-xL.

背景与目标： ：计算蛋白设计可用于选择与固定骨架模板兼容的序列。这种策略已在许多情况下用于工程化新型蛋白质。但是，固定骨干网的假设严重限制了可通过设计访问的序列空间。对于具有挑战性的问题，例如功能蛋白的设计，这可能是不可接受的。在这里，我们介绍了一种在蛋白质设计计算中引入骨架灵活性的方法，并将其应用于与抗凋亡蛋白Bcl-xL（Bcl-2蛋白家族的成员）结合的各种螺旋BH3配体的设计。我们演示了如何使用正常模式分析来采样不同的BH3骨架，并表明与使用天然高分辨率Bcl-xL复杂晶体结构来获得低能解决方案相比，这导致了更大，更多样化的一组低能解决方案。模板。我们通过实验测试了几种设计的解决方案，发现当使用普通模式计算使天然BH3螺旋结构变形时，此方法效果很好，但当用于使理想化螺旋变形时效果不佳。随后的一轮设计和测试确定了问题的可能根源是螺旋螺距的采样不足。我们总共测试了17个设计的BH3肽序列，包括几个点突变体。其中，八个与Bcl-xL的结合良好，另外四个则显示较弱但可检测的结合。成功的设计表明，仅使用固定的骨架很难或不可能实现的序列多样性。因此，通过正常模式分析引入骨架灵活性有效地拓宽了通过计算设计识别的序列集，并提供了对结合Bcl-xL重要的位置的见解。