BACKGROUND & AIMS: :Although associated with all plants, fungal endophytes (microfungi that live within healthy plant tissues) represent an unknown proportion of fungal diversity. While there is a growing appreciation of their ecological importance and human uses, little is known about their host specificity, geographic structure, or phylogenetic relationships. We surveyed endophytic Ascomycota from healthy photosynthetic tissues of three plant species (Huperzia selago, Picea mariana, and Dryas integrifolia, representing lycophytes, conifers, and angiosperms, respectively) in northern and southern boreal forest (Québec, Canada) and arctic tundra (Nunavut, Canada). Endophytes were recovered from all plant species surveyed, and were present in <1-41% of 2 mm2 tissue segments examined per host species. Sequence data from the nuclear ribosomal internal transcribed spacer region (ITS) were obtained for 280 of 558 isolates. Species-accumulation curves based on ITS genotypes remained non-asymptotic, and bootstrap analyses indicated that a large number of genotypes remain to be found. The majority of genotypes were recovered from only a single host species, and only 6% of genotypes were shared between boreal and arctic communities. Two independent Bayesian analyses and a neighbor-joining bootstrapping analysis of combined data from the nuclear large and small ribosomal subunits (LSUrDNA, SSUrDNA; 2.4 kb) showed that boreal and arctic endophytes represent Dothideomycetes, Sordariomycetes, Chaetothyriomycetidae, Leotiomycetes, and Pezizomycetes. Many well-supported phylotypes contained only endophytes despite exhaustive sampling of available sequences of Ascomycota. Together, these data demonstrate greater than expected diversity of endophytes at high-latitude sites and provide a framework for assessing the evolution of these poorly known but ubiquitous symbionts of living plants.

背景与目标： : 尽管与所有植物相关，但真菌内生菌 (生活在健康植物组织中的微真菌) 代表了未知的真菌多样性比例。尽管人们越来越认识到它们的生态重要性和人类用途，但对它们的宿主特异性，地理结构或系统发育关系知之甚少。我们调查了北部和南部北方森林 (加拿大魁北克) 和北极苔原 (加拿大努纳武特) 中三种植物 (石杉，云杉，马里亚纳云杉和干草) 的健康光合组织中的内生子囊菌。从调查的所有植物物种中回收内生菌，并且存在于每个宿主物种检查的2平方毫米个组织节段的 <1-41% 中。从核核糖体内部转录间隔区 (ITS) 获得280 558分离株的序列数据。基于其基因型的物种积累曲线仍然是非渐近的，并且bootstrap分析表明仍有大量基因型有待发现。大多数基因型仅从单个宿主物种中回收，并且在北方和北极社区之间仅共享6% 基因型。对来自核大核糖体亚基和小核糖体亚基 (LSUrDNA，SSUrDNA; 2.4 kb) 的合并数据进行了两次独立的贝叶斯分析和邻居连接的自举分析，结果表明，北方和北极内生菌代表独生菌，蛇纹菌，Chaetothyriomycetidae，Leotiomycetes和Pezizomycetes。尽管对子囊菌门的可用序列进行了详尽的采样，但许多支持良好的系统型仅包含内生菌。总之，这些数据证明了高纬度地点内生植物的多样性大于预期，并为评估这些鲜为人知但无处不在的生物共生体的进化提供了一个框架。

BACKGROUND & AIMS: :The aim of this study was to examine the different patterns of cerebellar and/or brainstem atrophy in spinocerebellar ataxia (SCA) type 3 and 6. Eighteen patients (SCA3 n=9, SCA6 n=9) and 15 healthy volunteers were studied. Voxel-based morphometry (VBM) was applied to segmented grey matter (GM) and white matter (WM) of high-resolution T1-weighted brain volumes of each group. We found reduction of grey matter in the pons as well as in the vermis in SCA3 as compared to control subjects. In SCA6 significant grey matter loss was found in hemispheric lobules bilaterally as well as in the vermis. White matter analysis revealed significant changes in SCA3, especially in the pons, in the white matter surrounding the dentate nucleus (DN) and in the cerebellar peduncles, whereas no significant white matter reduction was found in SCA6 patients. Our results demonstrate different patterns of grey and white matter affection detected by magnetic resonance imaging (MRI) in SCA3 and SCA6 patients, confirming the pathological concept of cortical cerebellar atrophy in SCA6. In contrast, SCA3 represents a form of ponto-cerebellar atrophy with predominant affection of pontine nuclei and fibre tracts.

背景与目标： : 这项研究的目的是检查3型和6型脊髓小脑共济失调 (SCA) 的小脑和/或脑干萎缩的不同模式。研究了18名患者 (SCA3 n = 9，SCA6 n = 9) 和15名健康志愿者。将基于体素的形态计量学 (VBM) 应用于每组高分辨率T1-weighted脑体积的分段灰质 (GM) 和白质 (WM)。与对照组相比，我们发现SCA3中的脑桥和ver中的灰质减少。在SCA6中，双侧半球小叶以及ver骨中都发现了明显的灰质损失。白质分析显示SCA3发生了显着变化，尤其是在脑桥，齿状核 (DN) 周围的白质和小脑梗中，而在SCA6患者中未发现明显的白质减少。我们的结果表明，通过磁共振成像 (MRI) 在SCA3和SCA6患者中检测到的灰质和白质的不同模式，证实了SCA6中皮质小脑萎缩的病理概念。相反，SCA3代表一种桥小脑萎缩的形式，主要影响桥脑核和纤维束。

BACKGROUND & AIMS: :Glucosamine- and N-acetyl glucosamine-containing polymers are being used in an increasing number of biomedical applications, including in products for surface (topical) hemostasis. The studies presented here investigate the relationship between the structure (conformation) and function (activation of hemostasis) of glucosamine-based materials. Several polymer systems were studied, including fibers isolated from a microalgal source containing poly-N-acetyl glucosamine polymers that are organized in a parallel, hydrogen-bonded tertiary structure and can be chemically modified to an antiparallel orientation; and gel formulation derivatives of the microalgal fibers consisting of partially deacetylated (F2 gel) and fully deacetylated (F3 gel) polymers. Comparison of the properties of the poly-N-acetyl glucosamine fiber-derived materials with chitin, chitosan, and commercial chitosan-based products are presented. Several studies were performed with the glucosamine-based materials, including (1) an analysis of the ability of materials to activate platelets and turnover of the intrinsic coagulation cascade, (2) an examination of the viscoelastic properties of mixtures of platelet-rich plasma and the glucosamine-based materials via thromboelastography, and (3) scanning electron microscopic studies to examine the morphology of the glucosamine-based materials. The results presented demonstrate that hemostatic responses to the glucosamine-based materials studied are highly dependent on their chemical nature and tertiary/quaternary structure. The unique natural microalgal fibers were found to have strongly prohemostatic activity compared to the other materials studied.

背景与目标： : 含氨基葡萄糖和N-乙酰氨基葡萄糖的聚合物正在越来越多的生物医学应用中使用，包括用于表面 (局部) 止血的产品。此处介绍的研究研究了基于氨基葡萄糖的材料的结构 (构象) 和功能 (止血的激活) 之间的关系。研究了几种聚合物体系，包括从微藻源分离的纤维，该微藻源含有聚-N-乙酰基葡糖胺聚合物，这些聚合物以平行的氢键合三级结构组织，可以化学改性为反平行取向; 和微藻纤维的凝胶制剂衍生物由部分脱乙酰化 (F2凝胶) 和完全脱乙酰化 (F3凝胶) 聚合物组成。比较了聚N-乙酰氨基葡萄糖纤维衍生材料与几丁质，壳聚糖和市售基于壳聚糖的产品的性能。使用基于氨基葡萄糖的材料进行了几项研究，包括 (1) 分析材料激活血小板的能力和内在凝血级联的周转，(2) 通过血栓弹力图检查富含血小板的血浆和基于氨基葡萄糖的材料的混合物的粘弹性，(3) 扫描电子显微镜研究以检查基于氨基葡萄糖的材料的形态。给出的结果表明，对所研究的基于氨基葡萄糖的材料的止血反应高度依赖于它们的化学性质和三级/四级结构。与研究的其他材料相比，发现独特的天然微藻纤维具有很强的止血活性。

BACKGROUND & AIMS: OBJECTIVE:The 24-hour creatinine clearance is the standard clinical technique for measuring kidney function; however, this measurement is cumbersome and inconvenient for patients. We hypothesized that a camera-based technetium-99m mercaptoacetyltriglycine (MAG3) clearance obtained simultaneously with a standard MAG3 scan would correlate well with the 24-hour creatinine clearance and could serve as a simple marker of kidney function. MATERIALS AND METHODS:Data were obtained from a retrospective analysis of 28 patients with varying degrees of kidney dysfunction and 85 subjects evaluated for kidney donation. The MAG3 clearance was calculated using a camera-based technique without blood or urine sampling. The creatinine clearance was measured using the plasma creatinine and a 24-hour urine collection. The MAG3 and creatinine clearances were corrected for body surface area, and clearance values in healthy subjects and patients were compared using the paired Student's t test. The linear association between the MAG3 and creatinine clearances was expressed by Pearson's correlation coefficient. RESULTS:The mean MAG3 clearance in the potential kidney donors was 321 +/- 95 mL/min/1.73 m2 (95% CI, 171-546 mL/min/1.73 m2), significantly higher than the mean creatinine clearance of 152 +/- 51 mL/min/1.73 m2 (79-278 mL/min/1.73 m2, p < 0.001). The mean MAG3 clearance in patients was 153 +/- 70 mL/min/1.73 m2 (32-316 mL/min/1.73 m2) and was also significantly higher than the mean creatinine clearance of 74 +/- 36 mL/min/1.73 m2 (21-138 mL/min/1.73 m2, p < 0.001). The ratio of the mean creatinine clearance to the mean MAG3 clearance was essentially the same for volunteers and patients, 0.47 and 0.48, respectively. The Pearson's correlation between the MAG3 and creatinine clearances was 0.80 (0.72-0.86). CONCLUSION:The camera-based 99mTc-MAG3 clearance correlates well with the 24-hour creatinine clearance and can provide a simple and convenient index of kidney function.

背景与目标：

BACKGROUND & AIMS: :Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT2A receptor were (pKi +/- S.E.M.): 8.80 +/- 0.11 (Cyp), 8.60 +/- 0.07 (2f), 8.40 +/- 0.02 (2g), 8.05 +/- 0.03 (2h), 7.87 +/- 0.12 (2j), 6.70 +/- 0.02 (2i) and 6.45 +/- 0.02 (3b); those at the rat stomach fundus 5-HT2B receptor (pA2 +/- S.E.M.) were: 9.14 +/- 0.25 (Cyp), 8.49 +/- 0.07 (2f), 7.58 +/- 0.58 (2g), 7.02 +/- 0.14 (2h), 6.07 +/- 0.20 (2j), and undetectable (2i, 3b): and those at the pig choroidal plexus 5-HT2C receptor (pKi +/- S.E.M.) were: 8.71 +/- 0.08 (Cyp), 8.68 +/- 0.01 (2f), 8.58 +/- 0.20 (2g), 7.95 +/- 0.05 (2h), 7.57 +/- 0.04 (2j), 6.98 +/- 0.04 (2i) and 6.63 +/- 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.

背景与目标： : 赛庚胺是一种对2型 (5-HT2) 受体显示高亲和力的药物。我们研究了通过修饰Cyp (二苯并环庚二烯) 的三环体系获得的一系列化合物: 2f (噻吩)，2g (xanthene)，2h (二氢二苯并环庚二烯)，2j (二苯基)，2i (芴) 和3b (苯基甲基)。它们在大鼠大脑皮层5-HT2A受体上的活性为 (pKi +/-s.e.M.): 8.80 +/- 0.11 (Cyp)，8.60 +/- 0.07 (2f)，8.40 +/- 0.02 (2g)，8.05 +/- 0.03 (2h)，7.87 +/- 0.12 (2j)，6.70 +/- 0.02 (2i) 和6.45 +/- 0.02 (3b); 大鼠胃底5-HT2B受体 (pA2 +/-s.e.M.) 为: 9.14 +/- 0.25 (Cyp)，8.49 +/- 0.07 (2f)，7.58 +/- 0.58 (2g)，7.02 +/- 0.14 (2h)，6.07 +/- 0.20 (2j) 和不可检测 (2i，3b): 猪脉络丛5-HT2C受体 (pKi +/-s.e.M.) 为: 8.71 +/- 0.08 (Cyp)，8.68 +/- 0.01 (2f)，8.58 +/- 0.20 (2g)，7.95 +/- 0.05 (2h) 、7.57 +/- 0.04 (2j) 、6.98 +/- 0.04 (2i) 和6.63 +/- 0.20 (3b)。坡度与统一没有显着差异。这些化合物在每种类型的受体上都表现出相同的活性顺序，并且最具活性的分子呈现某些空间 (三环系统的蝴蝶构象) 和静电 (中心环顶部的质子亲和力) 模式。结论是，赛庚胺衍生物在5-HT2受体上的活性与这些分子特征有关，这使得与所有三种5-HT2亚型相互作用的共同处置是可行的。

BACKGROUND & AIMS: BACKGROUND:Angiotensin-converting enzyme (ACE) inhibitors prevent the expansion and rupture of aortic aneurysms in animals. We investigated the association between ACE inhibitors and rupture in patients with abdominal aortic aneurysms. METHODS:We did a population-based case-control study of linked administrative databases in Ontario, Canada. The sample included consecutive patients older than 65 (n=15,326) admitted to hospital with a primary diagnosis of ruptured or intact abdominal aortic aneurysm between April 1, 1992, and April 1, 2002. FINDINGS:Patients who received ACE inhibitors before admission were significantly less likely to present with ruptured aneurysm (odds ratio [OR] 0.82, 95% CI 0.74-0.90) than those who did not receive ACE inhibitors. Adjustment for demographic characteristics, risk factors for rupture, comorbidities, contraindications to ACE inhibitors, measures of health-care use, and aneurysm screening yielded similar results (0.83, 0.73-0.95). Consistent findings were noted in subgroups at high risk of rupture, including patients older than 75 years and those with a history of hypertension. Conversely, such protective associations were not observed for beta blockers (1.02, 0.89-1.17), calcium channel blockers (1.01, 0.89-1.14), alpha blockers (1.15, 0.86-1.54), angiotensin receptor blockers (1.24, 0.71-2.18), or thiazide diuretics (0.91, 0.78-1.07). INTERPRETATION:ACE inhibitors are associated with a reduced risk of ruptured abdominal aortic aneurysm, unlike other antihypertensive agents. Randomised trials of ACE inhibitors for prevention of aortic rupture might be warranted.

背景与目标：

BACKGROUND & AIMS: :6-Pyruvoyltetrahydropterin synthase (PTPS) catalyzes the second step of tetrahydrobiopterin (BH4) synthesis. We previously identified PTPS orthologs (bPTPS-Is) in bacteria which do not produce BH4. In this study we disrupted the gene encoding bPTPS-I in Synechococcus sp. PCC 7942, which produces BH4-glucoside. The mutant was normal in BH4-glucoside production, demonstrating that bPTPS-I does not participate in BH4 synthesis in vivo and bringing us a new PTPS ortholog (bPTPS-II) of a bimodular polypeptide. The recombinant Synechococcus bPTPS-II was assayed in vitro to show PTPS activity higher than human enzyme. Further computational analysis revealed the presence of mono and bimodular bPTPS-II orthologs mostly in green sulfur bacteria and cyanobacteria, respectively, which are well known for BH4-glycoside production. In summary we found new bacterial PTPS orthologs, having either a single or dual domain structure and being responsible for BH4 synthesis in vivo, thereby disclosing all the bacterial PTPS homologs.

背景与目标： : 6-丙酮酸基四氢蝶呤合酶 (PTPS) 催化四氢生物蝶呤 (BH4) 合成的第二步。我们先前在不产生bh4的细菌中鉴定了PTPS直系同源物 (bPTPS-Is)。在这项研究中，我们破坏了Synechococcus sp. PCC 7942中编码bPTPS-I的基因，该基因产生了BH4-glucoside。该突变体在BH4-glucoside生产中是正常的，表明bPTPS-I在体内不参与BH4合成，并为我们带来了双峰多肽的新PTPS直系同源物 (bPTPS-II)。在体外测定了重组Synechococcus bptp-II，显示PTPS活性高于人酶。进一步的计算分析表明，分别在绿色硫细菌和蓝细菌中存在单和双模bPTPS-II直系同源物，这在BH4-glycoside生产中是众所周知的。总而言之，我们发现了新的细菌PTPS直系同源物，具有单个或双结构域结构，并负责体内BH4的合成，从而公开了所有细菌PTPS同源物。

BACKGROUND & AIMS: :The role of carbohydrate in the antigenic and immunogenic structure of bovine herpesvirus type 1 (BHV-1) glycoproteins gI and gIV was investigated. Deglycosylated proteins induced a significantly lower antibody response in rabbits than native glycoproteins suggesting that the immunogenicity of several epitopes on gI and gIV is carbohydrate-dependent. Loss of carbohydrate from gI also resulted in a significantly decreased ability to induce a serum neutralizing antibody response to BHV-1, due to modifications in three distinct carbohydrate-containing continuous epitopes. Similarly, in vitro lysis of BHV-1-infected cells was significantly reduced when antibodies raised against deglycosylated gI were employed; this was attributed to changes in two of the three carbohydrate-dependent neutralizing epitopes on gI. The oligosaccharides may be directly involved as actual components of these continuous epitopes, rather than in stabilization of the conformation of the protein. In contrast, carbohydrate removal from gIV did not have a significant effect on the capacity to stimulate a neutralizing antibody response. Accordingly, none of the neutralizing epitopes on gIV appeared to be carbohydrate-dependent. Similarly, lysis of virus-infected cells was not significantly reduced when antibodies specific for deglycosylated rather than native gIV were used. In contrast to the humoral response, the delayed-type hypersensitivity response was stronger in rabbits immunized with deglycosylated proteins than in those inoculated with native glycoproteins gI or gIV. Consequently, the carbohydrates on gI and gIV may play a dual role in the host's immune recognition and response by contributing to certain epitopes, but masking others. The implications for the development of a subunit vaccine against BHV-1 are discussed.

背景与目标： : 研究了碳水化合物在牛疱疹病毒1型 (BHV-1) 糖蛋白gI和gIV的抗原性和免疫原性结构中的作用。与天然糖蛋白相比，去糖基化蛋白诱导的兔抗体反应明显降低，这表明gI和gIV上几个表位的免疫原性是碳水化合物依赖性的。由于三个不同的含碳水化合物的连续表位的修饰，gI中碳水化合物的损失还导致诱导血清中和抗体对BHV-1的反应的能力显着降低。同样，当使用抗去糖基化gI的抗体时，BHV-1-infected细胞的体外裂解显着减少; 这归因于gI上三个碳水化合物依赖性中和表位中的两个的变化。寡糖可能直接作为这些连续表位的实际成分参与，而不是稳定蛋白质的构象。相反，从gIV中去除碳水化合物对刺激中和抗体反应的能力没有显着影响。因此，gIV上的中和表位似乎都不是碳水化合物依赖性的。同样，当使用对去糖基化而非天然gIV具有特异性的抗体时，病毒细胞的裂解也没有显着减少。与体液反应相反，用去糖基化蛋白免疫的兔子的迟发型超敏反应比用天然糖蛋白gI或gIV接种的兔子更强。因此，gI和gIV上的碳水化合物可能通过促进某些表位而在宿主的免疫识别和反应中起双重作用，但掩盖了其他表位。讨论了开发针对BHV-1的亚单位疫苗的意义。

BACKGROUND & AIMS: We have used 600 MHz 1H NMR spectroscopy data to determine the solution structure of a 31-residue domain of a murine class II major histocompatibility (MHC) protein. This domain, I-Ab(beta)-(60-90), binds to the superantigen staphylococcal enterotoxin A. Distance geometry and dynamical simulated annealing calculations were performed using NOESY- and COSY-deduced constraints. I-Ab(beta)-(60-90), which is mostly alpha-helical, is more similar to the corresponding region of the class II MHC protein HLA-DR1 than to the class I MHC protein HLA-A2. Arg-72 and Arg-80 lie on the same side of the helix and face away from the antigenic peptide binding groove. His-81, implicated in both superantigen and peptide binding, is located midway between the surface defined by Arg-72/Arg-80 and residues that define the inside of the peptide binding groove, allowing for its participation in both types of binding.

背景与目标： 我们使用了600 MHz 1H NMR光谱数据来确定鼠II类主要组织相容性 (MHC) 蛋白的31残基结构域的溶液结构。该结构域I-Ab(beta)-(60-90) 与超抗原葡萄球菌肠毒素A结合。使用NOESY和COSY推导的约束进行距离几何和动态模拟退火计算。I-Ab (β)-(60-90)，其主要是 α-螺旋的，比I类MHC蛋白HLA-DR1的相应区域更类似于I类MHC蛋白HLA-A2。Arg-72和Arg-80位于螺旋的同一侧，并远离抗原肽结合槽。His-81与超抗原和肽结合有关，位于由Arg-72/Arg-80定义的表面和定义肽结合凹槽内部的残基之间的中间，允许其参与两种类型的结合。

BACKGROUND & AIMS: :The sodium iodide symporter (NIS) mediates iodide (I(-)) transport in the thyroid gland and other tissues and is of increasing importance as a therapeutic target and nuclear imaging reporter. NIS activity in vitro is currently measured with radiotracers and electrophysiological techniques. We report on the development of a novel live cell imaging assay of NIS activity using the I(-)-sensitive and genetically encodable yellow fluorescent protein (YFP) variant YFP-H148Q/I152L. In FRTL-5 thyrocytes stably expressing YFP-H148Q/I152L, I(-) induced a rapid and reversible decrease in cellular fluorescence characterized by 1) high affinity for extracellular I(-) (35 muM), 2) inhibition by the NIS inhibitor perchlorate, 3) extracellular Na(+) dependence, and 4) TSH dependence, suggesting that fluorescence changes are due to I(-) influx via NIS. Individual cells within a population of FRTL-5 cells exhibited a 3.5-fold variation in the rate of NIS-mediated I(-) influx, illustrating the utility of YFP-H148Q/I152L to detect cell-to-cell difference in NIS activity. I(-) also caused a perchlorate-sensitive decrease in YFP-H148Q/I152L fluorescence in COS-7 cells expressing NIS but not in cells lacking NIS. These results demonstrate that YFP-H148Q/I152L is a sensitive biosensor of NIS-mediated I(-) uptake in thyroid cells and in nonthyroidal cells following gene transfer and suggest that fluorescence detection of cellular I(-) may be a useful tool by which to study the pathophysiology and pharmacology of NIS.

背景与目标： : 碘化钠同向转运体 (NIS) 介导碘 (I(-)) 在甲状腺和其他组织中的转运，作为治疗靶标和核成像报告基因的重要性日益提高。目前使用放射性示踪剂和电生理技术测量体外的NIS活性。我们报告了使用I(-) 敏感且可遗传编码的黄色荧光蛋白 (YFP) 变体YFP-H148Q/I152L对NIS活性进行新型活细胞成像测定的开发。在稳定表达YFP-H148Q/I152L的FRTL-5甲状腺细胞中，I(-) 诱导细胞荧光的快速和可逆降低，其特征是1) 对细胞外I(-) (35 muM) 的高亲和力，2) NIS抑制剂高氯酸盐的抑制，3) 细胞外Na(+) 依赖性，和4) TSH依赖性，表明荧光变化是由于I(-) 通过NIS流入所致。FRTL-5细胞群内的单个细胞表现出NIS介导的I(-) 流入速率的3.5倍变化，说明YFP-H148Q/I152L用于检测NIS活性的细胞间差异。I(-) 还导致表达NIS的COS-7细胞中YFP-H148Q/I152L荧光的高氯酸盐敏感降低，但在缺乏NIS的细胞中不引起。这些结果表明，YFP-H148Q/I152L是基因转移后甲状腺细胞和非甲状腺细胞中NIS介导的I(-) 摄取的敏感生物传感器，并表明细胞I(-) 的荧光检测可能是研究的有用工具。NIS的病理生理学和药理学。

BACKGROUND & AIMS: :Cyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

背景与目标： : 周期性和先天性中性粒细胞减少症是由人类中性粒细胞弹性蛋白酶 (HNE) 基因 (ELA2) 突变引起的，导致免疫缺陷，其特征是血液中中性粒细胞水平降低或振荡。HNE突变可能会导致酶活性丧失，从而导致免疫系统功能受损。为了了解疾病的结构基础，我们采用了生物信息学的方法，在序列和结构水平上分析了所有已知的HNE错义突变。我们的结果表明，32种不同的突变对HNE的结构和功能具有不同的影响，影响结构紊乱和聚集趋势，保持接触的稳定性和静电特性。大部分突变位于保守的氨基酸，这通常是确定蛋白质结构和功能的关键。大多数引起疾病的HNE错义突变会导致蛋白质的主要结构变化和稳定性丧失。一些突变也会影响功能残基，导致催化活性降低或配体结合改变。我们的分析揭示了HNE中所有已知的错义突变的推定作用，从而阐明了周期性和先天性中性粒细胞减少症的结构基础。我们已经采用并分析了一组30种不同的方法来预测氨基酸取代的影响。我们介绍了这些方法在众多基因，蛋白质和疾病分析中的适用性分析的结果和经验，以揭示蛋白质结构-功能关系和疾病基因型-表型相关性。

BACKGROUND & AIMS: The amino-terminal segment of the membrane-anchored subunit of influenza hemagglutinin (HA) plays a crucial role in membrane fusion and, hence, has been termed the fusion peptide. We have studied the secondary structure, orientation, and effects on the bilayer structure of synthetic peptides corresponding to the wild-type and several fusogenic and nonfusogenic mutants with altered N-termini of the influenza HA fusion peptide by fluorescence, circular dichroism, and Fourier transform infrared spectroscopy. All peptides contained segments of alpha-helical and beta-strand conformation. In the wild-type fusion peptide, 40% of all residues were in alpha-secondary and 30% in beta-secondary structures. By comparison, the nonfusogenic peptides exhibited larger beta/alpha secondary structure ratios. The order parameters of the helices and the amide carbonyl groups of the beta-strands of the wild-type fusion peptide were measured separately, based on the infrared dichroism of the respective absorption bands. Order parameters in the range 0.1-0.7 were found for both segments of the wild-type peptide, which indicates that they are most likely aligned at oblique angles to the membrane normal. The nonfusogenic but not the fusogenic peptides induced splitting of the infrared absorption band at 1735 cm(-1), which is assigned to stretching vibrations of the lipid ester carbonyl bond. This splitting, which reports on an alteration of the hydrogen bonds formed between the lipid ester carbonyls and water and/or hydrogen-donating groups of the fusion peptides, correlated with the beta/alpha ratio of the peptides, suggesting that unpaired beta-strands may replace water molecules and hydrogen-bond to the lipid ester carbonyl groups. The profound structural changes induced by single amino acid replacements at the extreme N-terminus of the fusion peptide further suggest that tertiary or quaternary structural interactions may be important when fusion peptides bind to lipid bilayers.

背景与目标： 流感血凝素 (HA) 的膜锚定亚基的氨基末端片段在膜融合中起着至关重要的作用，因此被称为融合肽。我们通过荧光，圆二色性和傅立叶变换研究了与野生型和几种融合和非融合突变体相对应的合成肽的二级结构，取向和对双层结构的影响。红外光谱。所有肽均包含 α-螺旋和 β 链构象的片段。在野生型融合肽中，所有残基的40% 为 α-二级结构，30% 为 β-二级结构。相比之下，非融合肽表现出较大的 β/α 二级结构比。基于各自吸收带的红外二色性，分别测量了野生型融合肽的 β 链的螺旋和酰胺羰基的有序参数。对于野生型肽的两个片段，发现了0.1-0.7范围内的顺序参数，这表明它们最有可能与膜法线成倾斜角度对齐。非融合肽而不是融合肽在1735厘米 (-1) 处诱导红外吸收带分裂，这被分配给脂质酯羰基键的拉伸振动。这种分裂报告了脂质酯羰基与融合肽的水和/或供氢基团之间形成的氢键的变化，与肽的 β/α 比相关，表明不成对的 β 链可能取代水分子并与脂质酯羰基氢键。在融合肽的极端N末端由单个氨基酸置换诱导的深刻结构变化进一步表明，当融合肽与脂质双层结合时，三级或四级结构相互作用可能很重要。

BACKGROUND & AIMS: UNLABELLED:Decreased left ventricular ejection fraction (LVEF) is a relative contraindication for the use of potentially cardiotoxic chemotherapy. A resting LVEF of 50% is usually used as the lower limit of normal values. The decision to change chemotherapy, however, is complex and is affected by many factors, including ejection fraction.

METHODS:To determine how LVEF data were used by clinical oncologists in clinical decision making, we performed a retrospective analysis of patients referred for ejection fraction measurements from the hematology/oncology divisionS of Stanford University from March 1992 through March 1995. The records of 565 patients treated with potentially cardiotoxic chemotherapy were evaluated.

RESULTS:LVEFs < 50% were found in 153 patients. The charts of patients with reduced ejection fractions were reviewed to determine if the radionuclide measurement resulted in either discontinuation of the cardiotoxic agent or substitution of a less cardiotoxic drug or mode of administration. These specific changes in therapy occurred in only 43 of the 153 (28%) patients with ejection fractions below 50%; 24 of the 43 (57%) had ejection fractions < or = 40%. Patients with lower ejection fraction values were more likely to have their therapy changed than those with LVEFs close to normal. Patients with ejection fractions < or = 30 generally had cardiotoxic agents discontinued. Of patients who had a resting LVEF < 50% and whose therapy was not changed, 81% had a normal increase in LVEF with exercise.

CONCLUSION:In clinical practice at our institution, ejection fraction < 50% is not used as an absolute contraindication to cardiotoxic chemotherapy. When the LVEF is less than 40%, potentially cardiotoxic therapy is most often discontinued or omitted. Radionuclide evidence of cardiac reserve may account for decisions to continue cardiotoxic agents despite ejection fractions < 50% in the majority of patients. Further study will be needed to establish standard criteria. Reserve function, as measured by the change in ejection fraction from rest to stress may be an important parameter used by oncologists to help select patients for continued therapy in spite of a reduced ejection fraction. Our results argue that use of fixed criteria may be too restrictive.

背景与目标： 未标记 : 左心室射血分数 (LVEF) 降低是使用潜在心脏毒性化学疗法的相对禁忌症。50% 的静息LVEF通常用作正常值的下限。然而，改变化疗的决定是复杂的，并且受到许多因素的影响，包括射血分数。
方法 : 为了确定临床肿瘤学家如何在临床决策中使用LVEF数据，我们对1992年3月至1995年3月期间接受斯坦福大学血液学/肿瘤学部门射血分数测量的患者进行了回顾性分析。评估了565例接受潜在心脏毒性化学疗法治疗的患者的记录。
结果 : 在153例患者中发现LVEFs <50%。回顾了射血分数降低的患者的图表，以确定放射性核素测量是否导致停用心脏毒性药物或替代心脏毒性较小的药物或给药方式。这些特定的治疗变化仅发生在射血分数低于50% 的153 (28%) 患者中; 43 (57%) 中的24的射血分数 <或 = 40%。射血分数值较低的患者比LVEFs接近正常的患者更有可能改变治疗。射血分数 <或 = 30的患者通常停用心脏毒性药物。在静息LVEF <50% 且治疗未改变的患者中，81% 的LVEF随运动而正常增加。
结论 : 在我们机构的临床实践中，射血分数 <50% 不作为心脏毒性化疗的绝对禁忌症。当LVEF小于40% 时，潜在的心脏毒性治疗通常被停止或省略。尽管大多数患者的射血分数 <50%，但心脏储备的放射性核素证据可能解释了继续服用心脏毒性药物的决定。需要进一步研究以建立标准。储备功能 (通过从静息到压力的射血分数变化来衡量) 可能是肿瘤学家使用的重要参数，尽管射血分数降低，但可以帮助选择患者继续治疗。我们的结果认为，使用固定标准可能过于严格。

BACKGROUND & AIMS: OBJECTIVE:To assess whether interindividual variation in renal plasma flow or in its response to angiotensin II infusion is associated with interindividual differences in blood pressure in a population-based sample of 287 non-Hispanic whites (143 women and 144 men), aged 20-49.9 years.

METHODS:After seven days of eating a high-sodium diet (260 mmol/day), the renal plasma flow was determined by measuring the clearance of p-aminohippurate before and after infusion of 3 ng/kg per min angiotensin II. Multiple linear regression methods were used to assess whether measures of the renal plasma flow and of its response to angiotensin II infusion were predictive of systolic or diastolic blood pressures measured prior to administration of the high-sodium diet, on day 6 of the high-sodium diet, or during the renal clearance procedure on day 7 prior to angiotensin II infusion.

RESULTS:There was some evidence that measures of the renal plasma flow and of its response to angiotensin II infusion during the high-sodium diet were statistically significant predictors of measures of blood pressure in women; there was less evidence for this for blood pressures in men. Interindividual variation in measures of the renal plasma flow and of its response to angiotensin II infusion explained less than 10% of the interindividual variation in any measure of the blood pressure in both sexes.

CONCLUSION:These results suggest that interindividual variation in renal plasma flow ad in its response to angiotensin II infusion during a high-sodium diet will be of limited utility in elucidating the basis for interindividual differences in blood pressure.

背景与目标： 目的 : 在基于人群的287非西班牙裔白人 (143名女性和144名男性) 样本中，评估肾血浆流量或对血管紧张素II输注的反应的个体差异是否与血压的个体差异相关，年龄在20-49.9岁之间。
方法 : 在食用高钠饮食 (260 mmol/天) 7天后，通过在每分钟输注3 ng/kg血管紧张素II之前和之后测量对氨基马尿酸盐的清除率来确定肾血浆流量。使用多元线性回归方法来评估肾血浆流量及其对血管紧张素II输注的反应的测量是否可以预测高钠饮食第6天在给予高钠饮食之前测得的收缩压或舒张压。钠饮食，或在输注血管紧张素II之前第7天的肾脏清除过程中。
结果 : 有证据表明，高钠饮食期间肾脏血浆流量的测量及其对血管紧张素II输注的反应是女性血压测量的统计学显着预测指标; 男性血压的证据较少。肾血浆流量测量及其对血管紧张素II输注的反应的个体差异解释了男女血压测量中个体间差异的10%。
结论 : 这些结果表明，在高钠饮食中对血管紧张素II输注的反应中，肾血浆流量ad的个体差异在阐明血压个体差异的基础方面将是有限的。

BACKGROUND & AIMS: :Reports on the efficacy of physical activity intervention trials usually only include discussion of the primary outcomes. However, assessing factors such as participant retention, adherence and compliance can assist in the accurate interpretation of the overall impact of a program in terms of reach and appeal. A quasi-randomised trial was carried out to assess and compare retention and adherence rates, and compliance with, a twice weekly resistance training program provided either individually at home or in a group format. Retirement villages (n=6) were assigned to either 'Have A Try' (HAT, home-based) or 'Come Have A Try' (CHAT, group-based); both programs included nine strength and two balance exercises. The program involved a 20-week Intervention Phase a 24-week Maintenance Phase and a 20-week On-going Maintenance Phase. One hundred and nineteen participants (mean age 80+/-6 years) were recruited (HAT=38, CHAT=81). There was no difference in retention rates at the end of the Intervention Phase, but significantly more HAT than CHAT participants had dropped out of the study (p<0.01) after the Maintenance Phase and the On-going Maintenance Phase. During the Intervention Phase, over half the HAT and CHAT participants completed > or =75% of the prescribed activity sessions, but adherence was significantly greater in CHAT than HAT during the Maintenance Phase (p<0.01). Participants in CHAT were significantly more compliant than HAT participants (p<0.05). Both home- and group-based formats were successful over the short-term, but, in retirement villages, the group program had better adherence and compliance in the longer-term.

背景与目标： : 关于体力活动干预试验有效性的报告通常只包括对主要结果的讨论。但是，评估参与者的保留率，依从性和合规性等因素可以帮助准确解释计划在覆盖范围和吸引力方面的总体影响。进行了一项准随机试验，以评估和比较保留率和依从性，以及每周两次在家里或以小组形式提供的阻力训练计划的依从性。退休村 (n = 6) 被分配为 “尝试” (帽子，家庭为基础) 或 “尝试” (聊天，基于小组); 这两个程序都包括9个力量和2个平衡练习。该计划涉及20周的干预阶段，24周的维护阶段和20周的持续维护阶段。招募了119名参与者 (平均年龄80/-6岁) (HAT = 38，CHAT = 81)。在干预阶段结束时，保留率没有差异，但在维持阶段和持续维持阶段后退出研究的CHAT参与者 (p<0.01) 的HAT明显多于CHAT参与者。在干预阶段，超过一半的HAT和CHAT参与者完成了> 或 = 75% 的规定活动会话，但在维护阶段，CHAT的依从性明显高于HAT (p<0.01)。聊天参与者比HAT参与者更顺从 (p<0.05)。基于家庭和基于团体的格式在短期内都是成功的，但是，在退休村，团体计划在长期内具有更好的依从性和合规性。