BACKGROUND & AIMS: :Related outer membrane proteins, termed secretins, participate in the secretion of macromolecules across the outer membrane of many Gram-negative bacteria. In the pullulanase-secretion system, PulS, an outer membrane-associated lipoprotein, is required both for the integrity and the proper outer membrane localization of the PulD secretin. Here we show that the PulS-binding site is located within the C-terminal 65 residues of PulD. Addition of this domain to the filamentous phage secretin, pIV, or to the unrelated maltose-binding protein rendered both proteins dependent on PulS for stability. A chimeric protein composed of bacteriophage f1 pIV and the C-terminal domain of PuID required properly localized PulS to support phage assembly. An in vivo complex formed between the pIV-PulD65 chimera and PulS was detected by co-immunoprecipitation and by affinity chromatography.

背景与目标： ：相关的外膜蛋白，称为促胰液素，参与许多革兰氏阴性细菌的外膜大分子的分泌。在支链淀粉酶分泌系统中，PulS是一种与外膜相关的脂蛋白，是PulD促胰液素的完整性和正确的外膜定位所必需的。在这里，我们显示PulS结合位点位于PulD的C末端65个残基内。该结构域添加到丝状噬菌体分泌蛋白，pIV或无关的麦芽糖结合蛋白上，使得这两种蛋白都依赖于PulS进行稳定性。由噬菌体f1 pIV和PuID的C末端结构域组成的嵌合蛋白需要适当定位的PulS才能支持噬菌体装配。通过共免疫沉淀和亲和色谱法检测到了pIV-PulD65嵌合体和PulS之间形成的体内复合物。

BACKGROUND & AIMS: :Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+ CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.

背景与目标： 已经证明：Foxp3对于小鼠中天然产生的CD4 CD25调节性T细胞的发育和功能既必要又充分。用IPEX突变的Scurfy小鼠中的Foxp3和人类中的FOXP3突变会导致致命的早期发作的自身免疫性疾病，并证明FOXP3在维持免疫稳态方面的关键作用。 FOXP3蛋白编码几个功能域，包括C2H2锌指，亮氨酸拉链和带翼螺旋/叉头（FKH）域。先前我们已经证明FOXP3充当转录阻遏物，并抑制激活诱导的IL-2基因转录。为了表征每个预测功能结构域对FOXP3体内活性的作用，我们评估了在一大批患有免疫功能异常，多内分泌病，肠病，X连锁综合征（IPEX）的患者中鉴定出的点突变的位置，并发现它们主要聚集在FKH结构域和亮氨酸拉链中，但也存在于蛋白质的N末端定义不明确的区域。研究了每个IPEX靶向域的分子功能。我们显示FOXP3组成性地定位于原子核，并且此定位需要在其FKH域的氨基和C末端都具有序列。此外，发现FOXP3通过其亮氨酸拉链同源二聚体。我们还确定了FOXP3 N末端一半内的新型功能域，这是FOXP3介导的从组成型活性启动子和NF-AT诱导型启动子转录抑制所必需的。此外，我们证明这些域中的IPEX突变与FOXP3阻遏物功能的缺陷相关，从而证实了它们的体内相关性。

BACKGROUND & AIMS: :We show that STAT5b is important for the in vivo accumulation of CD4+ CD25(high) T cells with regulatory cell function. A patient homozygous for a missense A630P STAT5b mutation displayed immune dysregulation and decreased numbers of CD4+ CD25(high) T cells. STAT5b(A630P/A630P) CD4+ CD25(high) T cells had low expression of forkhead box P3 and an impaired ability to suppress the proliferation of or to kill CD4+ CD25- T cells. Expression of CD25, a component of the high-affinity IL-2R, was also reduced in response to IL-2 or after in vitro propagation. The impact of the STAT5b mutation was selective in that IL-2-mediated up-regulation of the common gamma-chain cytokine receptor and perforin, and activation-induced expressions of CD154 and IFN-gamma were normal. These results indicate that STAT5b propagates an important IL-2-mediated signal for the in vivo accumulation of functional regulatory T cells.

背景与目标： ：我们表明STAT5b对于具有调节性细胞功能的CD4 CD25（high）T细胞在体内的积累很重要。一名纯合的错义A630P STAT5b突变患者表现出免疫失调和CD4 CD25（高）T细胞数量减少。 STAT5b（A630P / A630P）CD4 CD25（高）T细胞的叉头盒P3表达低，抑制CD4 CD25- T细胞增殖或杀死其的能力受损。高亲和力IL-2R的组成部分CD25的表达也响应IL-2或在体外繁殖后降低。 STAT5b突变的影响是选择性的，因为IL-2介导了共同的γ链细胞因子受体和穿孔素的上调，并且激活诱导的CD154和IFN-γ的表达是正常的。这些结果表明STAT5b传播重要的IL-2介导的信号，用于体内功能性调节性T细胞的蓄积。

BACKGROUND & AIMS: :The oncoprotein LMP1 mimics an activated CD40 receptor, yet it is not known whether constitutive CD40 signaling, like LMP1, is sufficient to transform cells. Here we demonstrate that constitutive activation of the CD40 pathway by a chimeric LMP1CD40 molecule resembles the transforming function of LMP1 in inducing loss of contact inhibition and anchorage independent growth of Rat1 fibroblasts. Rat1 transformation correlates with the expression level of LMP1CD40 and depends on its ability to oligomerize. Our data provide direct evidence for the oncogenic potential of the CD40 signaling pathway, which is also established as a model-mechanism for LMP1-induced transformation.

背景与目标： ：癌蛋白LMP1模仿激活的CD40受体，但尚不知道本构性CD40信号是否像LMP1一样足以转化细胞。在这里，我们证明了嵌合LMP1CD40分子对CD40途径的组成性激活类似于LMP1的转化功能，可诱导Rat1成纤维细胞失去接触抑制和锚定非依赖性生长。 Rat1转化与LMP1CD40的表达水平相关，并取决于其寡聚能力。我们的数据为CD40信号传导途径的致癌潜力提供了直接证据，该途径也被确立为LMP1诱导转化的模型机制。

BACKGROUND & AIMS: BACKGROUND:The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available. OBJECTIVES:The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose. METHODS:Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment. RESULTS:In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2-24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively CONCLUSION:Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.

背景与目标： 摘要背景：吸入性糖皮质激素（ICS）和长效β2-激动剂（LABA）的结合被治疗指南推荐用于持续性哮喘的治疗。两种这样的组合产品，沙美特罗/丙酸氟替卡松（SFC，英国Seretide GSK）和福莫特罗/布地奈德（FBC，Symbicort，阿斯利康，英国）可商购。
目的：这些研究的目的是评估和比较两种组合产品在单剂给药后直至24小时的支气管扩张持续时间。
方法：进行了两项随机，双盲，安慰剂对照，交叉研究。研究A在接受400-1200 mcg布地奈德或同等剂量的33位哮喘成人中进行。在24小时内测量一秒钟的连续呼气量（FEV1），以确定SFC（50/100 mcg）和FBC（4.5 / 160 mcg）的作用持续时间。研究B是在75名接受800-1200 mcg布地奈德或同等水平的哮喘成年人中进行的，包括4周400 mcg bd的Becotide磨合，然后用SFC 50/100 mcg bd或FBC 4.5 / 160 mcg bd进行4周治疗以交叉方式拍摄。在每4周治疗期后的第一剂和最后一剂之后，测量连续的24小时FEV1，以确定每种治疗的作用抵消。
结果：在研究A中，单次吸入SFC和FBC在16小时产生了持续的支气管扩张作用，与SFC和0.25 L（95 FBC的％CI 0.21、0.37 L），均显着高于两种治疗的安慰剂（-0.05 L； p <0.001）。在研究B中，从剂量后2-24小时开始，FEV1的下降斜率对于SFC为-16.0 ml / hr，对于FBC为-14.2 ml / hr。在24小时内，加权平均AUC为0.21 Lxmin和0.22 Lxmin，对于SFC，从剂量前FEV1到12小时的平均变化分别为0.21 Lx和FBC 0.20 L
结论：SFC和FBC均产生相似的持续支气管扩张药作用，给药后延长至12小时以上，并且在24 h时明显可测量。

BACKGROUND & AIMS: :Go/Gi coupled G-protein receptor mediated transactivation is critical in the activation of receptor tyrosine kinases (RTK). Here we show that mu opioid receptor (MOR) transactivates Flk1 and platelet-derived growth factor-beta (PDGF-beta) receptors and its agonist morphine stimulates pro-angiogenic and survival-promoting signaling in mouse retinal endothelial cells (mREC). Morphine stimulates mREC proliferation in a dose dependent fashion and promotes survival to the same extent as vascular endothelial growth factor164 (VEGF164). Morphine stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt phosphorylation in a time dependent manner like VEGF in mREC. Moreover, analogous to VEGF, morphine stimulates oncogenic signal transducer and activator of transcription 3 (STAT3) signaling. Morphine as well as VEGF-induced phospho-STAT3 and phospho-Flk1 immunoprecipitated with MOR-associated proteins. In addition morphine also stimulated MOR associated PDGF-beta receptor phosphorylation. Consistent with the relationship between VEGF and MOR we found that VEGF upregulates MOR protein and RNA expression in mREC. These data suggest that MOR associates and transactivates RTKs for Flk1 and PDGF-beta, which may have a compounding effect on angiogenic signaling in endothelium. Therefore, G-Protein coupled receptors including MOR provide novel targets to develop anti-angiogenic agents.

背景与目标： ：Go / Gi偶联的G蛋白受体介导的反式激活在受体酪氨酸激酶（RTK）的激活中至关重要。在这里，我们显示mu阿片类受体（MOR）激活Flk1和血小板衍生的生长因子-β（PDGF-β）受体，其激动剂吗啡刺激小鼠视网膜内皮细胞（mREC）促血管生成和促进生存的信号传导。吗啡以剂量依赖性方式刺激mREC增殖，并以与血管内皮生长因子164（VEGF164）相同的程度促进存活。吗啡像mREC中的VEGF一样，以时间依赖性方式刺激促分裂原活化的蛋白激酶/细胞外信号调节激酶（MAPK / ERK）和Akt磷酸化。此外，类似于VEGF，吗啡刺激致癌信号转导子和转录激活子3（STAT3）信号转导。吗啡以及VEGF诱导的磷酸化STAT3和磷酸化Flk1被MOR相关蛋白免疫沉淀。此外，吗啡还刺激了MOR相关的PDGF-β受体的磷酸化。与VEGF和MOR之间的关系一致，我们发现VEGF上调mREC中的MOR蛋白和RNA表达。这些数据表明，MOR与Flk1和PDGF-beta的RTK缔合并反激活，这可能对内皮中的血管生成信号具有复合作用。因此，包括MOR在内的G蛋白偶联受体为开发抗血管生成剂提供了新的靶标。

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： ：循环性和先天性嗜中性白血球减少症是由人类嗜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，其特征是血液中嗜中性粒细胞水平降低或振荡。 HNE突变可能导致酶活性下降，因此导致免疫系统功能受损。为了了解该疾病的结构基础，我们采用了生物信息学的方法来分析序列和结构水平上所有已知的HNE错义突变。我们的结果表明，这32种不同的突变对HNE的结构和功能具有多种影响，影响结构异常和聚集趋势，保持接触的稳定性以及静电性质。大部分突变位于保守氨基酸上，这通常是决定蛋白质结构和功能所必需的。大多数引起疾病的HNE错义突变会导致主要的结构变化和蛋白质稳定性的损失。一些突变也影响功能残基，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，因此可以阐明周期性和先天性中性粒细胞减少的结构基础。我们已经采用并分析了一组约30种不同的方法来预测氨基酸取代的影响。我们通过分析这些方法在分析众多基因，蛋白质和疾病中的适用性来提供结果和经验，以揭示蛋白质结构与功能的关系以及疾病的基因型与表型的相关性。

BACKGROUND & AIMS: :Different attempts were made to identify the variables that may be involved in the clinical course of cerebrovascular ischemia. In the case of stroke with mild severity (SMS), the clinical significance of neuroendocrine changes as well as of post-stroke depression (PSD) remains unknown. We therefore evaluated the presence of neuroendocrine changes in the acute and post-acute phase of SMS, and their potential role during convalescence. Serum cortisol, T4, T3, FT4, FT3, TSH and PRL levels were measured in 17 euthyroid patients with stroke on admission (day 1), following morning (day 2), 7 days and 3 months later. TSH and PRL secretion after TRH test were measured. Stroke severity on admission was determined by Scandinavian Stroke Scale (SSS). Montgomery-Asberg Depression Rating Scale (Madrs) was used for assessment of post-stroke depression. On admission, TSH and T3, were within normal limits and were greater compared to values on day 2. Lower basal TSH and decreased TSH response to TRH on day 2, were associated with stroke of greater severity. Delta-PRL after TRH on day 2 was higher in patients who develop PSD. Changes in serum thyroid hormones in SMS, reflects those of non-thyroidal illness. A mild stimulation of hypothalamic-pituitary-adrenal axis was detected. We provide evidence that PRL response to TRH, in the acute phase of stroke may be used as an index for early detection of PSD.

背景与目标： ：进行了不同的尝试来确定可能与脑血管缺血的临床过程有关的变量。对于轻度中风（SMS）的中风，神经内分泌变化以及中风后抑郁症（PSD）的临床意义仍然未知。因此，我们评估了SMS急性期和急性期后神经内分泌变化的存在及其在恢复期的潜在作用。在入院时（第1天），早晨（第2天），第7天和3个月后的17例中风的甲状腺功能正常的甲状腺疾病患者中测量了血清皮质醇，T4，T3，FT4，FT3，TSH和PRL的水平。测量TRH试验后的TSH和PRL分泌。入院时卒中严重程度由斯堪的纳维亚卒中量表（SSS）确定。使用蒙哥马利-阿斯伯格抑郁量表（Madrs）评估中风后抑郁。入院时，TSH和T3在正常范围之内，并且比第2天的值高。在第2天，较低的基础TSH和对TRH的TSH反应降低与严重程度更高的卒中相关。发生PSD的患者在TRH后第2天的Delta-PRL较高。 SMS中血清甲状腺激素的变化反映了非甲状腺疾病的变化。下丘脑-垂体-肾上腺轴受到轻度刺激。我们提供的证据表明，在卒中的急性期PRL对TRH的反应可用作早期检测PSD的指标。

BACKGROUND & AIMS: :Over the past decade, the old idea that the bone marrow contains endothelial cell precursors has become an area of renewed interest. While some still believe that there are no endothelial precursors in the blood, even among those who do, there is no consensus as to what they are or what they do. In this review, we describe the problems in identifying endothelial cells and conclude that expression of endothelial nitric oxide synthase may be the most reliable antigenic indicator of the phenotype. The evidence for two different classes of endothelial precursors is also presented. We suggest that, though there is no single endothelial cell precursor, we may be able to use these phenotypic variations to our advantage in better understanding their biology. We also discuss how a variety of genetic, epigenetic, and methodological differences can account for the seemingly contradictory findings on the physiological relevance of bone marrow-derived precursors in normal vascular maintenance and in response to injury. Data on the impact of tumor type and location on the contribution of bone marrow-derived cells to the tumor vasculature are also presented. These data provide hope that we may ultimately be able to predict those tumors in which bone marrow-derived cells will have a significant contribution and design therapies accordingly. Finally, factors that regulate bone marrow cell recruitment to and function in the endothelium are beginning to be identified, and several of these, including stromal derived factor 1, monocyte chemoattractant factor-1, and vascular endothelial growth factor are discussed.

背景与目标： ：在过去的十年中，关于骨髓中含有内皮细胞前体的古老观念已经引起人们的广泛关注。尽管有些人仍然认为血液中没有内皮前体，即使在有血液的人中也没有，但是关于它们是什么或它们的行为尚无共识。在这篇综述中，我们描述了鉴定内皮细胞的问题，并得出结论，内皮一氧化氮合酶的表达可能是最可靠的表型抗原指示剂。还提供了两种不同类别的内皮前体的证据。我们建议，尽管没有单个内皮细胞前体，但我们也许能够利用这些表型变异来更好地了解它们的生物学特性。我们还将讨论各种遗传，表观遗传学和方法学上的差异如何解释在正常血管维持和对损伤的反应中，骨髓来源的前体的生理相关性看似矛盾的发现。还提供了有关肿瘤类型和位置对骨髓衍生细胞对肿瘤脉管系统的影响的数据。这些数据提供了希望，使我们最终能够预测那些骨髓来源的细胞将发挥重要作用的肿瘤，并据此设计治疗方法。最后，已开始确定调节骨髓细胞向内皮募集并在内皮中起作用的因子，并讨论了其中的几种，包括基质衍生因子1，单核细胞趋化因子-1和血管内皮生长因子。

BACKGROUND & AIMS: OBJECTIVE:To compare prostate carcinoma, with and with no lymph node metastasis, to benign prostatic hyperplasia (BPH) tissue for lymphatic vessel density (LVD) and the expression of the lymph-endothelial specific growth factor, vascular endothelial growth factor C (VEGF-C), to determine their role in lymphogenic metastasis. PATIENTS, MATERIALS AND METHODS:Lymphatic vessels were stained using lymphatic vessel endothelial hyaluronan receptor 1 and assessed in standard areas. The expression of VEGF-C was assessed by the number of positive epithelial cells. The data were compared with the clinical staging. RESULTS:The lowest LVD was found in tumorous areas as opposed to periphery and nontumorous tissue (P = 0.007; P < 0.001). The highest LVD was in BPH tissue (P < 0.001). There was no correlation with clinical staging. There was more VEGF-C staining in pN1 than in pN0 and in BPH specimens (P = 0.002). CONCLUSION:LVD is not a prognostic variable for the process of lymphogenic metastasis in prostate cancer. VEGF-C is up-regulated in prostate cancer and its correlation with lymph node status suggests a role for the development of lymph node metastasis, e.g. via an increased permeability of lymphatic vessels.

背景与目标： 目的：比较有无淋巴结转移的前列腺癌与良性前列腺增生（BPH）组织的淋巴管密度（LVD）以及淋巴内皮特异性生长因子，血管内皮生长因子C（VEGF- C），确定其在淋巴转移中的作用。
患者，材料和方法：使用淋巴管内皮透明质酸受体1对淋巴管进行染色，并在标准区域进行评估。通过阳性上皮细胞的数量评估VEGF-C的表达。将数据与临床分期进行比较。
结果：与周围和非肿瘤组织相比，在肿瘤区域发现的LVD最低（P = 0.007； P <0.001）。 LVD最高的是BPH组织（P <0.001）。与临床分期无关。 pN1和BPH标本中的VEGF-C染色要多于pN0和PPH（P = 0.002）。
结论：LVD不是前列腺癌淋巴转移的预后变量。 VEGF-C在前列腺癌中被上调，并且其与淋巴结状态的相关性暗示了淋巴结转移的发展，例如肝癌的发生。通过增加淋巴管的通透性

BACKGROUND & AIMS: :Polo-like kinases (PLKs) are marked by C-terminal polo box modules with critical protein interaction and subcellular targeting roles. Slevin et al. in this issue of Structure reveal the architecture of a hidden set of polo boxes from the divergent PLK4, a critical player in centrosome duplication, shedding new light on the evolution of PLKs and their functionally related kinase ZYG-1.

背景与目标： ：Polo样激酶（PLKs）的C末端polo盒模块具有关键的蛋白质相互作用和亚细胞靶向作用。 Slevin等在本期《结构》中，我们揭示了来自不同PLK4的一组隐藏的马球盒的结构，PLK4是质体复制的关键角色，为PLK及其功能相关激酶ZYG-1的进化提供了新的思路。

BACKGROUND & AIMS: :We reviewed six cases of primary sarcomas requiring scapulectomy within the past 13 years in the Surgery Branch of the National Cancer Institute, Bethesda, Md. Five of these patients returned for evaluation of disease status, evaluation of functional defects as determined by muscle group testing, and assessment of daily living skills and limitations. We demonstrated excellent shoulder function with partial scapulectomy and significant impairment with the additional loss of the glenoid fossa. In addition, we developed a thorough method of postoperative evaluation. Involvement of rehabilitation therapists before and after operatively is integral to this process in preparation for surgery and subsequent treatment.

背景与目标： ：我们在美国马里兰州贝塞斯达的国家癌症研究所外科分院回顾了过去13年中需要进行肩ectomy骨切除术的6例原发性肉瘤。其中5例患者返回进行了疾病状态评估，通过肌肉群测试确定了功能缺陷，并评估日常生活技能和局限性。我们证实了部分肩cap骨切除术具有出色的肩部功能，并且由于关节盂窝的丢失而导致了明显的损伤。此外，我们开发了一种彻底的术后评估方法。手术前后，康复治疗师的参与是此过程不可或缺的准备手术和后续治疗的过程。

BACKGROUND & AIMS: :Musical training has emerged as a useful framework for the investigation of training-related plasticity in the human brain. Learning to play an instrument is a highly complex task that involves the interaction of several modalities and higher-order cognitive functions and that results in behavioral, structural, and functional changes on time scales ranging from days to years. While early work focused on comparison of musical experts and novices, more recently an increasing number of controlled training studies provide clear experimental evidence for training effects. Here, we review research investigating brain plasticity induced by musical training, highlight common patterns and possible underlying mechanisms of such plasticity, and integrate these studies with findings and models for mechanisms of plasticity in other domains.

背景与目标： ：音乐训练已成为研究人脑与训练有关的可塑性的有用框架。学习演奏乐器是一项高度复杂的任务，涉及多种模式和高阶认知功能的相互作用，并导致行为，结构和功能发生变化，时间范围从数天到数年不等。早期的工作着重于音乐专家和新手之间的比较，而最近，越来越多的受控训练研究为训练效果提供了明确的实验证据。在这里，我们回顾了研究由音乐训练引起的大脑可塑性的研究，突出了这种可塑性的常见模式和可能的潜在机制，并将这些研究与其他领域的可塑性机制的发现和模型相结合。

BACKGROUND & AIMS: :Flavohemoglobins (FHbs) are members of the globin superfamily, widely distributed among prokaryotes and eukaryotes that have been shown to carry out nitric oxide dioxygenase (NOD) activity. In prokaryotes, such as Escherichia coli, NOD activity is a defence mechanism against the NO release by the macrophages of the hosts' immune system during infection. Because of that, FHbs have been studied thoroughly and several drugs have been developed in an effort to fight infectious processes. Nevertheless, the protein's structural determinants involved in the NOD activity are still poorly understood. In this context, the aim of the present work is to unravel the molecular basis of FHbs structural dynamics-to-function relationship using state of the art computer simulation tools. In an effort to fulfill this goal, we studied three key processes that determine NOD activity, namely i) ligand migration into the active site ii) stabilization of the coordinated oxygen and iii) intra-protein electron transfer (ET). Our results allowed us to determine key factors related to all three processes like the presence of a long hydrophobic tunnel for ligand migration, the presence of a water mediated hydrogen bond to stabilize the coordinated oxygen and therefore achieve a high affinity, and the best possible ET paths between the FAD and the heme, where water molecules play an important role. Taken together the presented results close an important gap in our understanding of the wide and diverse globin structural-functional relationships.

背景与目标： 黄素血球蛋白（FHbs）是球蛋白超家族的成员，广泛分布于原核生物和真核生物之间，已被证明具有一氧化氮双加氧酶（NOD）活性。在诸如大肠杆菌的原核生物中，NOD活性是抵抗宿主免疫系统巨噬细胞在感染过程中释放NO的防御机制。因此，已经对FHb进行了深入研究，并开发了几种药物来对抗感染过程。然而，仍不清楚对涉及NOD活性的蛋白质的结构决定因素。在这种情况下，本工作的目的是使用最先进的计算机模拟工具来揭示FHbs结构动力学与功能关系的分子基础。为了实现这一目标，我们研究了确定NOD活性的三个关键过程，即i）配体迁移到活性位点ii）配位氧的稳定化和iii）蛋白质内电子转移（ET）。我们的结果使我们能够确定与所有三个过程相关的关键因素，例如存在长的疏水性配体迁移隧道，存在水介导的氢键以稳定配位的氧并因此实现高亲和力以及最佳的ET FAD和血红素之间的通道，其中水分子起着重要作用。综上所述，所提出的结果弥合了我们对广泛而多样的球蛋白结构-功能关系的理解中的一个重要空白。

BACKGROUND & AIMS: BACKGROUND:Choline is essential for fetal brain development, and it is not known whether a typical American diet contains enough choline to ensure optimal brain development. OBJECTIVE:The study was undertaken to determine whether supplementing pregnant women with phosphatidylcholine (the main dietary source of choline) improves the cognitive abilities of their offspring. DESIGN:In a double-blind, randomized controlled trial, 140 pregnant women were randomly assigned to receive supplemental phosphatidylcholine (750 mg) or a placebo (corn oil) from 18 wk gestation through 90 d postpartum. Their infants (n = 99) were tested for short-term visuospatial memory, long-term episodic memory, language development, and global development at 10 and 12 mo of age. RESULTS:The women studied ate diets that delivered ∼360 mg choline/d in foods (∼80% of the recommended intake for pregnant women, 65% of the recommended intake for lactating women). The phosphatidylcholine supplements were well tolerated. Groups did not differ significantly in global development, language development, short-term visuospatial memory, or long-term episodic memory. CONCLUSIONS:Phosphatidylcholine supplementation of pregnant women eating diets containing moderate amounts of choline did not enhance their infants' brain function. It is possible that a longer follow-up period would reveal late-emerging effects. Moreover, future studies should determine whether supplementing mothers eating diets much lower in choline content, such as those consumed in several low-income countries, would enhance infant brain development.

背景与目标： 背景：胆碱对胎儿的大脑发育至关重要，目前尚不清楚典型的美国饮食中是否含有足够的胆碱以确保最佳的大脑发育。
目的：本研究旨在确定孕妇补充磷脂酰胆碱（胆碱的主要饮食来源）是否能改善其后代的认知能力。
设计：在一项双盲，随机对照试验中，从怀孕18周到产后90天，随机分配了140名孕妇接受补充磷脂酰胆碱（750毫克）或安慰剂（玉米油）。他们的婴儿（n = 99）在10和12个月大时接受了短期视觉空间记忆，长期情境记忆，语言发展和整体发展的测试。
结果：这些妇女所研究的饮食中食物中的胆碱/日摄入量约为360毫克/天（孕妇的推荐摄入量约为80％，哺乳期妇女的推荐摄入量约为65％）。磷脂酰胆碱补充剂的耐受性良好。在全球发展，语言发展，短期视觉空间记忆或长期情境记忆方面，各组没有显着差异。
结论：孕妇食用含适量胆碱饮食的磷脂酰胆碱不能增强婴儿的脑功能。较长的随访期可能会显示出较晚出现的影响。此外，未来的研究应确定补充食用胆碱含量低得多的饮食的母亲（如在几个低收入国家食用的饮食）是否会增强婴儿的大脑发育。