BACKGROUND & AIMS: :Responses to [D-Ala2, MePhe4, Gly-ol5]enkephalin, a selective agonist for mu-receptors, were recorded intracellularly from 26 neurons in slices of guinea-pig hypothalamus. Of eight cells tested in the supraoptic nucleus, all of which had electrical properties characteristic of magnocellular neuroendocrine cells, four were sensitive to the agonist applied in the perfusion bath or with microdrops. The main effect was a decrease or suppression of spontaneous firing. In the paraventricular nucleus, seven of 18 cells tested also had electrophysiological characteristics similar to magnocellular neurons: two of them were sensitive to the mu-agonist and the effect was similar to that observed in the supraoptic nucleus. The remaining paraventricular neurons displayed low-threshold Ca2+ spikes, and thus had electrophysiological characteristics different from putative magnocellular neurons. Ten of 11 cells with low-threshold Ca2+ spikes were hyperpolarized by more than 10 mV by the mu-agonist, and showed a 33 +/- 1.9% (S.E.M.) decrease in input resistance. In both types of cells, when synaptic transmission was blocked with tetrodotoxin, the mu-agonist could still induce a hyperpolarization, suggesting that the effect was in part direct. Hyperpolarization was also obtained when the Cl- reversal potential was shifted to more positive values by using KCl electrodes, thus excluding a Cl- conductance mechanism. These results provide evidence that opioid peptides can directly inhibit hypothalamic neurons, that the mechanism is an increase in K+ conductance, and that two types of hypothalamic neurons appear to have different sensitivities to a mu-agonist.

背景与目标： : 从豚鼠下丘脑切片中的26个神经元在细胞内记录了对 [D-Ala2，MePhe4，Gly-ol5] 脑啡肽 (mu受体的选择性激动剂) 的反应。在视上核中测试的八个细胞中，所有这些细胞均具有大细胞神经内分泌细胞的电特性，其中四个对灌注浴或微滴中使用的激动剂敏感。主要效果是减少或抑制自发发射。在室旁核中，测试的18个细胞中有7个具有类似于大细胞神经元的电生理特征: 其中两个对mu激动剂敏感，其作用类似于在视上核中观察到的作用。其余的室旁神经元显示出低阈值的Ca2尖峰，因此具有与假定的大细胞神经元不同的电生理特征。具有低阈值Ca2尖峰的11个细胞中的10个被mu激动剂超极化超过10 mV，并显示输入阻力降低了33/- 1.9% (s.e.M.)。在两种类型的细胞中，当河豚毒素阻断突触传递时，mu激动剂仍可诱导超极化，这表明该作用部分是直接的。当使用KCl电极将Cl反转电位移至更多正值时，也获得了超极化，从而排除了Cl电导机制。这些结果提供了证据，表明阿片肽可以直接抑制下丘脑神经元，其机制是K电导的增加，并且两种类型的下丘脑神经元似乎对mu激动剂具有不同的敏感性。

BACKGROUND & AIMS: :Chronic pain may result from hyperexcitability following activation of spinal NMDA receptors. A naturally-derived mammalian peptide, histogranin, may possess NMDA antagonist activity. This study explored the possibility that stable analog [Ser1]Histogranin (SHG) could reduce chronic pain. Neuropathic pain was induced using the chronic constriction injury model (CCI). Intrathecal injection of SHG markedly attenuated the hyperalgesia and allodynia resulting from CCI, nearly normalizing responses. These results suggest that the natural peptide histogranin may be a novel adjunct in neuropathic pain management.

背景与目标： : 脊髓NMDA受体激活后过度兴奋可能导致慢性疼痛。天然衍生的哺乳动物肽组织蛋白可能具有NMDA拮抗剂活性。这项研究探讨了稳定的类似物 [Ser1] 组织蛋白 (SHG) 可以减轻慢性疼痛的可能性。使用慢性收缩损伤模型 (CCI) 诱发神经病理性疼痛。鞘内注射SHG可显着减轻由CCI引起的痛觉过敏和异常性疼痛，几乎使反应正常化。这些结果表明，天然肽组织粒蛋白可能是神经性疼痛管理的新型辅助手段。

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: :Aurelin is a 40-residue cationic antimicrobial peptide isolated from the mezoglea of a scyphoid jellyfish Aurelia aurita. Aurelin and its (15)N-labeled analogue were overexpressed in Escherichia coli and purified. Antimicrobial activity of the recombinant peptide was examined, and its spatial structure was studied by NMR spectroscopy. Aurelin represents a compact globule, enclosing one 3(10)-helix and two α-helical regions cross-linked by three disulfide bonds. The peptide binds to anionic lipid (POPC/DOPG, 3:1) vesicles even at physiological salt concentration, it does not interact with zwitterionic (POPC) vesicles and interacts with the DPC micelle surface with moderate affinity via two α-helical regions. Although aurelin shows structural homology to the BgK and ShK toxins of sea anemones, its surface does not possess the "functional dyad" required for the high-affinity interaction with the K(+)-channels. The obtained data permit to correlate the modest antibacterial properties and membrane activity of aurelin.

背景与目标： : Aurelin是从scyphoid水母Aurelia aurita的mezoglea中分离出的40残基阳离子抗菌肽。Aurelin及其 (15)N标记的类似物在大肠杆菌中过表达并纯化。研究了重组肽的抗菌活性，并通过NMR光谱研究了其空间结构。Aurelin代表紧凑的小球，包含一个3(10)-螺旋和两个由三个二硫键交联的 α-螺旋区域。该肽即使在生理盐浓度下也与阴离子脂质 (POPC/DOPG，3:1) 囊泡结合，它不与两性离子 (POPC) 囊泡相互作用，并且通过两个 α 螺旋区域以中等亲和力与DPC胶束表面相互作用。尽管aurelin显示出与海葵的BgK和ShK毒素的结构同源性，但其表面不具有与K ()-通道高亲和力相互作用所需的 “功能性二体”。获得的数据允许将aurelin的适度抗菌特性和膜活性相关联。

BACKGROUND & AIMS: :Amyloid beta peptide (Aβ) oligomers increase intracellular reactive oxygen species (ROS) and calcium cation (Ca(2+)) concentrations, which causes neuronal cell death in Alzheimer's disease (AD). Thus, the use of neuroprotective agents with antioxidative activity might be effective in the treatment of AD. In the present study, the neuroprotective effects of the methanol extract from edible brown alga Eisenia bicyclis (Laminariaceae) and its solvent soluble fractions together with the isolated phlorotannins on Aβ-induced toxicity were assessed by cell viability, intracellular ROS, and Ca(2+) levels in PC12 cells. The addition of the methanol extract as well as its ethyl acetate and n-butanol fractions of E. bicyclis markedly reversed the Aβ-induced toxicity. Among six phlorotannins, including phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofucofuroeckol A (4), dieckol (5), and 7-phloroeckol (6), isolated from the most active ethyl acetate fraction, 3-6 significantly decreased Aβ-induced cell death. Furthermore, these compounds also inhibited intracellular ROS generation and Ca(2+) generation, indicating the neuroprotective effects may be mediated through reduced intracellular ROS and Ca(2+) generation. Thus, the results of the present study imply that E. bicyclis and its active components attenuated the oxidative stress and reduced neuronal cell death, suggesting that it may be used as a dietary neuroprotective agent in AD.

背景与目标： : 淀粉样 β 肽 (a β) 低聚物会增加细胞内活性氧 (ROS) 和钙阳离子 (Ca(2)) 的浓度，从而导致阿尔茨海默氏病 (AD) 中的神经元细胞死亡。因此，使用具有抗氧化活性的神经保护剂可能有效治疗AD。在本研究中，通过细胞活力，细胞内ROS和Ca(2) 评估了食用褐藻Eisenia bicyclis (Laminariaceae) 及其溶剂可溶性级分以及分离的phlorotannins对a β 诱导的毒性的神经保护作用。) 在PC12细胞中。添加甲醇提取物及其双环E的乙酸乙酯和正丁醇馏分可显着逆转a β 诱导的毒性。从最活跃的乙酸乙酯级分中分离出的六种木酚素，包括间苯三酚 (1)，间苯二酚脱氢 (2)，艾可 (3)，间苯三酚A (4)，间苯三酚 (5) 和7-phloroeckol (6)，3-6显着降低了A β 诱导的细胞死亡。此外，这些化合物还抑制细胞内ROS的产生和Ca(2) 的产生，表明神经保护作用可能是通过减少细胞内ROS和Ca(2) 的产生来介导的。因此，本研究的结果表明，双环杆菌及其活性成分减轻了氧化应激并减少了神经元细胞死亡，这表明它可以用作AD的饮食神经保护剂。

BACKGROUND & AIMS: :Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.

背景与目标： : 越来越多的证据表明，Toll样受体 (TLR) 信号衔接蛋白与感觉神经元中存在的Toll/Interleukin-1受体 (TIR) 结构域的相互作用可能调节神经性疼痛状态。配体与tlr相互作用后，TIR既可启动细胞内信号传导，又可促进信号衔接蛋白向胞浆内结构域的募集。尽管TLR TIR是许多TLR信号级联的核心，但对其在感觉神经元中的作用知之甚少。在这项研究中，我们调查了修饰为包含TAT序列 (HIV中转录基因的反式激活因子; TAT-4BB) 的TLR TIR诱饵肽对LPS诱导的细胞内钙通量和感觉神经元的兴奋以及由于TLR4活性代谢物引起的行为变化的影响程度，morphine-3-glucuronide (M3G) 体内暴露。TAT-4BB抑制了大多数感觉神经元中LPS诱导的钙变化，并降低了小直径神经元中LPS依赖性神经元的兴奋性。TAT-4BB的急性全身给药以剂量依赖性方式逆转了M3G-induced的触觉异常性疼痛，但不影响运动活动，焦虑或对有害热刺激的反应。这些数据表明，靶向TLR TIR结构域可以提供新的药理学靶标，以减少或逆转啮齿动物的TLR4-dependent疼痛行为。

BACKGROUND & AIMS: :The main objective of this work is to provide an update on synthetic nucleic acid analogues and nanoassemblies as tools in gene therapy. In particular, the synthesis and properties of peptide-oligonucleotide conjugates (POCs), which have high potential in research and as therapeutics, are described in detail. The exploration of POCs has already led to fruitful results in the treatment of neurological diseases, lung disorders, cancer, leukemia, viral, and bacterial infections. However, delivery and in vivo stability are the major barriers to the clinical application of POCs and other analogues that still have to be overcome. This review summarizes recent achievements in the delivery and in vivo administration of synthetic nucleic acid analogues, focusing on POCs, and compares their efficiency.

背景与目标： : 这项工作的主要目的是提供有关合成核酸类似物和纳米组件作为基因治疗工具的更新。特别地，详细描述了肽-寡核苷酸缀合物 (poc) 的合成和性质，它们在研究中具有很高的潜力并作为治疗剂。POCs的探索已经在治疗神经系统疾病，肺部疾病，癌症，白血病，病毒和细菌感染方面取得了丰硕的成果。然而，递送和体内稳定性是POCs和其他类似物临床应用的主要障碍，仍需克服。这篇综述总结了合成核酸类似物的递送和体内给药方面的最新成就，重点是poc，并比较了它们的效率。

BACKGROUND & AIMS: BACKGROUND:A combinatorial phage display approach was previously used to evolve a 12-mer peptide (SVSVGMKPSPRP) with the highest affinity for different semiconductor surfaces. The discovery of the multiple occurrences of the SVSVGMKPSPRP sequence in an all-against-all basic local alignment search tool search of PepBank sequences was unexpected, and a Google search using the peptide sequence recovered 58 results concerning 12 patents and 16 scientific publications. The number of patent and articles indicates that the peptide is perhaps a broad range adhesion peptide. METHODS:To evaluate peptide properties, we conducted a study to investigate peptide adhesion on different inorganic substrates by mass spectrometry and atomic force microscopy for gold, carbon nanotubes, cobalt, chrome alloy, titanium, and titanium alloy substrates. RESULTS:Our results showed that the peptide has a great potential as a linker to functionalize metallic surfaces if specificity is not a key factor. This peptide is not specific to a particular metal surface, but it is a good linker for the functionalization of a wide range of metallic materials. CONCLUSION:The fact that this peptide has the potential to adsorb on a large set of inorganic surfaces suggests novel promising directions for further investigation. Affinity determination of SVSVGMKPSPRP peptide would be an important issue for eventual commercial uses.

背景与目标：

BACKGROUND & AIMS: :Tumor-specific immunotherapy with a Wilms' tumor 1 (WT1) peptide has been on clinical trial for leukemia, myelodysplastic syndrome, breast and lung cancers and is producing promising results. In this study, we treated three patients with renal cell carcinoma with an anchor modified, HLA-A*2402 binding WT1 peptide which was emulsified in Freund's incomplete adjuvant. In two patients tumor growth was suppressed and clinical response was evaluated as stable disease by the RECIST criteria after 3 months of weekly immunizations. Notably, development of new metastases has stopped in these patients for a prolonged period. No deleterious side effects were observed. Peptide-specific T cells were expanded in PBMCs of the patients and a substantial fraction of them bore the surface phenotype consistent with a CD8+ cytotoxic effector population. Although established tumors did not regress further, considering the component of the vaccine, i.e. peptide alone, the stabilization effect suggested the potential of WT1 peptide to develop into a more effective vaccine. To our knowledge, this is the first report of WT1 immunotherapy for renal cell carcinoma. Hopefully, the results will stimulate more extensive clinical studies.

背景与目标： : 使用Wilms' 肿瘤1 (WT1) 肽进行的肿瘤特异性免疫疗法已在白血病，骨髓增生异常综合征，乳腺癌和肺癌的临床试验中，并取得了可喜的结果。在这项研究中，我们用锚定修饰的hla-a * 2402结合WT1肽治疗了3例肾细胞癌患者，该肽在弗氏不完全佐剂中乳化。在每周免疫3个月后，两名患者的肿瘤生长受到抑制，并根据RECIST标准评估临床反应为稳定疾病。值得注意的是，这些患者的新转移已经停止了很长时间。没有观察到有害的副作用。肽特异性T细胞在患者的pbmc中扩增，其中很大一部分具有与CD8细胞毒性效应子群一致的表面表型。尽管确定的肿瘤没有进一步消退，但考虑到疫苗的成分，即单独的肽，稳定作用表明WT1肽有可能发展成为更有效的疫苗。据我们所知，这是WT1免疫疗法治疗肾细胞癌的首次报道。希望这些结果将刺激更广泛的临床研究。

BACKGROUND & AIMS: :The antigenicity of the major outer membrane protein of Chlamydia trachomatis serovar C was assessed by using overlapping hexapeptide homologs of serovar C major outer membrane protein and rabbit antisera in a peptide enzyme-linked immunosorbent assay. Five immunogenic sites were found distributed within variable sequences of the protein: four were immunodominant and three were surface exposed on native elementary bodies of serovar C. None was surface exposed on serovars H, I, and J.

背景与目标： : 通过在肽酶联免疫吸附试验中使用血清C主要外膜蛋白和兔抗血清的重叠六肽同源物评估沙眼衣原体血清型C主要外膜蛋白的抗原性。在蛋白质的可变序列中发现了五个免疫原性位点: 四个是免疫优势，三个表面暴露在血清型C的天然基本体上。没有一个表面暴露在血清型H，I和J上。

BACKGROUND & AIMS: :An undecapeptide which potentiates the beat of the ventricle in the African giant snail, Achatina fulica Ferussac, was purified from the atria of the snail. Its primary structure was determined to be H-Ser-Gly-Gln-Ser-Trp-Arg-Pro-Gln-Gly-Arg-Phe-NH2. This peptide was found to have excitatory actions not only on the ventricle but also on the penis retractor muscle, the buccal muscle and the identified neurons controlling the buccal muscle movement of Achatina.

背景与目标： : 从蜗牛的心房中纯化了一种增强非洲巨型蜗牛Achatina fulica Ferussac心室搏动的十一肽。它的一级结构被确定为H-Ser-Gly-Gln-Ser-Trp-Arg-Pro-Gln-Gly-Arg-Phe-NH2。发现该肽不仅对心室具有兴奋作用，而且对阴茎牵开器肌肉，颊肌和控制Achatina颊肌运动的已识别神经元具有兴奋作用。

BACKGROUND & AIMS: :The synthesis and characterisation of iridium(III) bis(2-(2,4-difluorophenyl)pyridinato-N, C2')-2(4-carboxylphenyl)imidazo[4,5-f][1,10]phenanthroline perchlorate, [Ir(dfpp)(2)(picCOOH)](+) and its octaarginine conjugate [Ir(dfpp)(2)(picCONH-Arg(8))](9+) are reported. Both complex and conjugate exhibit intense and long-lived luminescence, which is O(2) and pH sensitive. Conjugation to the polyarginine peptide renders the complex very water soluble. The uptake of the parent iridium(III) complex and conjugate are compared in two mammalian cell lines; SP2 myeloma and Chinese hamster ovary (CHO). Both complexes internalise into the cytoplasm, however dye uptake rate and distribution vary with peptide conjugation and with cell identity. Whereas transmembrane transport is thought to have been facilitated by the dimethyl sulfoxide (DMSO) used as co-solvent (0.05% v/v) for the parent complex, the octaarginine, the dye-conjugate (iridium-R(8)) is membrane permeable in water only. Both complexes exhibit high cytotoxicity, evident through blebbing and vacuole formation within living cells, indicative of apoptosis, within 30min of exposure to the probe. The IC(50) recorded for the cells in the dark was independent, in the case of the parent complex, of the identity of the cell, with IC(50) of 84.8μM and 88μM respectively for SP2 and CHO cells. The IC(50) approximately doubled for the polyarginine conjugate and displayed a significant dependence on cell type with IC(50) of 35μM and 54.1μM respectively for SP2 and CHO cells. These IC(50) values were recorded in the dark. However under irradiation cell death is considerably faster. Evidence from imaging suggests that the conjugate penetrates the nucleus whereas the parent does not, indicating that nuclear penetration may play a role in cytotoxicity.

背景与目标： : 铱 (III) 双 (2-(2,4-二氟苯基) 吡啶-N，C2 ')-2(4-羧基苯基) 咪唑并 [4,5-f][1,10] 菲咯啉高氯酸盐的合成和表征，报道了 [Ir(dfpp)(2)(picCOOH)]() 及其八精氨酸缀合物 [Ir(dfpp)(2)(picCONH-Arg(8))](9)。复合物和缀合物都表现出强烈和长寿命的发光，O(2) 和pH敏感。与聚精氨酸肽的结合使复合物非常水溶性。在两种哺乳动物细胞系中比较了母体铱 (III) 复合物和结合物的吸收; SP2骨髓瘤和中国仓鼠卵巢 (CHO)。两种复合物都内化到细胞质中，然而，染料的吸收速率和分布随肽缀合和细胞特性而变化。而跨膜运输被认为是由用作母体复合物 (八精氨酸) 的共溶剂 (0.05% v/v) 的二甲基亚砜 (DMSO) 促进的。染料偶联物 (铱-R(8)) 仅在水中具有膜渗透性。两种复合物均表现出高细胞毒性，通过活细胞内的起泡和液泡形成明显，表明细胞凋亡，在暴露于探针的30分钟内，在黑暗中记录的细胞的IC(50) 是独立的，在母体复合体的情况下，细胞的身份，对于SP2和CHO细胞，IC(50) 分别为84.8 μ m和88 μ m。对于聚精氨酸缀合物，IC(50) 大约增加了一倍，并且对于SP2和CHO细胞，IC(50) 分别为35 μ m和54.1 μ m的细胞类型显示出显着依赖性。这些IC(50) 值被记录在黑暗中。然而，在辐射下，细胞死亡要快得多。来自成像的证据表明，缀合物穿透细胞核，而亲本没有穿透细胞核，表明核渗透可能在细胞毒性中起作用。

BACKGROUND & AIMS: :Whereas ribosomes efficiently catalyze peptide bond synthesis by most amino acids, the imino acid proline is a poor substrate for protein synthesis. Previous studies have shown that the translation factor eIF5A and its bacterial ortholog EF-P bind in the E site of the ribosome where they contact the peptidyl-tRNA in the P site and play a critical role in promoting the synthesis of polyproline peptides. Using misacylated Pro-tRNAPhe and Phe-tRNAPro, we show that the imino acid proline and not tRNAPro imposes the primary eIF5A requirement for polyproline synthesis. Though most proline analogs require eIF5A for efficient peptide synthesis, azetidine-2-caboxylic acid, a more flexible four-membered ring derivative of proline, shows relaxed eIF5A dependency, indicating that the structural rigidity of proline might contribute to the requirement for eIF5A. Finally, we examine the interplay between eIF5A and polyamines in promoting translation elongation. We show that eIF5A can obviate the polyamine requirement for general translation elongation, and that this activity is independent of the conserved hypusine modification on eIF5A. Thus, we propose that the body of eIF5A functionally substitutes for polyamines to promote general protein synthesis and that the hypusine modification on eIF5A is critically important for poor substrates like proline.

背景与目标： : 尽管核糖体可以有效地催化大多数氨基酸的肽键合成，但亚氨基酸脯氨酸是蛋白质合成的不良底物。先前的研究表明，翻译因子eIF5A及其细菌直系同源物EF-P在核糖体的E位点结合，它们与P位点的肽基-tRNA接触，并在促进聚脯氨酸肽的合成中起关键作用。使用未酰化的前tRNAPhe和Phe-tRNAPro，我们表明亚氨基酸脯氨酸而不是tRNAPro对聚脯氨酸合成施加了主要的eIF5A要求。尽管大多数脯氨酸类似物需要eIF5A来进行有效的肽合成，但azetidine-2-caboxylic酸 (脯氨酸的更灵活的四元环衍生物) 显示出松弛的eIF5A依赖性，表明脯氨酸的结构刚性可能有助于eIF5A的需求。最后，我们研究了eIF5A和多胺在促进翻译伸长方面的相互作用。我们证明eIF5A可以消除对一般翻译伸长的多胺要求，并且该活性与eIF5A上保守的hypusine修饰无关。因此，我们建议eIF5A的主体在功能上替代多胺以促进一般蛋白质合成，并且eIF5A上的hypusine修饰对于诸如脯氨酸之类的不良底物至关重要。

BACKGROUND & AIMS: BACKGROUND:N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations predict cardiovascular outcome in many settings. There are very few data assessing the utility of NT-proBNP concentrations in the prediction of long-term outcome after cardiac surgery. We assessed the ability of NT-proBNP to predict 3 yr mortality compared with validated clinical risk prediction tools. METHODS:A secondary analysis of a prospectively recruited patient cohort of 1010 patients undergoing cardiac surgery. Baseline clinical details were obtained including EuroSCORE. Multi-variable modelling, area under the receiver operating characteristic curves (AUCs), and net reclassification improvement were utilized. RESULTS:NT-proBNP was a univariable predictor of 3 yr mortality but was no longer a significant predictor in a multivariable model (hazard ratio 1.00 per 250 ng litre(-1), 95% confidence interval 0.98-1.02, P=0.80). The relative and additive predictive values of the preoperative EuroSCORE (both additive and logistic versions) and NT-proBNP concentrations were compared. All were predictive of 3 yr mortality (P<0.001) with almost identical AUCs (0.71 for EuroSCORE, 0.70 for NT-proBNP). When either the EuroSCORE or NT-proBNP concentrations are known, the addition of the other does not improve the ability to predict 3 yr mortality. CONCLUSIONS:Preoperative NT-proBNP concentrations and the EuroSCORE have equivalent, and moderate, predictive accuracy for mortality 3 yr after cardiac surgery. EuroSCORE uses clinical data but is not routinely used for individual clinical risk prediction. NT-proBNP measurement would incur additional costs but can be measured quickly and objectively. With such similar predictive accuracy, factors such as the ease of calculation and cost will likely determine their use in clinical practice.

背景与目标：

BACKGROUND & AIMS: :Alzheimer's disease (AD) is a progressive neurodegenerative disorder that shows cognitive deficits and memory impairment. Extract from the leaves of Gotu Kola (Centella Asiatica) have been used as an alternative medicine for memory improvement in Indian Ayurvedic system of medicine for a long time. Although several studies have revealed its effect in ameliorating the cognitive impairment in rat models of AD and stimulating property on neuronal dendrites of hippocampal region, the molecular mechanism of Gotu Kola on neuroprotection still remains to be elucidated. In this study, we report that phosphorylation of cyclic AMP response element binding protein (CREB) is enhanced in both a neuroblastoma cell line expressing amyloid beta 1-42 (Abeta) and in rat embryonic cortical primary cell culture. In addition, the contribution of two major single components to the enhanced CREB phosphorylatioin was examined. Furthermore, inhibitors were applied in this study revealing that ERK/RSK signaling pathway might mediate this effect of Gotu Kola extract. Taken together, we provide a possible molecular mechanism for memory enhancing property of Gotu Kola extract for the first time.

背景与目标： 阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，表现为认知缺陷和记忆障碍。长期以来，从Gotu Kola (积雪草) 的叶子中提取的提取物已被用作印度阿育吠陀医学系统中改善记忆的替代药物。尽管有几项研究表明其在改善AD大鼠模型的认知障碍以及对海马区神经元树突的刺激作用，但Gotu Kola对神经保护的分子机制仍有待阐明。在这项研究中，我们报告了在表达淀粉样蛋白beta 1-42 (Abeta) 的神经母细胞瘤细胞系和大鼠胚胎皮质原代细胞培养物中，环状AMP反应元件结合蛋白 (CREB) 的磷酸化均增强。此外，还检查了两个主要单一成分对增强的CREB磷酸化蛋白的贡献。此外，本研究还应用了抑制剂，表明ERK/RSK信号通路可能介导了Gotu Kola提取物的这种作用。合在一起，我们首次提供了一种可能的分子机制来增强Gotu Kola提取物的记忆。