BACKGROUND & AIMS: :It was long believed that central arrows needed to be spatially predictive to produce a shift in spatial attention. Recent evidence indicates, however, that central spatially nonpredictive directional cues, like arrows, will trigger reflexive shifts in attention. We asked what this recent discovery means for past studies that used predictive directional cues such as arrows. Our findings indicate that predictive arrows produce attention effects that greatly exceed the individual or summed effects of reflexive orienting to nonpredictive arrows and volitional orienting to predictive numbers. This suggests that the especially large effect produced by predictive arrows reflects an interaction between reflexive and volitional orienting. Given the broad application of the predictive arrow cueing paradigm in both past and current research, the present data shed new light on a wide range of investigations, from psychophysical studies of basic attention to behavioural and neuroimaging studies of cognition and social development.

背景与目标： ：长期以来，人们一直认为中心箭头需要具有空间预测性，才能引起空间注意力的转移。但是，最近的证据表明，中心的空间非预测性方向提示（如箭头）将触发注意力的反思性转变。我们问到最近的发现对于使用预测性方向提示（例如箭头）的以往研究意味着什么。我们的发现表明，预测箭头产生的注意力效应大大超过反射性指向非预测性箭头和自愿性指向预测性数字的个体或合计效果。这表明预测箭头所产生的特别大的效果反映了反射性和自愿性定向之间的相互作用。鉴于预测性箭头提示范例在过去和当前的研究中得到了广泛的应用，目前的数据为从基本关注的心理物理学研究到认知和社会发展的行为和神经影像研究等广泛的研究提供了新的思路。

BACKGROUND & AIMS: MyristoylCoA:protein N-myristoyltransferase (NMT) catalyzes the cotranslational covalent attachment of a rare cellular fatty acid, myristate, to the N-terminal Gly residue of a variety of eukaryotic proteins. The myristoyl moiety is often essential for expression of the biological functions for these proteins.

Attachment of C14:0 alone provides barely enough hydrophobicity to allow stable association with membranes. The partitioning of N-myrisotylproteins is therefore often modulated by "switches" that function through additional covalent or noncovalent modifications. Candida albicans, the principal cause of systemic fungal infection in immunocompromised humans, contains a single NMT gene that is essential for its viability. The functional properties of the acylCoA binding site of human and C. albicans NMT are very similar. However, there are distinct differences in their peptide binding sites. An ADP ribosylation factor (Arf) is included among the few cellular protein substrates of the fungal enzyme. Alanine scanning mutagenesis of an octapeptide derived from an N-terminal Arf sequence (GLYASKLS-NH2) disclosed that Gly1, Ser5, and Lys6 play predominant roles in binding. ALYASKLS-NH2 is an inhibitor competitive for peptide [Ki(app) = 15.3 +/- 6.4 microM] and noncompetitive for myristoylCoA. Remarkably, replacement of the N-terminal tetrapeptide with an 11-aminoundecanoyl group results in a competitive inhibitor (11-aminoundecanoyl-SKLS-NH2) that is approximately 40-fold more potent [Ki(app) = 0.40 +/- 0.03 microM] than the starting octapeptide. Removal of Leu-Ser from the C-terminus generates a competitive dipeptide inhibitor (11-aminoundecanoyl-SK-NH2) with a Ki(app) of 11.7 +/- 0.4 microM, equivalent to that of the starting octapeptide. A derivative dipeptide inhibitor containing a C-terminal N-cyclohexylethyl lysinamide moiety has the advantage of being more potent (IC50 = 0.11 +/- 0.03 microM) and resistant to digestion by cellular carboxypeptidases. Rigidifying the flexible aminoundecanoyl chain results in very potent general NMT inhibitors (IC50 = 40-50 nM). Substituting a 2-methylimidazole for the N-terminal amine and adding a benzylic alpha-methyl group with R stereochemistry to the rigidifying element produces even more potent inhibitors (IC50 = 20-50 nM) that are up to 500-fold selective for the fungal compared to human enzyme. A related less potent member of this series of compounds is fungistatic. Its growth inhibitory effects are associated with a reduction in cellular protein N-myristoylation, judged using cellular Arf as a reporter. These studies establish that NMT is a new antifungal target.

背景与目标： MyristoylCoA ：蛋白N-肉豆蔻酰基转移酶（NMT）催化稀有细胞脂肪酸肉豆蔻酸酯与多种真核蛋白N-末端Gly残基的共翻译共价连接。肉豆蔻酰基部分通常对于表达这些蛋白质的生物学功能是必不可少的。

仅C14 ：0的附件仅提供了不足以使与膜稳定结合的疏水性。因此，N-肉豆蔻酰蛋白的分区通常由通过附加的共价或非共价修饰起作用的“开关”调节。白色念珠菌是免疫力低下的人体内全身真菌感染的主要原因，它包含一个对其生存能力至关重要的单个NMT基因。人和白色念珠菌NMT的酰基辅酶A结合位点的功能特性非常相似。但是，它们的肽结合位点存在明显差异。 ADP核糖基化因子（Arf）包括在真菌酶的几种细胞蛋白底物中。来自N末端Arf序列（GLYASKLS-NH2）的八肽的丙氨酸扫描诱变显示，Gly1，Ser5和Lys6在结合中起主要作用。 ALYASKLS-NH2是一种对肽[Ki（app）= 15.3 /-6.4 microM]具有竞争性的抑制剂，对肉豆蔻酰辅酶A不具有竞争性。值得注意的是，用11-氨基十一烷酰基取代N末端四肽会产生竞争性抑制剂（11-氨基十一烷酰基-SKLS-NH2），其效力比[Ki（app）= 0.40 /-0.03 microM]高40倍左右。起始八肽。从C末端去除Leu-Ser会产生竞争性的二肽抑制剂（11-氨基十一烷酰基-SK-NH2），Ki（app）为11.7 /-0.4 microM，与起始八肽相当。含有C-末端N-环己基乙基赖氨酰胺部分的衍生物二肽抑制剂具有更有效的优势（IC 50 ＝ 0.11 /0.03μM），并且对细胞羧肽酶的消化具有抵抗力。刚性化柔性氨基十一烷酰基链会产生非常有效的常规NMT抑制剂（IC50 = 40-50 nM）。用2-甲基咪唑取代N端胺，并在刚性元素中添加具有R立体化学的苄基α-甲基，可产生更强效的抑制剂（IC50 = 20-50 nM），对真菌的选择性高达500倍与人类酶相比。该系列化合物的一个相关的效力较弱的成员是抑真菌的。使用细胞Arf作为报告基因判断，其生长抑制作用与细胞蛋白N-肉豆蔻酰化的减少有关。这些研究确定NMT是一种新的抗真菌靶标。