Nature 周刊封面
聚胺对“抗酶”的调控作用机制
鸟氨酸脱羧酶(ODC) （聚胺的生物合成中限制速度的酶）是由一种“抗酶”(OAZ)调控的。聚胺通过促进OAZ信使RNA (mRNA)内的核糖体框架转变诱导“抗酶”表达。虽然过去人们曾假设聚胺与完全转录的mRNA或核糖体本身发生相互作用，但Kurian等人发现，调控是通过聚胺与新生的OAZ多肽的相互作用发生的，其作用是抑制核糖体停顿和促进其翻译。
原文摘要：
Polyamine sensing by nascent ornithine decarboxylase antizyme stimulates decoding of its mRNA
Polyamines are essential organic polycations with multiple cellular functions relevant for cell division, cancer and ageing. Regulation of polyamine synthesis is mainly achieved by controlling the activity of ornithine decarboxylase (ODC) through an unusual mechanism involving ODC antizyme, the binding of which disrupts homodimeric ODC and targets it for ubiquitin-independent degradation by the 26S proteasome. Whereas mammals express several antizyme genes, we have identified a single orthologue, termed OAZ1, in Saccharomyces cerevisiae. Similar to its mammalian counterparts, OAZ1 synthesis is induced with rising intracellular polyamine concentrations, which also inhibit ubiquitin-dependent degradation of the OAZ1 protein. Together, these mechanisms contribute to a homeostatic feedback regulation of polyamines. Antizyme synthesis involves a conserved +1 ribosomal frameshifting (RFS) event at an internal STOP codon during decoding of its messenger RNA6. Here we used S. cerevisiae OAZ1 to dissect the enigmatic mechanism underlying polyamine regulation of RFS. In contrast with previous assumptions, we report here that the nascent antizyme polypeptide is the relevant polyamine sensor that operates in cis to negatively regulate upstream RFS on the polysomes, where its own mRNA is being translated. At low polyamine levels, the emerging antizyme polypeptide inhibits completion of its synthesis causing a ribosome pile-up on antizyme mRNA, whereas polyamine binding to nascent antizyme promotes completion of its synthesis. Thus, our study reveals a novel autoregulatory mechanism, in which binding of a small metabolite to a nascent sensor protein stimulates the latter’s synthesis co-translationally.
拟南芥不同品种之间的差异
研究人员将18个天然拟南芥品种的基因组和转录组与Col-0的基因组和转录组进行了对比，其中Col-0是使用最为广泛的拟南芥野生品种，其基因组是作为“拟南芥基因组项目”(Arabidopsis Genome Initiative)的一部分被测序的。对比的结果被用来对这一经典“实验”植物的基因差异进行全面评估。研究人员采用一种“多对多”(many-to-many)的方法将每个基因组与其他所有基因组都做了对比，这样可以最大限度地捕捉基因差异。
原文摘要：
Multiple reference genomes and transcriptomes for Arabidopsis thaliana
Genetic differences between Arabidopsis thaliana accessions underlie the plant’s extensive phenotypic variation, and until now these have been interpreted largely in the context of the annotated reference accession Col-0. Here we report the sequencing, assembly and annotation of the genomes of 18 natural A. thaliana accessions, and their transcriptomes. When assessed on the basis of the reference annotation, one-third of protein-coding genes are predicted to be disrupted in at least one accession. However, re-annotation of each genome revealed that alternative gene models often restore coding potential. Gene expression in seedlings differed for nearly half of expressed genes and was frequently associated with cis variants within 5 kilobases, as were intron retention alternative splicing events. Sequence and expression variation is most pronounced in genes that respond to the biotic environment. Our data further promote evolutionary and functional studies in A. thaliana, especially the MAGIC genetic reference population descended from these accessions.
VH和D位点之间的调控序列被确定
“免疫球蛋白重链”(IgH) 的可变区域是通过从VH、D 和 JH位点中每个选择一个片段产生的。很多研究都提出，在VH和D位点之间存在一个调控VH-to-D重组的控制区域，但其身份一直无法确定。现在，Frederick Alt及其同事已定位了这一调控序列， 它就是IGCR1（基因间控制区域-1），并且发现，它利用CTCF点来促进与远端增强子元素的成环(looping)和互动。它还能抑制会破坏VH、D 和 JH位点有序重排的其他事件。
原文摘要：
CTCF-binding elements mediate control of V(D)J recombination
Immunoglobulin heavy chain (IgH) variable region exons are assembled from VH, D and JH gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the VH and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of DH-proximal VH gene segments and promoting rearrangement of distal VH segments. IGCR1 maintains ordered and lineage-specific VH(D)JH recombination by suppressing VH joining to D segments not joined to JH segments, and VH to DJH joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal VH-to-DJH recombination. Our studies elucidate a long-sought Igh V(D)J recombination control region and indicate a new role for the generally expressed CTCF protein.
憎恶一切物质的表面
在以昆虫为食的“捕虫草”(Nepenthes)启发下（这种草能够在一个被非常光滑的水质分泌物润滑的表面上来捕捉其猎物），Joanna Aizenberg及其同事合成了憎恶一切物质的(omniphobic)表面，它们在高压下能够自我修复和发挥功能。它们“注入了光滑液体的多孔表面”(SLIPS)对于极性液体、有机液体和复合物液体都能表现出近乎完美的光滑度。SLIPS在极端条件下发挥功能，易于从廉价材料来构建，并且可以通过适当基质和润滑剂的选择而被赋予其他有用性能，如增强的透光性。这种类型的超滑表面也许在生物医学液体的处理、燃料运输、防污、防结冰、光学成像和其他方面找到用途。
原文摘要：
Bioinspired self-repairing slippery surfaces with pressure-stable omniphobicity
Creating a robust synthetic surface that repels various liquids would have broad technological implications for areas ranging from biomedical devices and fuel transport to architecture but has proved extremely challenging. Inspirations from natural nonwetting structures, particularly the leaves of the lotus, have led to the development of liquid-repellent microtextured surfaces that rely on the formation of a stable air–liquid interface. Despite over a decade of intense research, these surfaces are, however, still plagued with problems that restrict their practical applications: limited oleophobicity with high contact angle hysteresis, failure under pressure and upon physical damage, inability to self-heal and high production cost. To address these challenges, here we report a strategy to create self-healing, slippery liquid-infused porous surface(s) (SLIPS) with exceptional liquid- and ice-repellency, pressure stability and enhanced optical transparency. Our approach—inspired by Nepenthes pitcher plants—is conceptually different from the lotus effect, because we use nano/microstructured substrates to lock in place the infused lubricating fluid. We define the requirements for which the lubricant forms a stable, defect-free and inert ‘slippery’ interface. This surface outperforms its natural counterparts and state-of-the-art synthetic liquid-repellent surfaces in its capability to repel various simple and complex liquids (water, hydrocarbons, crude oil and blood), maintain low contact angle hysteresis (<2.5°), quickly restore liquid-repellency after physical damage (within 0.1–1 s), resist ice adhesion, and function at high pressures (up to about 680 atm). We show that these properties are insensitive to the precise geometry of the underlying substrate, making our approach applicable to various inexpensive, low-surface-energy structured materials (such as porous Teflon membrane). We envision that these slippery surfaces will be useful in fluid handling and transportation, optical sensing, medicine, and as self-cleaning and anti-fouling materials operating in extreme environments.
抗生素抗药性的根源
抗生素抗药性被认为是早在天然出现的抗生素和它们的衍生物被用来治疗人类疾病之前就已经出现了，但有关编码抗药性的基因的直接证据一直没有。现在，一个远古的万古霉素抗药性基因已从距今3万年的西伯利亚永久冻土样本中被提取出来，并且其产物的三维结构也被与其现代对应基因产物的三维结构做了对比。在远古版本与现代版本之间有很小的结构差别，但这些差别并没有反映在酶功能上。
原文摘要：
Antibiotic resistance is ancient
The discovery of antibiotics more than 70 years ago initiated a period of drug innovation and implementation in human and animal health and agriculture. These discoveries were tempered in all cases by the emergence of resistant microbes. This history has been interpreted to mean that antibiotic resistance in pathogenic bacteria is a modern phenomenon; this view is reinforced by the fact that collections of microbes that predate the antibiotic era are highly susceptible to antibiotics. Here we report targeted metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics. Structure and function studies on the complete vancomycin resistance element VanA confirmed its similarity to modern variants. These results show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.
可用于HIV/艾滋病治疗的中和抗体
能够中和一种病毒的很多不同毒株的抗体（被称为“广谱中和抗体”），是寻找一种具有普遍适用性的流感疫苗的关注焦点。Dennis Burton及其同事报告，他们分离出新的一组具有针对HIV的广谱中和活性的单克隆抗体，这些抗体有望成为免疫治疗药物。这些抗体能够识别病毒刺突上的新的糖基化表原（抗原决定基），而且其中一些的效能要比以前报告的抗体强十倍。
原文摘要：
Broad neutralization coverage of HIV by multiple highly potent antibodies
Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.
一个部分合成的酵母基因组
2010年，生物学上实现了一个里程碑：研究人员培养出一种可以存活的细菌，它有一个从合成的DNA片段人工重新组装的基因组。现在，Jeff Boeke及其同事报告，他们生成了世界上第一个合成的真核染色体臂，这是一个名为“Sc2.0”的项目中所取得的第一个成果，该项目的目标是，设计和构建酿酒酵母基因组的一个完全合成的版本。在这一最初阶段，两个定制设计的合成染色体臂被融合到了该酵母基因组中，代替其内生序列。
原文摘要：
Synthetic chromosome arms function in yeast and generate phenotypic diversity by design
Recent advances in DNA synthesis technology have enabled the construction of novel genetic pathways and genomic elements, furthering our understanding of system-level phenomena. The ability to synthesize large segments of DNA allows the engineering of pathways and genomes according to arbitrary sets of design principles. Here we describe a synthetic yeast genome project, Sc2.0, and the first partially synthetic eukaryotic chromosomes, Saccharomyces cerevisiae chromosome synIXR, and semi-synVIL. We defined three design principles for a synthetic genome as follows: first, it should result in a (near) wild-type phenotype and fitness; second, it should lack destabilizing elements such as tRNA genes or transposons; and third, it should have genetic flexibility to facilitate future studies. The synthetic genome features several systemic modifications complying with the design principles, including an inducible evolution system, SCRaMbLE (synthetic chromosome rearrangement and modification by loxP-mediated evolution). We show the utility of SCRaMbLE as a novel method of combinatorial mutagenesis, capable of generating complex genotypes and a broad variety of phenotypes. When complete, the fully synthetic genome will allow massive restructuring of the yeast genome, and may open the door to a new type of combinatorial genetics based entirely on variations in gene content and copy number.
不会产生副作用的特异性PPARγ配体
核受体PPARγ是包括“罗格列酮”(rosiglitazone)和“匹格列酮”(pioglitazone)在内的“噻唑烷二酮”(thiazolidinedione)抗糖尿病药物的作用目标。这些“全PPARγ激动剂”对大多数患者都是有效的和能够很好耐受的，但对少数患者能引起液体潴留和体重增加。在这一概念证明研究中，Choi等人研制出特异性PPARγ配体，它们能够通过阻断Cdk5-调控的PPARγ磷酸化来保留抗糖尿病活性，但它们不是“全PPARγ激动剂”。 在小鼠模型中，这些配体不会引起有时与“全PPARγ激动剂”相关的副作用。
原文摘要：
Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation
PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5 . Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ.
对Sirtuin过度表达的寿命延长效应的重新评估
Sirtuins的过度表达曾被报告能延长线虫和果蝇的寿命。限制饮食对果蝇寿命的影响也曾被报告是依赖于Sir2的。这项研究表明，这些发现可以归因于基因背景的混淆效应。该研究表明，Sirtuin过度表达的寿命延长效应可能仅限于酵母；该研究还支持用酵母和线虫所做的其他研究工作，后者表明：限制饮食所产生的效应不是由Sirtuins调控的。
原文摘要：
Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila
Overexpression of sirtuins (NAD+-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported3, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.
